# data[].attributes.body
Patho of Type 1

# data[].attributes.body
Guideline for Treatment of Diabetes Type 1

# data[].attributes.attachment_link.readable_text
Am Fam Physician. 2018 Aug 1;98(3):154-162.

Patient information: See related handout on type 1 diabetes, written by the authors of this article.

Author disclosure: No relevant financial affiliations.

There is considerable benefit of tight glucose control in patients with type 1 diabetes mellitus. Tight blood glucose control dramatically decreases the incidence of microvascular and macrovascular complications. Although glycemic goals should be individualized, most nonpregnant adults should strive for an A1C level less than 7%. Greater frequency of glucose monitoring and continuous glucose monitoring are both associated with lower A1C levels. The choice to monitor glucose levels via multiple daily capillary blood samples or continuous glucose monitoring is based on cost and patient preference. Intensive insulin treatment is recommended with a combination of multiple mealtime bolus and basal injections or with continuous insulin infusion through an insulin pump. The option to administer insulin with multiple daily injections vs. a pump should be individualized. Adjunctive medical therapy is under investigation but is not currently recommended. All patients with type 1 diabetes should participate in diabetes self-management education and develop individualized premeal insulin bolus plans under the guidance of a dietitian, if possible. Blood pressure and lipid control are important to prevent cardiovascular disease events. Patients with type 1 diabetes should have sick-day plans and be able to identify warning signs of hypoglycemia and diabetic ketoacidosis. Advances in diabetes care, including the bionic pancreas and the closed-loop system of glucose monitoring with an automated insulin pump, may have a significant effect on type 1 diabetes care in the years ahead.

The benefit of tight glucose control in patients with type 1 diabetes mellitus is well established. 1- 4 Microvascular complications (e.g., neuropathy, nephropathy, retinopathy) and macrovascular complications (e.g., myocardial infarction, cerebrovascular accident, cardiovascular disease- related deaths) are dramatically decreased when glucose levels are maintained as close to the nondiabetic range as possible. 4 The numbers needed to treat with intensive therapy (A1C of approximately 7% vs. 9%) for a 10-year period to prevent progression of retinopathy and clinical neuropathy are 3 and 1.5, respectively. 2 Additionally, intensive glycemic control reduces the risk of cardiovascular disease by 42% and severe cardiovascular events (nonfatal myocardial infarction, stroke, or death from cardiovascular disease) by 57% over 11 years among patients with type 1 diabetes. 3 Long-term follow-up of the Diabetes Control and Complications Trial shows that the benefit of early, aggressive insulin therapy and intensive glycemic control persists for several decades after initiation of treatment. Although the exact pathophysiologic explanation for prolonged improved outcomes remains unclear, there is a decrease in all-cause mortality. 5

WHAT IS NEW ON THIS TOPIC: TYPE 1 DIABETES

Long-term follow-up of the Diabetes Control and Complications Trial shows that the benefit of early, aggressive insulin therapy and intensive glycemic control persists for several decades after treatment and is associated with a decrease in all-cause mortality.

A well-designed double-blind randomized controlled trial of adults with type 1 diabetes who were taking metformin did not show significant improvement in glycemic control. The potential cardiovascular disease benefit remains under investigation.

In September 2016, the U.S. Food and Drug Administration approved the first combination glucose monitoring and automated insulin delivery device, a hybrid closed-loop system.

Glycemic Goals

Tight glycemic control remains the standard of care for most patients with type 1 diabetes. The American Diabetes Association recommends an A1C goal of less than 7% for non-pregnant adults ( Table 1). 6 Despite the benefits of lower A1C levels, goals should be personalized to account for individual preference, history of severe hypoglycemia, older age, and frailty. Higher glycemic targets for older adults or those with functional impairments, multiple comorbidities, or limited life expectancy are advisable. 7

Self-Monitoring

There is a strong association between more frequent self-monitoring of blood glucose and lower A1C levels. 8 The conventional approach, practiced by approximately 83% of patients with type 1 diabetes, is to monitor glucose levels via capillary blood testing. 9 Testing is advised before meals, before exercise, before bedtime, occasionally postprandially, and anytime hypoglycemia is perceived. 6 Although the optimal number of daily tests should be individualized, using these indications corresponds to six to 10 tests per day.

The newer practice of continuous glucose monitoring, used by approximately 17% of persons with type 1 diabetes, can also achieve tight glycemic control.( 9 With this method, a sensor inserted into the subcutaneous tissue measures interstitial glucose levels in real time and transmits them to a receiving device and monitor Figure 1). The effectiveness of continuous glucose monitoring devices depends on adherence and does not completely eliminate the need for capillary testing, which is still required for device calibration and to confirm abnormal levels.

FIGURE 1.

Compared with conventional self-monitoring, continuous glucose monitoring has been associated with improved glycemic control. 10 One randomized controlled trial demonstrated a reduction in A1C levels from approximately 7.6% to 7.1% over six months in persons 25 years or older with type 1 diabetes who used continuous glucose monitoring, compared with traditional self-monitoring of blood glucose at least four times daily. 11 Data do not show a definitive reduction in overall severe hypoglycemic events, but continuous glucose monitoring alarm features and trend alerts can notify patients and caregivers to expeditiously administer treatment. 12 The significant increase in cost associated with continuous glucose monitoring needs to be considered when an individual is choosing between glucose monitoring approaches. 13

Insulin Therapy

Consensus guidelines recommend intensive treatment with a combination of multiple mealtime bolus and basal injections or continuous insulin infusion through an insulin pump. 14

Approximately 64% of persons with type 1 diabetes in the United States use an insulin pump.( 9 The conventional portable insulin pump consists of an insulin reservoir, a computer chip to manage dosage delivery, and an infusion set with flexible tubing Figure 2). The unit can be clipped onto a belt or waistband. A soft plastic cannula at the end of the tubing inserts under the skin to deliver the insulin. Alternatively, a patch pump attaches an entire unit directly to the skin, does not require a line of plastic tubing to deliver the insulin to the cannula, and receives insulin delivery programming via a wireless handheld unit. Regardless of the type of pump used, the cannula insertion site is rotated every two to three days. Despite the risks of lipodystrophy, cannula site discomfort, and increased cost, many patients still prefer the pump to performing multiple daily injections.

FIGURE 2.

Basal-bolus regimens, whether through a pump or injections, are considered more physiologic because they attempt to mimic normal β-cell secretion. This is in contrast to the conventional insulin therapy used before the Diabetes Control and Complications Trial in which patients used mixed short- and intermediate-acting insulins in twice-daily dosing. 15 Some studies have shown improved A1C levels in adults with type 1 diabetes who use continuous infusion pumps. However, studies have not shown better effectiveness universally for either approach. Therefore, the decision between multiple daily injections or continuous pump therapy should be individualized. 16

Most patients who use the pump use rapid-acting insulin (e.g., aspart [Novolog], glulisine [Apidra], lispro [Humalog]), whereas a small minority still use regular insulin. Rapid-acting insulin boluses can be administered immediately before meals to allow more flexibility. 17 Small amounts of rapid-acting insulin are continuously infused to provide basal insulin. Depending on pump type, basal rates can be titrated as low as 0.01 units per hour. 18 Patients who do not use the pump tend to use long-acting insulin (e.g., detemir [Levemir], glargine [Lantus]) to meet basal demands.

Intensive glucose control requires knowing the various factors affecting a patient's insulin sensitivity and dosing requirements ((( Table 2). 19, 20 Insulin sensitivity varies throughout the day and throughout a person's lifetime. Puberty, pregnancy, and illness are physiologic states that often require extra insulin titration. Before dosing of pre-meal insulin, consideration needs to be made regarding planned carbohydrate intake, planned exercise or activity levels, and current blood glucose levels eTable A). Choice of insulin type needs to account for duration of action, cost, and route of administration 15, 21 eTable B).

Adjunctive Therapies

Adjunctive therapies for patients with type 1 diabetes are under investigation but are not currently recommended. 22 Sodium glucose cotransporter-2 inhibitors, which promote the renal excretion of glucose, are approved for use in patients with type 2 diabetes but have not been approved for use in patients with type 1 diabetes. Pramlintide (Symlin)-a synthetic analogue of human amylin that reduces postprandial glucose via slowed gastric emptying, inhibition of glucagon secretion, and satiety promotion-is approved by the U.S. Food and Drug Administration for use in type 1 diabetes and may have an association with improved glycemic control; however, long-term benefits remain unclear. 23 Despite studies suggesting that the addition of metformin might reduce insulin doses in patients with type 1 diabetes, 24 this has not been substantiated. Additionally, a recent well-designed double-blind randomized controlled trial of adults with type 1 diabetes taking metformin did not show significant improvement in glycemic control. 25 The potential cardiovascular disease benefit from adjunctive therapies remains under investigation.

Lifestyle Management and Disease Prevention

DIABETES SELF-MANAGEMENT EDUCATION

All patients with type 1 diabetes should participate in continuous diabetes self-management education, which works to empower patients to understand how diet, physical activity, and insulin affect their glucose levels and how glycemic levels relate to acute and chronic complications ( Table 3). 6, 26- 29 Diabetes self-management education has been shown to improve A1C levels and quality of life, and reduce health care costs. 30, 31 National standards for diabetes self-management education have been published by the American Diabetes Association in conjunction with the American Association of Diabetes Educators. 32 Online diabetes education resources are available at http://professional.diabetes.org/content/diabetes-educator-resources. To find a diabetes educator or a preexisting diabetes education program, visit http://www.diabeteseducator.org/living-with-diabetes.

MOTIVATIONAL INTERVIEWING

Motivational interviewing techniques can be an effective strategy for improving glycemic control. One randomized controlled trial demonstrated that adolescents with newly diagnosed type 1 diabetes were able to decrease their A1C level by an average of 0.6% over 12 months (compared with an increase of 0.2% in the control group) by participating in motivational interviewing sessions every six to eight weeks. 33 For resources on motivational interviewing specifically for diabetes, visit https://www.niddk.nih.gov/health-information/communication-programs/ndep/health-professionals/practice-transformation-physicians-health-care-teams/diabetes-practice-changes/engaging-patients/motivational-interviewing.

NUTRITION

Nutritional therapy should be individualized and supervised under the care of a dietitian. Matching carbohydrate intake with insulin therapy and activity level is a complex practice. One approach to managing mealtime insulin is to eat a set amount of carbohydrates with each meal and use a fixed insulin dose. A second approach is to match insulin doses according to variable amounts of carbohydrates that one plans to consume. Alcohol intake should be restricted to no more than one drink per day for women and two drinks per day for men.

PHYSICAL ACTIVITY

The American Diabetes Association suggests that adults with type 1 diabetes should engage in 150 minutes of moderate- to vigorous-intensity physical activity per week with no more than two consecutive days without activity. 26 Prolonged sitting should be interrupted every 30 minutes with light activity. 34

CARDIOVASCULAR DISEASE PREVENTION

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality among persons with diabetes.( 27 Particular attention should be given to maximizing blood pressure and lipid control Table 4). 27 Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be used preferentially in patients with diabetes who have hypertension and microalbuminuria (urinary albumin-to-creatinine ratio greater than 30 mg per g). 27

Acute Issues of Type 1 Diabetes

HYPOGLYCEMIA

Clinically significant hypoglycemia is defined as a plasma glucose level less than 54 mg per dL (3.0 mmol per L) with or without symptoms. Severe hypoglycemia is defined as a hypoglycemic event in which a patient requires the assistance of another individual for treatment. A blood glucose level of less than 70 mg per dL (3.9 mmol per L) is considered a "glucose alert level" and should trigger treatment with fast-acting carbohydrates and consideration for changes in medication. 6, 35 The risk of severe hypoglycemia, as demonstrated by the Diabetes Control and Complications Trial, increases with intensive diabetes treatment and lower A1C levels. 1 More recent data suggest that as glucose monitoring techniques and insulin types become more sophisticated, this pattern may be changing, and the rate of severe hypoglycemia may not be greater in those with tight glucose control. 9

Hypoglycemia symptoms vary in severity, and range from hunger and confusion to loss of consciousness, seizure, and death. An individual's physiologic response to hypoglycemia depends on the frequency of hypoglycemic events. 36 For example, patients who experience frequent episodes of hypoglycemia may have less severe symptoms at the same glucose levels as patients who rarely experience hypoglycemia. Patients must maintain a tight balance between providing sufficient iatrogenic (exogenous) insulin to prevent hyperglycemia but not so much as to cause hypoglycemia. Regardless of the amount of insulin administered, the risk of recurrent hypoglycemia is exacerbated by decreased glucose counter regulation (epinephrine and glucagon response) and hypoglycemic unawareness. 36

Recommended treatment for hypoglycemia is 15 g of oral glucose. Any type of carbohydrate can increase blood glucose levels; however, complex carbohydrates and increased fat content can delay acute resolution of a hypoglycemic event. Repeat administration of glucose may be required. Glucagon (Glucagen) can be delivered by injection to an unconscious patient with hypoglycemia. Patients and their caregivers should understand the symptoms of hypoglycemia and how to administer proper treatment with glucagon.

HYPERGLYCEMIA

One of the most serious acute complications of type 1 diabetes is diabetic ketoacidosis (DKA). Precipitating factors of DKA include infection, discontinuation or inadequate administration of insulin (including insulin pump failure), myocardial infarction, and other drugs. Prevention strategies for DKA include ensuring adequate access to supplies and prescriptions, and education regarding sick-day management. A previous article from American Family Physician on DKA management is available at https://www.aafp.org/afp/2013/0301/p337.html.

SICK DAYS

Patients often require increased amounts of insulin during acute illness. Patients experiencing acute illness should increase the frequency of glucose testing and should not self-discontinue insulin ( Table 5). 14, 37 Frequent administration of rapid-acting insulin every two to four hours based on glucose levels may be required. In the setting of vomiting or hyperglycemia, ketone testing can help guide management. 37 Recognizing early signs and symptoms of dehydration and DKA is important. Patients and caregivers should contact their physician as soon as DKA is suspected.

Future Directions

Technologic advances have helped improve the usability of continuous glucose monitors and insulin pumps. Various models and manufacturers allow for choice based on size, insertion type, and tubing.

Current research is focused on improving communication between devices and more automation of insulin delivery based on recorded blood glucose levels. In September 2016, the U.S. Food and Drug Administration approved the first combination glucose monitoring and automated insulin delivery device, a hybrid closed-loop system.( 38 Some commercially available closed-loop systems use a continuous glucose monitor, which transmits directly to the insulin pump Figure 3).

FIGURE 3.

In addition to the closed-loop system, an automated, bihormonal (insulin and glucagon) bionic pancreas is under development. Studies of the bihormonal system have shown improved glycemic control and reduced hypoglycemia during testing. 39

Pancreas and islet cell transplantation has also been effective in restoring insulin production and normalizing glucose levels. However, it requires lifelong immunosuppressive therapy. Therefore, it is currently recommended only for patients who also require renal transplantation. 40

Several recent advances in type 1 diabetes research have been driven by improved patient databases. The T1D Exchange, which includes more than 30,000 registry participants, manages the largest registry of patients with type 1 diabetes in the United States. Table 6 provides a list of key findings from the T1D Exchange registry. 9

Data Sources: A literature search was completed in Medline via Ovid, EBSCOhost, DynaMed, and the Cochrane Database of Systematic Reviews using the following keywords: type 1 diabetes, management of diabetes, insulin therapy, and glucose monitoring. Additionally, the Essential Evidence Plus evidence summary literature search sent by the AFP medical editors was reviewed. Search dates: July 3 and August 21, 2017, and May 2018.

The Authors

ANDREW SMITH, MD, is a faculty member at the Lawrence Family Medicine Residency Program, Lawrence, Mass., and an assistant professor of Family Medicine at the Tufts University School of Medicine, Boston, Mass....

CHELSEA HARRIS, MD, is a fourth-year resident at Lawrence Family Medicine Residency Program.

Address correspondence to Andrew Smith, MD, Lawrence Family Health Center, 34 Haverhill St., Lawrence, MA 01841. Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

References

1. Nathan DM, Genuth S, Lachin J, et al.; Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-986. ...

9. T1D Exchange. Better, faster research: the value of the T1D Exchange Clinic Registry. 2016. https://t1dexchange.org/pages/slideshows/value-of-the-t1d-exchange-clinic-registry/. Accessed August 30, 2017.

13. Huang ES, O'Grady M, Basu A, et al.; Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. The cost-effectiveness of continuous glucose monitoring in type 1 diabetes [published correction appears in Diabetes Care. 2010;33(9):2129]. Diabetes Care. 2010;33(6):1269-1274.

21. Donner T. Insulin - Pharmacology, Therapeutic Regimens and Principles of Intensive Insulin Therapy. South Dartmouth, Mass.: MDText.com, Inc.; https://www.ncbi.nlm.nih.gov/books/NBK278938/. Accessed August 23, 2017.

38. U.S. Food and Drug Administration. FDA news release: FDA approves first automated insulin delivery device for type 1 diabetes. September 28, 2016. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm522974.htm. Accessed August 30, 2017.

MOST RECENT ISSUE

May 15, 2021
Access the latest issue of American Family Physician
Read the Issue

Email Alerts

Don't miss a single issue. Sign up for the free AFP email table of contents.
Sign Up Now

# data[].attributes.attachment_link.description
There is considerable benefit of tight glucose control in patients with type 1 diabetes mellitus. Tight blood glucose control dramatically decreases the incidence of microvascular and macrovascular complications. Although glycemic goals should be individualized, most nonpregnant adults should strive for an A1C level less than 7%.

# data[].attributes.body
Uptodate guideline for Management of DM1 in adults

# data[].attributes.attachment_link.readable_text
Type 1 diabetes is characterized by destruction of the pancreatic beta cells, leading to insulin deficiency. It accounts for approximately 5 to 10 percent of cases of diabetes in the United States, Canada, and Europe (whereas type 2 diabetes accounts for over 90 percent). It is one of the most common chronic diseases of childhood, although type 1 diabetes may present in adulthood. In general, the younger the age of diagnosis and the longer the duration of type 1 diabetes, the greater the likelihood that the individual will have absolute insulin deficiency with undetectable C-peptide levels.

This topic will review the management of blood glucose in nonpregnant adults with type 1 diabetes. Management of type 1 diabetes in children, adolescents, and during pregnancy is reviewed separately. A general discussion of the classification of diabetes, clinical presentation and diagnosis of diabetes, and evaluation for diabetes-related complications is reviewed separately.

●(See "Overview of the management of type 1 diabetes mellitus in children and adolescents".)

●(See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control".)

●(See "Pregestational (preexisting) and gestational diabetes: Intrapartum and postpartum glycemic control".)

The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of UpToDate content is governed by the UpToDate Terms of Use. ©2021 UpToDate, Inc. All rights reserved.

# data[].attributes.attachment_link.title
Management of blood glucose in adults with type 1 diabetes mellitus - UpToDate

# data[].attributes.attachment_link.description
Type 1 diabetes is characterized by destruction of the pancreatic beta cells, leading to insulin deficiency. It accounts for approximately 5 to 10 percent of cases of diabetes in the United States, Canada, and Europe (whereas type 2 diabetes accounts for over 90 percent).

# data[].attributes.body
Ndikum, H. B., Gilbert, M., & Robinson, M. V. (2020). Drugs affecting the endocrine system: Pancreatic hormones and antidiabetic drugs. In T. M. Woo & M. V. Robinson (Eds.), Pharmacotherapeutics for advanced practice nurse prescribers (5th ed., pp. 523-570). F.A. Davis. https://fadavisreader.vitalsource.com/#/books/9781719642149/cfi/6/64!/4/2/2/2@0:0

# data[].attributes.headline
Treatment for different types of diabetes

# data[].attributes.subject
Treatment for different types of diabetes

# data[].attributes.attachment_link.readable_text
Diagnosis

Type 1 diabetes FAQs

Endocrinologist Yogish Kudva, M.B.B.S., answers the most frequently asked questions about type 1 diabetes.

Hi, I'm Dr. Yogish C Kudva. I'm an endocrinologist at Mayo Clinic and I'm here to answer some of the important questions you may have about type one diabetes.

The best current treatment for type one diabetes is an automated insulin delivery system. This system includes a continuous glucose monitor, insulin pump, and a computer algorithm that continually adjusts insulin responding to the continuous glucose monitoring signal. The patient still has to enter information about the amount of carbohydrate he or she eats at mealtimes to provide the meal time related insulin.

Testing using a glucose meter is not enough because glucose measurements in people with type one diabetes, vary from normal to low and normal to high very rapidly in the course of a day, a continuous glucose monitor is needed to assess whether treatment is effective and also to determine how to improve treatment.

Current guidelines recommend use of a continuous glucose monitor. The percentage of time that is spent daily with glucose between 70 and 180 milligram per deciliter is the main measurement of appropriate treatment. This percentage should be 70% or higher daily. In addition, percentage of time spent with glucose below 70 should be less than four percent and greater than 250 should be less than five percent. Clearly, hemoglobin A1C testing to evaluate adequacy of treatment is not enough.

In certain people with type one diabetes transplantation can be undertaken. This could be pancreas transplantation or transplantation of insulin making cells called islet. Islet transplantation is considered research in the US. Pancreas transplantation is available as a clinical treatment. These patients with hypoglycemia unawareness may benefit from a pancreas transplant. People with type one diabetes who develop recurrent diabetic ketoacidosis may also benefit from a pancreas transplant. People with type one diabetes who have developed kidney failure, could have their lives transformed by transplantation of both the pancreas and the kidney.

There is active research going on to prevent type one diabetes from happening in children and adults who are less than 45 years old. People who are eligible for such research studies are people who have a positive antibody test for type one diabetes and are willing to be in such studies. The treatment being tested is medication that suppresses the immune system. Willing participants would be randomized to receive immune suppressive treatment or placebo treatment. Placebo looks like the medication, but does not do the same thing in the body. Initial research studies have been successful in decreasing the risk of development of type one diabetes in people that have received the immune system suppressing treatment and therefore, larger studies are now being undertaken.

Try to be informed about research going on and treatments that may be approved for type one diabetes. You can get this information through already available publications. Make sure that at least annually you see a physician who is an expert on your disorder. Never hesitate to ask your medical team any questions or concerns you have. Being informed makes all the difference. Thanks for your time and we wish well.

Type 1 diabetes symptoms often start suddenly and are often the reason for checking blood sugar levels. Because symptoms of other types of diabetes and prediabetes come on more gradually or may not be easy to see, the American Diabetes Association (ADA) has developed screening guidelines. The ADA recommends that the following people be screened for diabetes:

Anyone with a body mass index higher than 25 (23 for Asian Americans), regardless of age, who has additional risk factors. These factors include high blood pressure, non-typical cholesterol levels, an inactive lifestyle, a history of polycystic ovary syndrome or heart disease, and having a close relative with diabetes.

Anyone older than age 35 is advised to get an initial blood sugar screening. If the results are normal, they should be screened every three years after that.

Women who have had gestational diabetes are advised to be screened for diabetes every three years.

Anyone who has been diagnosed with prediabetes is advised to be tested every year.

Anyone who has HIV is advised to be tested.

Tests for type 1 and type 2 diabetes and prediabetes

A1C test. This blood test, which doesn't require not eating for a period of time (fasting), shows your average blood sugar level for the past 2 to 3 months. It measures the percentage of blood sugar attached to hemoglobin, the oxygen-carrying protein in red blood cells. It's also called a glycated hemoglobin test.

The higher your blood sugar levels, the more hemoglobin you'll have with sugar attached. An A1C level of 6.5% or higher on two separate tests means that you have diabetes. An A1C between 5.7% and 6.4% means that you have prediabetes. Below 5.7% is considered normal.

Random blood sugar test. A blood sample will be taken at a random time. No matter when you last ate, a blood sugar level of 200 milligrams per deciliter (mg/dL) - 11.1 millimoles per liter (mmol/L) - or higher suggests diabetes.

Fasting blood sugar test. A blood sample will be taken after you haven't eaten anything the night before (fast). A fasting blood sugar level less than 100 mg/dL (5.6 mmol/L) is normal. A fasting blood sugar level from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is considered prediabetes. If it's 126 mg/dL (7 mmol/L) or higher on two separate tests, you have diabetes.

Glucose tolerance test. For this test, you fast overnight. Then, the fasting blood sugar level is measured. Then you drink a sugary liquid, and blood sugar levels are tested regularly for the next two hours.

A blood sugar level less than 140 mg/dL (7.8 mmol/L) is normal. A reading of more than 200 mg/dL (11.1 mmol/L) after two hours means you have diabetes. A reading between 140 and 199 mg/dL (7.8 mmol/L and 11.0 mmol/L) means you have prediabetes.

If your provider thinks you may have type 1 diabetes, they may test your urine to look for the presence of ketones. Ketones are a byproduct produced when muscle and fat are used for energy. Your provider will also probably run a test to see if you have the destructive immune system cells associated with type 1 diabetes called autoantibodies.

Your provider will likely see if you're at high risk for gestational diabetes early in your pregnancy. If you're at high risk, your provider may test for diabetes at your first prenatal visit. If you're at average risk, you'll probably be screened sometime during your second trimester.

Treatment

Depending on what type of diabetes you have, blood sugar monitoring, insulin and oral drugs may be part of your treatment. Eating a healthy diet, staying at a healthy weight and getting regular physical activity also are important parts of managing diabetes.

Treatments for all types of diabetes

An important part of managing diabetes - as well as your overall health - is keeping a healthy weight through a healthy diet and exercise plan:

Healthy eating. Your diabetes diet is simply a healthy-eating plan that will help you control your blood sugar. You'll need to focus your diet on more fruits, vegetables, lean proteins and whole grains. These are foods that are high in nutrition and fiber and low in fat and calories. You'll also cut down on saturated fats, refined carbohydrates and sweets. In fact, it's the best eating plan for the entire family. Sugary foods are OK once in a while. They must be counted as part of your meal plan.

Understanding what and how much to eat can be a challenge. A registered dietitian can help you create a meal plan that fits your health goals, food preferences and lifestyle. This will likely include carbohydrate counting, especially if you have type 1 diabetes or use insulin as part of your treatment.

Physical activity. Everyone needs regular aerobic activity. This includes people who have diabetes. Physical activity lowers your blood sugar level by moving sugar into your cells, where it's used for energy. Physical activity also makes your body more sensitive to insulin. That means your body needs less insulin to transport sugar to your cells.

Get your provider's OK to exercise. Then choose activities you enjoy, such as walking, swimming or biking. What's most important is making physical activity part of your daily routine.

Aim for at least 30 minutes or more of moderate physical activity most days of the week, or at least 150 minutes of moderate physical activity a week. Bouts of activity can be a few minutes during the day. If you haven't been active for a while, start slowly and build up slowly. Also avoid sitting for too long. Try to get up and move if you've been sitting for more than 30 minutes.

Treatments for type 1 and type 2 diabetes

Treatment for type 1 diabetes involves insulin injections or the use of an insulin pump, frequent blood sugar checks, and carbohydrate counting. For some people with type 1 diabetes, pancreas transplant or islet cell transplant may be an option.

Treatment of type 2 diabetes mostly involves lifestyle changes, monitoring of your blood sugar, along with oral diabetes drugs, insulin or both.

Monitoring your blood sugar

Depending on your treatment plan, you may check and record your blood sugar as many as four times a day or more often if you're taking insulin. Careful blood sugar testing is the only way to make sure that your blood sugar level remains within your target range. People with type 2 diabetes who aren't taking insulin generally check their blood sugar much less often.

People who receive insulin therapy also may choose to monitor their blood sugar levels with a continuous glucose monitor. Although this technology hasn't yet completely replaced the glucose meter, it can lower the number of fingersticks necessary to check blood sugar and provide important information about trends in blood sugar levels.

Even with careful management, blood sugar levels can sometimes change unpredictably. With help from your diabetes treatment team, you'll learn how your blood sugar level changes in response to food, physical activity, medications, illness, alcohol and stress. For women, you'll learn how your blood sugar level changes in response to changes in hormone levels.

Besides daily blood sugar monitoring, your provider will likely recommend regular A1C testing to measure your average blood sugar level for the past 2 to 3 months.

Compared with repeated daily blood sugar tests, A1C testing shows better how well your diabetes treatment plan is working overall. A higher A1C level may signal the need for a change in your oral drugs, insulin regimen or meal plan.

Your target A1C goal may vary depending on your age and various other factors, such as other medical conditions you may have or your ability to feel when your blood sugar is low. However, for most people with diabetes, the American Diabetes Association recommends an A1C of below 7%. Ask your provider what your A1C target is.

Insulin

People with type 1 diabetes must use insulin to manage blood sugar to survive. Many people with type 2 diabetes or gestational diabetes also need insulin therapy.

Many types of insulin are available, including short-acting (regular insulin), rapid-acting insulin, long-acting insulin and intermediate options. Depending on your needs, your provider may prescribe a mixture of insulin types to use during the day and night.

Insulin can't be taken orally to lower blood sugar because stomach enzymes interfere with insulin's action. Insulin is often injected using a fine needle and syringe or an insulin pen - a device that looks like a large ink pen.

An insulin pump also may be an option. The pump is a device about the size of a small cellphone worn on the outside of your body. A tube connects the reservoir of insulin to a tube (catheter) that's inserted under the skin of your abdomen.

A continuous glucose monitor, on the left, is a device that measures blood sugar every few minutes using a sensor inserted under the skin. An insulin pump, attached to the pocket, is a device that's worn outside of the body with a tube that connects the reservoir of insulin to a catheter inserted under the skin of the abdomen. Insulin pumps are programmed to deliver specific amounts of insulin continuously and with food.

A tubeless pump that works wirelessly is also now available. You program an insulin pump to dispense specific amounts of insulin. It can be adjusted to give out more or less insulin depending on meals, activity level and blood sugar level.

A closed loop system is a device implanted in the body that links a continuous glucose monitor to an insulin pump. The monitor checks blood sugar levels regularly. The device automatically delivers the right amount of insulin when the monitor shows that it's needed.

The Food and Drug Administration has approved several hybrid closed loop systems for type 1 diabetes. They are called "hybrid" because these systems require some input from the user. For example, you may have to tell the device how many carbohydrates are eaten, or confirm blood sugar levels from time to time.

A closed loop system that doesn't need any user input isn't available yet. But more of these systems currently are in clinical trials.

Oral or other drugs

Sometimes your provider may prescribe other oral or injected drugs as well. Some diabetes drugs help your pancreas to release more insulin. Others prevent the production and release of glucose from your liver, which means you need less insulin to move sugar into your cells.

Still others block the action of stomach or intestinal enzymes that break down carbohydrates, slowing their absorption, or make your tissues more sensitive to insulin. Metformin (Glumetza, Fortamet, others) is generally the first drug prescribed for type 2 diabetes.

Another class of medication called SGLT2 inhibitors may be used. They work by preventing the kidneys from reabsorbing filtered sugar into the blood. Instead, the sugar is eliminated in the urine.

Transplantation

In some people who have type 1 diabetes, a pancreas transplant may be an option. Islet transplants are being studied as well. With a successful pancreas transplant, you would no longer need insulin therapy.

But transplants aren't always successful. And these procedures pose serious risks. You need a lifetime of immune-suppressing drugs to prevent organ rejection. These drugs can have serious side effects. Because of this, transplants are usually reserved for people whose diabetes can't be controlled or those who also need a kidney transplant.

Bariatric surgery

Some people with type 2 diabetes who are obese and have a body mass index higher than 35 may be helped by some types of bariatric surgery. People who've had gastric bypass have seen major improvements in their blood sugar levels. But this procedure's long-term risks and benefits for type 2 diabetes aren't yet known.

Treatment for gestational diabetes

Controlling your blood sugar level is essential to keeping your baby healthy. It can also keep you from having complications during delivery. In addition to having a healthy diet and exercising regularly, your treatment plan for gestational diabetes may include monitoring your blood sugar. In some cases, you may also use insulin or oral drugs.

Your provider will monitor your blood sugar level during labor. If your blood sugar rises, your baby may release high levels of insulin. This can lead to low blood sugar right after birth.

Treatment for prediabetes

Treatment for prediabetes usually involves healthy lifestyle choices. These habits can help bring your blood sugar level back to normal. Or it could keep it from rising toward the levels seen in type 2 diabetes. Keeping a healthy weight through exercise and healthy eating can help. Exercising at least 150 minutes a week and losing about 7% of your body weight may prevent or delay type 2 diabetes.

Drugs - such as metformin, statins and high blood pressure medications - may be an option for some people with prediabetes and other conditions such as heart disease.

Signs of trouble in any type of diabetes

Many factors can affect your blood sugar. Problems may sometimes come up that need care right away.

High blood sugar

High blood sugar ( hyperglycemia in diabetes) can occur for many reasons, including eating too much, being sick or not taking enough glucose-lowering medication. Check your blood sugar level as directed by your provider. And watch for symptoms of high blood sugar, including:

Urinating often

Feeling thirstier than usual

Blurred vision

Tiredness (fatigue)

Headache

Irritability

If you have hyperglycemia, you'll need to adjust your meal plan, drugs or both.

Increased ketones in your urine

Diabetic ketoacidosis is a serious complication of diabetes. If your cells are starved for energy, your body may begin to break down fat. This makes toxic acids known as ketones, which can build up in the blood. Watch for the following symptoms:

Nausea

Vomiting

Stomach (abdominal) pain

A sweet, fruity smell on your breath

Shortness of breath

Dry mouth

Weakness

Confusion

Coma

You can check your urine for excess ketones with a ketones test kit that you can get without a prescription. If you have excess ketones in your urine, talk with your provider right away or seek emergency care. This condition is more common in people with type 1 diabetes.

Hyperglycemic hyperosmolar nonketotic syndrome

Hyperosmolar syndrome is caused by very high blood sugar that turns blood thick and syrupy.

Symptoms of this life-threatening condition include:

A blood sugar reading over 600 mg/dL (33.3 mmol/L)

Dry mouth

Extreme thirst

Fever

Drowsiness

Confusion

Vision loss

Hallucinations

This condition is seen in people with type 2 diabetes. It often happens after an illness. Call your provider or seek medical care right away if you have symptoms of this condition.

Low blood sugar (hypoglycemia)

If your blood sugar level drops below your target range, it's known as low blood sugar ( diabetic hypoglycemia). If you're taking drugs that lower your blood sugar, including insulin, your blood sugar level can drop for many reasons. These include skipping a meal and getting more physical activity than normal. Low blood sugar also occurs if you take too much insulin or too much of a glucose-lowering medication that causes the pancreas to hold insulin.

Check your blood sugar level regularly and watch for symptoms of low blood sugar, including:

Low blood sugar is best treated with carbohydrates that your body can absorb quickly, such as fruit juice or glucose tablets.

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

Diabetes is a serious disease. Following your diabetes treatment plan takes total commitment. Careful management of diabetes can lower your risk of serious or life-threatening complications.

Commit to managing your diabetes. Learn all you can about diabetes. Build a relationship with a diabetes educator. Ask your diabetes treatment team for help when you need it.

Choose healthy foods and stay at a healthy weight. If you're overweight, losing just 7% of your body weight can make a difference in your blood sugar control if you have prediabetes or type 2 diabetes. A healthy diet is one with plenty of fruits, vegetables, lean proteins, whole grains and legumes. And limit how much food with saturated fat you eat.

Make physical activity part of your daily routine. Regular physical activity can help prevent prediabetes and type 2 diabetes. It can also help those who already have diabetes to maintain better blood sugar control. A minimum of 30 minutes of moderate physical activity - such as brisk walking - most days of the week is recommended. Aim for at least 150 minutes of moderate aerobic physical activity a week.

Getting regular aerobic exercise along with getting at least two days a week of strength training exercises can help control blood sugar more effectively than does either type of exercise alone. Aerobic exercises can include walking, biking or dancing. Resistance training can include weight training and body weight exercises.

Also try to spend less time sitting still. Try to get up and move around for a few minutes at least every 30 minutes or so when you're awake.

Lifestyle recommendations for type 1 and type 2 diabetes

Also, if you have type 1 or type 2 diabetes:

Identify yourself. Wear a tag or bracelet that says you have diabetes. Keep a glucagon kit nearby in case of a low blood sugar emergency. Make sure your friends and loved ones know how to use it.

Schedule a yearly physical and regular eye exams. Your regular diabetes checkups aren't meant to replace yearly physicals or routine eye exams. During the physical, your provider will look for any diabetes-related complications and screen for other medical problems. Your eye care specialist will check for signs of eye damage, including retinal damage (retinopathy), cataracts and glaucoma.

Keep your vaccinations up to date. High blood sugar can weaken your immune system. Get a flu shot every year. Your provider may recommend the pneumonia and COVID-19 vaccines, as well.

The Centers for Disease Control and Prevention (CDC) also currently recommends hepatitis B vaccination if you haven't previously had it and you're an adult ages 19 to 59 with type 1 or type 2 diabetes.

The most recent CDC guidelines suggest vaccination as soon as possible after diagnosis with type 1 or type 2 diabetes. If you are age 60 or older, have been diagnosed with diabetes, and haven't previously received the vaccine, talk to your provider about whether it's right for you.

Pay attention to your feet. Wash your feet daily in lukewarm water. Dry them gently, especially between the toes. Moisturize with lotion, but not between the toes. Check your feet every day for blisters, cuts, sores, redness or swelling. Talk to your provider if you have a sore or other foot problem that doesn't heal quickly on its own.

Control your blood pressure and cholesterol. Eating healthy foods and exercising regularly can help control high blood pressure and cholesterol. Drugs may be needed, too.

Take care of your teeth. Diabetes may leave you prone to more-serious gum infections. Brush and floss your teeth at least twice a day. And if you have type 1 or type 2 diabetes, schedule regular dental exams. Talk to your dentist right away if your gums bleed or look red or swollen.

If you smoke or use other types of tobacco, ask your provider to help you quit. Smoking increases your risk of many diabetes complications. Smokers who have diabetes are more likely to die of cardiovascular disease than are nonsmokers who have diabetes. Talk to your provider about ways to stop smoking or to stop using other types of tobacco.

If you drink alcohol, do so responsibly. Alcohol can cause either high or low blood sugar. This depends on how much you drink and if you eat at the same time. If you choose to drink, do so only in moderation - one drink a day for women and up to two drinks a day for men - and always with food.

Remember to include the carbohydrates from any alcohol you drink in your daily carbohydrate count. And check your blood sugar levels before going to bed.

Take stress seriously. The hormones your body may make in response to long-term stress may prevent insulin from working properly. This will raise your blood sugar and stress you even more. Set limits for yourself and prioritize your tasks. Learn relaxation techniques. And get plenty of sleep.

Alternative medicine

Many substances have been shown to improve the body's ability to process insulin in some studies. Other studies fail to find any benefit for blood sugar control or in lowering A1C levels. Because of the conflicting findings, there aren't any alternative therapies that are currently recommended to help everyone to manage blood sugar.

If you decide to try any type of alternative therapy, don't stop taking the drugs that your provider has prescribed. Be sure to discuss the use of any of these therapies with your provider. Make sure that they won't cause bad reactions or interact with your current therapy.

Also, no treatments - alternative or conventional - can cure diabetes. If you're using insulin therapy for diabetes, never stop using insulin unless directed to do so by your provider.

Coping and support

Living with diabetes can be difficult and frustrating. Sometimes, even when you've done everything right, your blood sugar levels may rise. But stick with your diabetes management plan and you'll likely see a positive difference in your A1C when you visit your provider.

Good diabetes management can take a great deal of time and feel overwhelming. Some people find that it helps to talk to someone. Your provider can probably recommend a mental health professional for you to speak with. Or you may want to try a support group.

Sharing your frustrations and triumphs with people who understand what you're going through can be very helpful. And you may find that others have great tips to share about diabetes management.

Your provider may know of a local support group. You can also call the American Diabetes Association at 800-DIABETES (800-342-2383) or the Juvenile Diabetes Research Foundation at 800-533-CURE (800-533-2873).

Preparing for your appointment

You're likely to start by seeing your health care provider if you're having diabetes symptoms. If your child is having diabetes symptoms, you might see your child's health care provider. If blood sugar levels are very high, you'll likely be sent to the emergency room.

If blood sugar levels aren't high enough to put you or your child immediately at risk, you may be referred to a provider trained in diagnosing and treating diabetes (endocrinologist). Soon after diagnosis, you'll also likely meet with a diabetes educator and a registered dietitian to get more information on managing your diabetes.

Here's some information to help you get ready for your appointment and to know what to expect.

What you can do

Be aware of any pre-appointment restrictions. When you make the appointment, ask if you need to do anything in advance. This will likely include restricting your diet, such as for a fasting blood sugar test.

Write down any symptoms you're experiencing, including any that may seem unrelated.

Write down key personal information, including major stresses or recent life changes. If you're monitoring your glucose values at home, bring a record of the glucose results, detailing the dates and times of testing.

Make a list of any allergies you have and all medications, vitamins and supplements you're taking.

Record your family medical history. Be sure to note any relatives who have had diabetes, heart attacks or strokes.

Bring a family member or friend, if possible. Someone who accompanies you can help you remember information you need.

Write down questions to ask your provider. Ask about aspects of your diabetes management you're unclear about.

Be aware if you need any prescription refills. Your provider can renew your prescriptions while you're there.

Preparing a list of questions can help you make the most of your time with your provider. For diabetes, some questions to ask include:

Are the symptoms I'm having related to diabetes or something else?

Do I need any tests?

What else can I do to protect my health?

What are other options to manage my diabetes?

I have other health conditions. How can I best manage these conditions together?

Are there restrictions I need to follow?

Should I see another specialist, such as a dietitian or diabetes educator?

Is there a generic alternative to the medicine you're prescribing?

Are there brochures or other printed material I can take with me? What websites do you recommend?

What to expect from your doctor

Your provider is likely to ask you many questions, such as:

Can you describe your symptoms?

Do you have symptoms all the time, or do they come and go?

How severe are your symptoms?

Do you have a family history of preeclampsia or diabetes?

Tell me about your diet.

Do you exercise? What type and how much?

# data[].attributes.attachment_link.description
Learn more about the different types of this blood sugar disorder, who's at risk and how each type can be treated.

# data[].attributes.attachment_link.title
The global rise of diabetes—and how to prevent it | TED Institute

# data[].attributes.body
Patient Education:

What should I do?
Check your blood glucose level at least every three to four hours if you are sick. Check your glucose level every one to two hours if you have critical blood glucose values. Ask your doctor what your critical level should be. Most patients should watch their glucose levels closely when they are higher than 250 mg per dL. Keep testing at least every four hours during the night.

Test your urine for ketones or your blood for beta-hydroxybutyrate every four hours or if your blood glucose is over 250 mg per dL.

If you are not eating, do NOT stop your insulin completely. Your body needs insulin even if you are not eating. Call your doctor if you do not know how to change your insulin dose.

If your blood glucose is high, take extra insulin to control it. Call your doctor if you do not have an extra insulin dose or if the extra dose is not working.

Drink lots of sugar-free, caffeine-free liquids. Sip small amounts every few minutes if you are feeling sick to your stomach.

If your blood glucose is more than 250 mg per dL, do not eat or drink foods that are high in carbohydrates.

Contact your doctor if you have:

Vomiting more than once

Stomach pain

Diarrhea five or more times in six hours

Two blood glucose level tests higher than 300 mg per dL

A blood glucose level less than 70 mg per dL more than once or symptoms of low blood sugar

Trouble breathing

Moderate or large ketones if you are using urine test strips

Diabetic ketoacidosis: What it is and how to prevent it. (2005). American Family Physician, 71(9), 1721-1722.

# data[].attributes.attachment_link.title
Microvascular and Macrovascular Complications of Diabetes

# data[].attributes.attachment_link.description
Diabetes is a group of chronic diseases characterized by hyperglycemia. Modern medical care uses a vast array of lifestyle and pharmaceutical interventions aimed at preventing and controlling hyperglycemia. In addition to ensuring the adequate delivery of glucose to the tissues of the body, treatment of diabetes attempts to decrease the likelihood that the tissues of the body are harmed by hyperglycemia.

# data[].attributes.attachment_link.readable_text
Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) is a potentially deadly condition that can develop as a result of infection or illness in people with uncontrolled type 2 diabetes or when diabetes medications aren't taken as directed. Some also refer to this as a "diabetic coma."

HHNS is a relatively rare complication of diabetes, accounting for just 1% of hospital admissions among people with diabetes.﻿﻿

The symptoms of HHNS may appear slowly, taking days or even weeks to fully develop. Common symptoms include:﻿﻿

Blood glucose levels over 600 milligrams per deciliter (mg/dl)

Frequent urination

Extreme thirst

Confusion or sleepiness

Skin that is warm and dry without sweating

Fever (usually over 101 F)

Weakness or paralysis on one side of the body

Loss of vision

Hallucinations

HHNS develops when glucose levels surge (typically above 600 mg/dl), leading to severe dehydration. This dehydration occurs because elevated levels of glucose cause blood to become thicker and result in the body needing to produce more urine in order to lower them.﻿﻿

The result is frequent urination, which can result in serious or even life-threatening dehydration. If these fluids are not adequately replenished, the condition may eventually result in a seizure, coma, or even death.

HHNS is typically brought on by:

An infection, such as pneumonia or a urinary tract infection

Poor management of blood sugar and/or not taking diabetes medications as prescribed

Taking certain medications, such as glucocorticoids (which alter glucose levels) and diuretics (which increase urine output)

Having chronic conditions in addition to diabetes, such as congestive heart failure or kidney disease﻿﻿

The condition is more likely to affect older adults, and especially those of African-American, Native American, or Hispanic ethnic backgrounds. Rarely, HHNS can occur in people who have not yet been diagnosed with diabetes.

HHNS is diagnosed based on symptoms and by measuring blood glucose levels, which can be performed with a finger stick.

A blood glucose level of 600 mg/dL and low ketone levels are the main factors for diagnosis of HHNS.

Serum osmolality, a test that measures the body's water/electrolyte balance, also is used to diagnose HHNS. Serum osmolality specifically measures the chemicals dissolved in the liquid part of blood (serum), such as sodium, chloride, bicarbonate, proteins, and glucose. The test is done by taking a sample of blood from a vein.﻿﻿

Treatment typically involves starting intravenous (IV) fluids (saline solution delivered through a needle into a vein) to rehydrate the body quickly. It also may require IV insulin to bring down blood sugar levels.

Potassium and sometimes sodium phosphate replenishment may also be required to support cell function.﻿﻿

If you are hospitalized due to HHNS, you may be kept overnight for observation. The main goal of treatment of this condition is to identify the underlying factors, whether that's an infection, a certain medication, or poor blood sugar management.

Prevention

The best way to prevent this serious condition is to manage your diabetes by:﻿﻿

Checking your blood sugar according to your doctor's instructions. When you are sick, you should check your blood every four hours. Your blood sugar tends to be naturally higher when your body is fighting a virus or infection.

Taking your diabetes medications, including insulin, as directed by your doctor

Drinking an ample amount of fluid each day, especially when you are ill

Staying in contact with your diabetes healthcare team when your blood sugar is consistently above 300 mg/dl

Staying up-to-date on vaccinations, including getting an annual flu shot and discussing with your doctor the advisability of getting the pneumococcal vaccine

How Is HHNS Different From Diabetic Ketoacidosis (DKA)?

DKA is also a serious condition and potentially life-threatening if not treated promptly. In contrast to HHNS, DKA is almost exclusively a condition that occurs in people with type 1 diabetes.﻿﻿

A lack of insulin causes a build-up of glucose in the blood that cannot get into the cells of the body to be used for energy. The body compensates by looking for an alternative energy source in stored fat. When stored fat is used for energy it creates a toxic waste product called ketones, which can poison the body.

HHNS does not produce ketones, and the symptoms of DKA are different, including:﻿﻿

Breath that has a fruity odor

Labored breathing

Nausea and vomiting

A rapid and weak pulse

Abdominal pain

A Word From Verywell

The best way to prevent HHNS is by keeping your blood sugar levels under control. Test them regularly using a glucometer, work with your doctor to make sure you're taking any diabetes medications as prescribed, and learn the warning signs of elevated glucose levels and dehydration, such as extreme thirst and frequent urination, so you know to seek treatment when you need it. Educate your loved ones and coworkers to also recognize the early signs of blood sugar imbalance, so they can send for help, too.

# data[].attributes.attachment_link.description
Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) is a potentially deadly condition that can develop as a result of infection or illness in people with uncontrolled type 2 diabetes or when diabetes medications aren't taken as directed. Some also refer to this as a "diabetic coma."

# data[].attributes.attachment_link.readable_text
Insulin therapy is the mainstay of treatment for type 1 diabetes mellitus (T1DM). The goal of insulin therapy is to replace the deficient hormone and attain normoglycemia. However, this goal remains elusive because of the difficulty in replicating the minute-to-minute variations of physiologic insulin secretion and the difference in delivery of exogenous insulin, which is absorbed from the subcutaneous injection or infusion site into the systemic circulation, compared with normal secretion of endogenous insulin directly into the portal vein. The acute and chronic complications of diabetes are largely attributable to hyperglycemia as a consequence of the failure of exogenous insulin to completely mimic physiologic insulin secretion.

Many different insulin preparations and delivery systems are available. The selected regimen is individualized for the child and family/caregiver to fit their lifestyle and optimize compliance while providing optimal glycemic control. Input from the patient, if age-appropriate, and the family (eg, timing of meals and snacks, school/daycare, physical activity) is important to ensure optimal glycemic control and minimize glycemic variability and episodes of hypoglycemia. As a result, the optimal types of insulin and regimen will vary among children and can change for an individual child over time.

This topic review will focus on monitoring of glycemic control and details of insulin therapy, including dosing and dose adjustment, as well as options for administration, including insulin pumps and related devices.

Other aspects of childhood-onset T1DM are discussed separately:

●Routine management:

The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of UpToDate content is governed by the UpToDate Terms of Use. ©2021 UpToDate, Inc. All rights reserved.

REFERENCES

1. American Diabetes Association. 13. Children and Adolescents: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020; 43:S163.

2. DiMeglio LA, Acerini CL, Codner E, et al. ISPAD Clinical Practice Consensus Guidelines 2018: Glycemic control targets and glucose monitoring for children, adolescents, and young adults with diabetes. Pediatr Diabetes 2018; 19 Suppl 27:105.

3. Chiang JL, Kirkman MS, Laffel LM, et al. Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes Care 2014; 37:2034.

4. Barnea-Goraly N, Raman M, Mazaika P, et al. Alterations in white matter structure in young children with type 1 diabetes. Diabetes Care 2014; 37:332.

5. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 2003; 290:2159.

6. Donaghue KC, Fung AT, Hing S, et al. The effect of prepubertal diabetes duration on diabetes. Microvascular complications in early and late adolescence. Diabetes Care 1997; 20:77.

7. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977.

8. Karges B, Schwandt A, Heidtmann B, et al. Association of Insulin Pump Therapy vs Insulin Injection Therapy With Severe Hypoglycemia, Ketoacidosis, and Glycemic Control Among Children, Adolescents, and Young Adults With Type 1 Diabetes. JAMA 2017; 318:1358.

9. Beck RW, Miller KM, Foster NC. The T1D Exchange Clinic Network and Registry: 10 Years of Enlightenment on the State of Type 1 Diabetes in the United States. Diabetes Technol Ther 2019; 21:310.

10. Ziegler R, Heidtmann B, Hilgard D, et al. Frequency of SMBG correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes. Pediatr Diabetes 2011; 12:11.

11. Miller KM, Beck RW, Bergenstal RM, et al. Evidence of a strong association between frequency of self-monitoring of blood glucose and hemoglobin A1c levels in T1D exchange clinic registry participants. Diabetes Care 2013; 36:2009.

12. Haller MJ, Stalvey MS, Silverstein JH. Predictors of control of diabetes: monitoring may be the key. J Pediatr 2004; 144:660.

13. Gonder-Frederick L, Zrebiec J, Bauchowitz A, et al. Detection of hypoglycemia by children with type 1 diabetes 6 to 11 years of age and their parents: a field study. Pediatrics 2008; 121:e489.

14. Helgeson VS, Honcharuk E, Becker D, et al. A focus on blood glucose monitoring: relation to glycemic control and determinants of frequency. Pediatr Diabetes 2011; 12:25.

15. Danne T, Lange K, Kordonouri O. Real-time glucose sensors in children and adolescents with type-1 diabetes. Horm Res 2008; 70:193.

16. Improving surgical outcomes with data tool. Healthcare Benchmarks Qual Improv 2008; 15:118.

17. Laffel L. Improved Accuracy of Continuous Glucose Monitoring Systems in Pediatric Patients with Diabetes Mellitus: Results from Two Studies. Diabetes Technol Ther 2016; 18 Suppl 2:S223.

18. American Diabetes Association. 7. Diabetes Technology: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020; 43:S77.

19. Laffel LM, Kanapka LG, Beck RW, et al. Effect of Continuous Glucose Monitoring on Glycemic Control in Adolescents and Young Adults With Type 1 Diabetes: A Randomized Clinical Trial. JAMA 2020; 323:2388.

20. Laffel LM, Limbert C, Phelan H, et al. ISPAD Clinical Practice Consensus Guidelines 2018: Sick day management in children and adolescents with diabetes. Pediatr Diabetes 2018; 19 Suppl 27:193.

21. Tremblay ES, Millington K, Monuteaux MC, et al. Plasma β-Hydroxybutyrate for the Diagnosis of Diabetic Ketoacidosis in the Emergency Department. Pediatr Emerg Care 2020.

22. Biester T, Blaesig S, Remus K, et al. Insulin degludec's ultra-long pharmacokinetic properties observed in adults are retained in children and adolescents with type 1 diabetes. Pediatr Diabetes 2014; 15:27.

23. Chase HP, Dixon B, Pearson J, et al. Reduced hypoglycemic episodes and improved glycemic control in children with type 1 diabetes using insulin glargine and neutral protamine Hagedorn insulin. J Pediatr 2003; 143:737.

24. Hathout EH, Fujishige L, Geach J, et al. Effect of therapy with insulin glargine (lantus) on glycemic control in toddlers, children, and adolescents with diabetes. Diabetes Technol Ther 2003; 5:801.

25. Berhe T, Postellon D, Wilson B, Stone R. Feasibility and safety of insulin pump therapy in children aged 2 to 7 years with type 1 diabetes: a retrospective study. Pediatrics 2006; 117:2132.

26. Alemzadeh R, Ellis JN, Holzum MK, et al. Beneficial effects of continuous subcutaneous insulin infusion and flexible multiple daily insulin regimen using insulin glargine in type 1 diabetes. Pediatrics 2004; 114:e91.

27. Murphy NP, Keane SM, Ong KK, et al. Randomized cross-over trial of insulin glargine plus lispro or NPH insulin plus regular human insulin in adolescents with type 1 diabetes on intensive insulin regimens. Diabetes Care 2003; 26:799.

28. Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. J Pediatr 1994; 125:177.

29. Simon D. Diabetes treatment with insulin glargine and risk of malignancy: methodological pitfalls and ethical issues. Diabetologia 2010; 53:204.

30. Tang X, Yang L, He Z, Liu J. Insulin glargine and cancer risk in patients with diabetes: a meta-analysis. PLoS One 2012; 7:e51814.

31. Phillip M, Battelino T, Rodriguez H, et al. Use of insulin pump therapy in the pediatric age-group: consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes, endorsed by the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2007; 30:1653.

32. Sundberg F, Barnard K, Cato A, et al. ISPAD Guidelines. Managing diabetes in preschool children. Pediatr Diabetes 2017; 18:499.

33. Danne T, Phillip M, Buckingham BA, et al. ISPAD Clinical Practice Consensus Guidelines 2018: Insulin treatment in children and adolescents with diabetes. Pediatr Diabetes 2018; 19 Suppl 27:115.

34. Zabeen B, Craig ME, Virk SA, et al. Insulin Pump Therapy Is Associated with Lower Rates of Retinopathy and Peripheral Nerve Abnormality. PLoS One 2016; 11:e0153033.

35. Qin Y, Yang LH, Huang XL, et al. Efficacy and Safety of Continuous Subcutaneous Insulin Infusion vs. Multiple Daily Injections on Type 1 Diabetes Children: A Meta-Analysis of Randomized Control Trials. J Clin Res Pediatr Endocrinol 2018; 10:316.

36. Litton J, Rice A, Friedman N, et al. Insulin pump therapy in toddlers and preschool children with type 1 diabetes mellitus. J Pediatr 2002; 141:490.

37. Fox LA, Buckloh LM, Smith SD, et al. A randomized controlled trial of insulin pump therapy in young children with type 1 diabetes. Diabetes Care 2005; 28:1277.

38. Weinzimer SA, Swan KL, Sikes KA, Ahern JH. Emerging evidence for the use of insulin pump therapy in infants, toddlers, and preschool-aged children with type 1 diabetes. Pediatr Diabetes 2006; 7 Suppl 4:15.

39. Blair JC, McKay A, Ridyard C, et al. Continuous subcutaneous insulin infusion versus multiple daily injection regimens in children and young people at diagnosis of type 1 diabetes: pragmatic randomised controlled trial and economic evaluation. BMJ 2019; 365:l1226.

40. Kamrath C, Tittel SR, Kapellen TM, et al. Early versus delayed insulin pump therapy in children with newly diagnosed type 1 diabetes: results from the multicentre, prospective diabetes follow-up DPV registry. Lancet Child Adolesc Health 2021; 5:17.

41. Alsaleh FM, Smith FJ, Taylor KM. Experiences of children/young people and their parents, using insulin pump therapy for the management of type 1 diabetes: qualitative review. J Clin Pharm Ther 2012; 37:140.

42. Glaser NS, Iden SB, Green-Burgeson D, et al. Benefits of an insulin dosage calculation device for adolescents with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2004; 17:1641.

43. McMahon SK, Airey FL, Marangou DA, et al. Insulin pump therapy in children and adolescents: improvements in key parameters of diabetes management including quality of life. Diabet Med 2005; 22:92.

44. Mueller-Godeffroy E, Vonthein R, Ludwig-Seibold C, et al. Psychosocial benefits of insulin pump therapy in children with diabetes type 1 and their families: The pumpkin multicenter randomized controlled trial. Pediatr Diabetes 2018; 19:1471.

45. DiMeglio LA, Pottorff TM, Boyd SR, et al. A randomized, controlled study of insulin pump therapy in diabetic preschoolers. J Pediatr 2004; 145:380.

46. Wiebe DJ, Croom A, Fortenberry KT, et al. Parental involvement buffers associations between pump duration and metabolic control among adolescents with type 1 diabetes. J Pediatr Psychol 2010; 35:1152.

47. Plotnick LP, Clark LM, Brancati FL, Erlinger T. Safety and effectiveness of insulin pump therapy in children and adolescents with type 1 diabetes. Diabetes Care 2003; 26:1142.

48. Conwell LS, Pope E, Artiles AM, et al. Dermatological complications of continuous subcutaneous insulin infusion in children and adolescents. J Pediatr 2008; 152:622.

49. Cope JU, Samuels-Reid JH, Morrison AE. Pediatric use of insulin pump technology: a retrospective study of adverse events in children ages 1-12 years. J Diabetes Sci Technol 2012; 6:1053.

50. Bergenstal RM, Tamborlane WV, Ahmann A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med 2010; 363:311.

51. Slover RH, Welsh JB, Criego A, et al. Effectiveness of sensor-augmented pump therapy in children and adolescents with type 1 diabetes in the STAR 3 study. Pediatr Diabetes 2012; 13:6.

52. Kordonouri O, Pankowska E, Rami B, et al. Sensor-augmented pump therapy from the diagnosis of childhood type 1 diabetes: results of the Paediatric Onset Study (ONSET) after 12 months of treatment. Diabetologia 2010; 53:2487.

53. Ly TT, Nicholas JA, Retterath A, et al. Effect of sensor-augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial. JAMA 2013; 310:1240.

54. Buckingham BA, Raghinaru D, Cameron F, et al. Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis. Diabetes Care 2015; 38:1197.

55. Maahs DM, Calhoun P, Buckingham BA, et al. A randomized trial of a home system to reduce nocturnal hypoglycemia in type 1 diabetes. Diabetes Care 2014; 37:1885.

56. Abraham MB, Nicholas JA, Smith GJ, et al. Reduction in Hypoglycemia With the Predictive Low-Glucose Management System: A Long-term Randomized Controlled Trial in Adolescents With Type 1 Diabetes. Diabetes Care 2018; 41:303.

57. Brown SA, Kovatchev BP, Raghinaru D, et al. Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes. N Engl J Med 2019; 381:1707.

58. Breton MD, Kanapka LG, Beck RW, et al. A Randomized Trial of Closed-Loop Control in Children with Type 1 Diabetes. N Engl J Med 2020; 383:836.

59. Forlenza GP, Pinhas-Hamiel O, Liljenquist DR, et al. Safety Evaluation of the MiniMed 670G System in Children 7-13 Years of Age with Type 1 Diabetes. Diabetes Technol Ther 2019; 21:11.

60. Summary of Safety and Effectiveness Data, t:slim X2 insulin pump with basal-IQ technology; FDA approval June 2018. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf18/P180008B.pdf (Accessed on September 01, 2020).

61. Summary of Safety and Effectiveness Data, MiniMed 670G System; FDA approval June 2018. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160017S031B.pdf (Accessed on September 01, 2020).

62. US Food and Drug Administration News Release: FDA Approves First-of-its-Kind Automated Insulin Delivery and Monitoring System for Use in Young Pediatric Patients (August 31, 2020). Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-automated-insulin-delivery-and-monitoring-system-use-young-pediatric (Accessed on September 09, 2020).

63. Weinzimer SA, Steil GM, Swan KL, et al. Fully automated closed-loop insulin delivery versus semiautomated hybrid control in pediatric patients with type 1 diabetes using an artificial pancreas. Diabetes Care 2008; 31:934.

64. Hovorka R, Allen JM, Elleri D, et al. Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial. Lancet 2010; 375:743.

65. Russell SJ, El-Khatib FH, Sinha M, et al. Outpatient glycemic control with a bionic pancreas in type 1 diabetes. N Engl J Med 2014; 371:313.

66. Russell SJ, Hillard MA, Balliro C, et al. Day and night glycaemic control with a bionic pancreas versus conventional insulin pump therapy in preadolescent children with type 1 diabetes: a randomised crossover trial. Lancet Diabetes Endocrinol 2016; 4:233.

67. Pańkowska E, Szypowska A, Lipka M, et al. Application of novel dual wave meal bolus and its impact on glycated hemoglobin A1c level in children with type 1 diabetes. Pediatr Diabetes 2009; 10:298.

68. Chase HP, Saib SZ, MacKenzie T, et al. Post-prandial glucose excursions following four methods of bolus insulin administration in subjects with type 1 diabetes. Diabet Med 2002; 19:317.

69. Amiel SA, Sherwin RS, Simonson DC, et al. Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes. N Engl J Med 1986; 315:215.

70. Colino E, Álvarez MÁ, Carcavilla A, et al. Insulin dose adjustment when changing from multiple daily injections to continuous subcutaneous insulin infusion in the pediatric age group. Acta Diabetol 2010; 47 Suppl 1:1.

# data[].attributes.attachment_link.title
Insulin therapy for children and adolescents with type 1 diabetes mellitus - UpToDate

# data[].attributes.attachment_link.description
Insulin therapy is the mainstay of treatment for type 1 diabetes mellitus (T1DM). The goal of insulin therapy is to replace the deficient hormone and attain normoglycemia.

# data[].attributes.attachment_link.readable_text
doi: 10.1586/14779072.6.3.323.

Affiliation

¹ Department of Endocrinology & Metabolism, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. s.h.meeuwisse@int.umcg.nl

doi: 10.1586/14779072.6.3.323.

Affiliation

¹ Department of Endocrinology & Metabolism, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. s.h.meeuwisse@int.umcg.nl

Abstract

Type 2 diabetes mellitus is a disease that affects a rapidly increasing number of patients. Most patients with Type 2 diabetes will develop vascular complications. This may be microvascular disease, such as nephropathy, retinopathy or polyneuropathy, and also macrovascular disease, such as coronary heart disease, stroke or peripheral artery disease. Optimal control of elevated blood glucose levels will reduce the symptoms of hyperglycemia and help to prevent the development of complications. In addition, treatment of hypertension and lipid disturbances has been shown to reduce the incidence and severity of vascular complications significantly. The current treatment goals focus on adequate and aggressive treatment of these three risk factors. The central dogma for treatment of blood glucose, blood pressure and cholesterol levels is 'the lower the better'. Ongoing trials evaluate the effect of further lowering these treatment goals and of specific types of medication on cardiovascular events.

# data[].attributes.attachment_link.keywords[]
diabetic angiopathies / prevention & control*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Type 2 diabetes mellitus: prevention of macrovascular complications - PubMed

# data[].attributes.attachment_link.description
Type 2 diabetes mellitus is a disease that affects a rapidly increasing number of patients. Most patients with Type 2 diabetes will develop vascular complications. This may be microvascular disease, such as nephropathy, retinopathy or polyneuropathy, and also macrovascular disease, such as coronary ...

# data[].attributes.attachment_link.title
Pharmacology - DRUGS FOR DIABETES (MADE EASY)

# data[].attributes.attachment_link.readable_text
Highlights

*

Microvascular complications in patients with diabetes are present non only in eyes, kidneys, and nerves, but also in other organs such as the heart.

*

The concerted action of several processes concur to the pathogenesis of microvascular complications in diabetes.

*

The presence of any retinopathy and DME confer an increased cardiovascular risk.

*

Microvascular complications are responsible for coronary plaque instability.

*

The use of glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporters inhibitors should be considered to reduce CV events.

Abstract

Randomized, cross-sectional, and prospective studies have demonstrated that microvascular complications in patients with diabetes are not only the cause of blindness, renal failure and non-traumatic amputations, but also powerful predictors of cardiovascular complications. Beside the metabolic theory, the pathophysiology of diabetic microvascular complications is determined by the interaction among several factors, including epigenetic modifications and the reduced release of progenitor cells by the bone marrow, that contribute simultaneously to damage and impaired vascular protection against hyperglycemia. Identifying and preventing microvascular complications has the significant potential to reduce major adverse cardiovascular events. For these reasons, there may no longer be a rational to consider microangiopathy and macroangiopathy as entirely separate entities, but they should most likely be viewed as a continuum of the widespread vascular damage determined by diabetes mellitus.

View full text

# data[].attributes.attachment_link.title
Microvascular complications in diabetes: A growing concern for cardiologists

# data[].attributes.attachment_link.description
Microvascular complications in patients with diabetes are present non only in eyes, kidneys, and nerves, but also in other organs such as the heart. * The concerted action of several processes concur to the pathogenesis of microvascular complications in diabetes. * The presence of any retinopathy and DME confer an increased cardiovascular risk.

# data[].attributes.attachment_link.readable_text
Overview

What is type 1 diabetes? A Mayo Clinic expert explains

Learn more about type 1 diabetes from endocrinologist Yogish Kudva, M.B.B.S.

I'm Dr. Yogish C. Kudva an endocrinologist at Mayo Clinic. In this video, we'll cover the basics of type 1 diabetes. What is it? Who gets it? The symptoms, diagnosis, and treatment. Whether you're looking for answers for yourself or someone you love. We are here to give you the best information available. Type 1 diabetes is a chronic condition that affects the insulin making cells of the pancreas. It's estimated that about 1.25 million Americans live with it. People with type 1 diabetes don't make enough insulin. An important hormone produced by the pancreas. Insulin allows your cells to store sugar or glucose and fat and produce energy. Unfortunately, there is no known cure. But treatment can prevent complications and also improve everyday life for patients with type 1 diabetes. Lots of people with type 1 diabetes live a full life. And the more we learn and develop treatment for the disorder, the better the outcome.

We don't know what exactly causes type 1 diabetes. We believe that it is an auto-immune disorder where the body mistakenly destroys insulin producing cells in the pancreas. Typically, the pancreas secretes insulin into the bloodstream. The insulin circulates, letting sugar enter your cells. This sugar or glucose, is the main source of energy for cells in the brain, muscle cells, and other tissues. However, once most insulin producing cells are destroyed, the pancreas can't produce enough insulin, meaning the glucose can't enter the cells, resulting in an excess of blood sugar floating in the bloodstream. This can cause life-threatening complications. And this condition is called diabetic ketoacidosis. Although we don't know what causes it, we do know certain factors can contribute to the onset of type 1 diabetes. Family history. Anyone with a parent or sibling with type 1 diabetes has a slightly increased risk of developing it. Genetics. The presence of certain genes can also indicate an increased risk. Geography. Type 1 diabetes becomes more common as you travel away from the equator. Age, although it can occur at any age there are two noticeable peaks. The first occurs in children between four and seven years of age and the second is between 10 and 14 years old.

Signs and symptoms of type 1 diabetes can appear rather suddenly, especially in children. They may include increased thirst, frequent urination, bed wetting in children who previously didn't wet the bed. Extreme hunger, unintended weight loss, fatigue and weakness, blurred vision, irritability, and other mood changes. If you or your child are experiencing any of these symptoms, you should talk to your doctor.

The best way to determine if you have type 1 diabetes is a blood test. There are different methods such as an A1C test, a random blood sugar test, or a fasting blood sugar test. They are all effective and your doctor can help determine what's appropriate for you. If you are diagnosed with diabetes, your doctor may order additional tests to check for antibodies that are common in type 1 diabetes in the test called C-peptide, which measures the amount of insulin produced when checked simultaneously with a fasting glucose. These tests can help distinguish between type 1 and type 2 diabetes when a diagnosis is uncertain.

If you have been diagnosed with type 1 diabetes, you may be wondering what treatment looks like. It could mean taking insulin, counting carbohydrates, fat protein, and monitoring your glucose frequently, eating healthy foods, and exercising regularly to maintain a healthy weight. Generally, those with type 1 diabetes will need lifelong insulin therapy. There are many different types of insulin and more are being developed that are more efficient. And what you may take may change. Again, your doctor will help you navigate what's right for you. A significant advance in treatment from the last several years has been the development and availability of continuous glucose monitoring and insulin pumps that automatically adjust insulin working with the continuous glucose monitor. This type of treatment is the best treatment at this time for type 1 diabetes. This is an exciting time for patients and for physicians that are keen to develop, prescribe such therapies. Surgery is another option. A successful pancreas transplant can erase the need for additional insulin. However, transplants aren't always available, not successful and the procedure can pose serious risks. Sometimes it may outweigh the dangers of diabetes itself. So transplants are often reserved for those with very difficult to manage conditions. A successful transplant can bring life transforming results. However, surgery is always a serious endeavor and requires ample research and concentration from you, your family, and your medical team.

The fact that we don't know what causes type 1 diabetes can be alarming. The fact that we don't have a cure for it even more so. But with the right doctor, medical team and treatment, type 1 diabetes can be managed. So those who live with it can get on living. If you would like to learn even more about type 1 diabetes, watch our other related videos or visit mayoclinic.org. We wish you well.

Type 1 diabetes, once known as juvenile diabetes or insulin-dependent diabetes, is a chronic condition. In this condition, the pancreas makes little or no insulin. Insulin is a hormone the body uses to allow sugar (glucose) to enter cells to produce energy.

Different factors, such as genetics and some viruses, may cause type 1 diabetes. Although type 1 diabetes usually appears during childhood or adolescence, it can develop in adults.

Even after a lot of research, type 1 diabetes has no cure. Treatment is directed toward managing the amount of sugar in the blood using insulin, diet and lifestyle to prevent complications.

Symptoms

Type 1 diabetes symptoms can appear suddenly and may include:

Feeling more thirsty than usual

Urinating a lot

Bed-wetting in children who have never wet the bed during the night

Feeling very hungry

Losing weight without trying

Feeling irritable or having other mood changes

Feeling tired and weak

Having blurry vision

When to see a doctor

Talk to your health care provider if you notice any of the above symptoms in you or your child.

Causes

The exact cause of type 1 diabetes is unknown. Usually, the body's own immune system - which normally fights harmful bacteria and viruses - destroys the insulin-producing (islet) cells in the pancreas. Other possible causes include:

Genetics

Exposure to viruses and other environmental factors

The role of insulin

Once a large number of islet cells are destroyed, the body will produce little or no insulin. Insulin is a hormone that comes from a gland behind and below the stomach (pancreas).

The pancreas puts insulin into the bloodstream.

Insulin travels through the body, allowing sugar to enter the cells.

Insulin lowers the amount of sugar in the bloodstream.

As the blood sugar level drops, the pancreas puts less insulin into the bloodstream.

The role of glucose

Glucose - a sugar - is a main source of energy for the cells that make up muscles and other tissues.

Glucose comes from two major sources: food and the liver.

Sugar is absorbed into the bloodstream, where it enters cells with the help of insulin.

The liver stores glucose in the form of glycogen.

When glucose levels are low, such as when you haven't eaten in a while, the liver breaks down the stored glycogen into glucose. This keeps glucose levels within a typical range.

In type 1 diabetes, there's no insulin to let glucose into the cells. Because of this, sugar builds up in the bloodstream. This can cause life-threatening complications.

Risk factors

Some factors that can raise your risk for type 1 diabetes include:

Family history. Anyone with a parent or sibling with type 1 diabetes has a slightly higher risk of developing the condition.

Genetics. Having certain genes increases the risk of developing type 1 diabetes.

Geography. The number of people who have type 1 diabetes tends to be higher as you travel away from the equator.

Age. Type 1 diabetes can appear at any age, but it appears at two noticeable peaks. The first peak occurs in children between 4 and 7 years old. The second is in children between 10 and 14 years old.

Complications

Over time, type 1 diabetes complications can affect major organs in the body. These organs include the heart, blood vessels, nerves, eyes and kidneys. Having a normal blood sugar level can lower the risk of many complications.

Diabetes complications can lead to disabilities or even threaten your life.

Heart and blood vessel disease. Diabetes increases the risk of some problems with the heart and blood vessels. These include coronary artery disease with chest pain (angina), heart attack, stroke, narrowing of the arteries (atherosclerosis) and high blood pressure.

Nerve damage (neuropathy). Too much sugar in the blood can injure the walls of the tiny blood vessels (capillaries) that feed the nerves. This is especially true in the legs. This can cause tingling, numbness, burning or pain. This usually begins at the tips of the toes or fingers and spreads upward. Poorly controlled blood sugar could cause you to lose all sense of feeling in the affected limbs over time.

Damage to the nerves that affect the digestive system can cause problems with nausea, vomiting, diarrhea or constipation. For men, erectile dysfunction may be an issue.

Kidney damage (nephropathy). The kidneys have millions of tiny blood vessels that keep waste from entering the blood. Diabetes can damage this system. Severe damage can lead to kidney failure or end-stage kidney disease that can't be reversed. End-stage kidney disease needs to be treated with mechanical filtering of the kidneys (dialysis) or a kidney transplant.

Eye damage. Diabetes can damage the blood vessels in the retina (part of the eye that senses light) (diabetic retinopathy). This could cause blindness. Diabetes also increases the risk of other serious vision conditions, such as cataracts and glaucoma.

Foot damage. Nerve damage in the feet or poor blood flow to the feet increases the risk of some foot complications. Left untreated, cuts and blisters can become serious infections. These infections may need to be treated with toe, foot or leg removal (amputation).

Skin and mouth conditions. Diabetes may leave you more prone to infections of the skin and mouth. These include bacterial and fungal infections. Gum disease and dry mouth also are more likely.

Pregnancy complications. High blood sugar levels can be dangerous for both the parent and the baby. The risk of miscarriage, stillbirth and birth defects increases when diabetes isn't well-controlled. For the parent, diabetes increases the risk of diabetic ketoacidosis, diabetic eye problems (retinopathy), pregnancy-induced high blood pressure and preeclampsia.

Prevention

There's no known way to prevent type 1 diabetes. But researchers are working on preventing the disease or further damage of the islet cells in people who are newly diagnosed.

Ask your provider if you might be eligible for one of these clinical trials. It is important to carefully weigh the risks and benefits of any treatment available in a trial.

Show references

1. Summary of revisions: Standards of medical care in diabetes - 2022. Diabetes Care. 2022; doi:10.2337/dc22-Srev.

2. Papadakis MA, et al., eds. Diabetes mellitus. In: Current Medical Diagnosis & Treatment 2022. 61st ed. McGraw Hill; 2022. https://accessmedicine.mhmedical.com. Accessed May 4, 2022.

3. What is diabetes? National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes. Accessed May 4, 2022.

4. Levitsky LL, et al. Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents. https://www.uptodate.com/contents/search. Accessed May 4, 2022.

5. Diabetes mellitus (DM). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm. Accessed May 4, 2022.

6. AskMayoExpert. Type 1 diabetes mellitus. Mayo Clinic; 2021.

7. Robertson RP. Pancreas and islet transplantation in diabetes mellitus. https://www.uptodate.com/contents/search. Accessed May 4, 2022.

8. Levitsky LL, et al. Management of type 1 diabetes mellitus in children during illness, procedures, school, or travel. https://www.uptodate.com/contents/search. Accessed May 4, 2022.

9. Hyperglycemia (high blood glucose). American Diabetes Association. https://www.diabetes.org/healthy-living/medication-treatments/blood-glucose-testing-and-control/hyperglycemia. Accessed May 4, 2022.

10. Diabetes and DKA (ketoacidosis). American Diabetes Association. https://www.diabetes.org/diabetes/dka-ketoacidosis-ketones. Accessed May 4, 2022.

11. Insulin resistance & prediabetes. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/prediabetes-insulin-resistance. Accessed May 4, 2022.

12. Blood sugar and insulin at work. American Diabetes Association. https://www.diabetes.org/tools-support/diabetes-prevention/high-blood-sugar. Accessed May 4, 2022.

13. Inzucchi SE, et al. Glycemic control and vascular complications in type 1 diabetes. https://www.uptodate.com/contents/search. Accessed May 4, 2022.

14. Diabetes and oral health. American Diabetes Association. https://www.diabetes.org/diabetes/keeping-your-mouth-healthy. Accessed May 4, 2022.

15. Drug treatment of diabetes mellitus. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/drug-treatment-of-diabetes-mellitus. Accessed May 4, 2022.

16. Weinstock DK, et al. Management of blood glucose in adults with type 1 diabetes mellitus. https://www.uptodate.com/contents/search. Accessed May 7, 2022.

17. FDA proves first automated insulin delivery device for type 1 diabetes. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-automated-insulin-delivery-device-type-1-diabetes. Accessed May 4, 2022.

18. Boughton CK, et al. Advances in artificial pancreas systems. Science Translational Medicine. 2019; doi:10.1126/scitranslmed.aaw4949.

19. Hypoglycemia (low blood sugar). American Diabetes Association. https://www.diabetes.org/healthy-living/medication-treatments/blood-glucose-testing-and-control/hypoglycemia. Accessed May 4, 2022.

20. Diabetes in the workplace and the ADA. U.S. Equal Opportunity Employment Commission. https://www.eeoc.gov/laws/guidance/diabetes-workplace-and-ada. Accessed May 4, 2022.

21. Cardiovascular disease and risk management: Standards of medical care in diabetes - 2022. Diabetes Care. 2022; doi:10.2337/dc22-S010.

22. Diabetes technology. Standards of Medical Care in Diabetes - 2022. 2022; doi:10.2337/dc22-S007.

23. FDA authorizes a second artificial pancreas system. JDRF. https://www.jdrf.org/blog/2019/12/13/jdrf-reports-fda-authorizes-second-artificial-pancreas-system/. Accessed May 4, 2022.

24. Classification and diagnosis of diabetes: Standards of medical care in diabetes - 2022. Diabetes Care. 2022; doi:10.2337/dc22-S002.

25. Retinopathy, neuropathy, and foot care: Standards of medical care in diabetes - 2022. Diabetes Care. 2022; doi:10.2337/dc22-S012.

26. Glycemic targets: Standards of medical care in diabetes - 2022. Diabetes Care. 2022; doi:10.2337/dc22-S012.

27. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes - 2022. Diabetes Care. 2022; doi:10.2337/dc22-S009.

28. Facilitating behavior change and well-being to improve health outcomes: Standards of medical care in diabetes - 2022. Diabetes Care. 2022; doi:10.2337/dc22-S005.

29. Centers for Disease Control and Prevention. Use of hepatitis B vaccination for adults with diabetes mellitus: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report. 2011;60:1709.

30. Management of diabetes in pregnancy: Standards of medical care in diabetes - 2022. Diabetes Care. 2022; doi:10.2337/dc22-S015.

31. Older adults: Standards of medical care in diabetes - 2022. Diabetes Care. 2022; doi:10.2337/dc22-S013.

32. FDA approves first-of-its-kind automated insulin delivery and monitoring system for use in young pediatric patients. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-automated-insulin-delivery-and-monitoring-system-use-young-pediatric#:~:text=Today, the U.S. Food and,by individuals aged 2 to. Accessed May 8, 2022.

33. What you need to know: Getting a COVID-19 vaccine. American Diabetes Association. https://www.diabetes.org/coronavirus-covid-19/vaccination-guide. Accessed June 1, 2022.

# data[].attributes.attachment_link.description
Learn about the symptoms, causes, treatment of this chronic condition in which the pancreas produces little or no insulin.

# data[].attributes.body
https://www.ncbi.nlm.nih.gov/books/NBK279175/

# data[].attributes.attachment_link.readable_text
Diabetes increases your risk for many serious health problems. The good news? With the correct treatment and recommended lifestyle changes, many people with diabetes are able to prevent or delay the onset of complications.

Skin complications

Stay alert for symptoms of skin infections and other skin disorders common in people with diabetes.

Eye complications

Keep your risk of glaucoma, cataracts and other eye problems low with regular checkups.

Neuropathy

Nerve damage from diabetes is called diabetic neuropathy (new-ROP-uh-thee). About half of all people with diabetes have some form of nerve damage.

Foot complications

Learn about neuropathy (which can cause numbness in the feet) as well as other complications.

DKA (ketoacidosis) & ketones

Know the warning signs of DKA and check urine for ketones, especially when you're sick.

Kidney disease (nephropathy)

Keep your diabetes and blood pressure under control to lower the chance of getting kidney disease.

High blood pressure

High blood pressure-also called hypertension-raises your risk for heart attack, stroke, eye problems, and kidney disease.

Stroke

Maintain target levels for blood glucose, blood pressure, and cholesterol to reduce your risk of stroke.

# data[].attributes.attachment_link.description
Diabetes increases your risk for many serious health problems. The good news? With the correct treatment and recommended lifestyle changes, many people with diabetes are able to prevent or delay the onset of complications. Stay alert for symptoms of skin infections and other skin disorders common in people with diabetes.

# data[].attributes.attachment_link.provider_name
Centers for Disease Control and Prevention

# data[].attributes.attachment_link.readable_text
Diabetic ketoacidosis (DKA) is a serious complication of diabetes that can be life-threatening. DKA is most common among people with type 1 diabetes. People with type 2 diabetes can also develop DKA.

DKA develops when your body doesn't have enough insulin to allow blood sugar into your cells for use as energy. Instead, your liver breaks down fat for fuel, a process that produces acids called ketones. When too many ketones are produced too fast, they can build up to dangerous levels in your body.

Read on to learn more about DKA, how you can prevent DKA, and how to treat it if needed.

DKA Signs and Symptoms

DKA usually develops slowly. Early symptoms include:

Being very thirsty.

Urinating a lot more than usual.

If untreated, more severe symptoms can appear quickly, such as:

Fast, deep breathing.

Dry skin and mouth.

Flushed face.

Fruity-smelling breath.

Headache.

Muscle stiffness or aches.

Being very tired.

Nausea and vomiting.

Stomach pain.

Sometimes DKA is the first sign of diabetes in people who haven't yet been diagnosed.

Causes of DKA

Very high blood sugar and low insulin levels lead to DKA. The two most common causes are:

Illness. When you get sick, you may not be able to eat or drink as much as usual, which can make blood sugar levels hard to manage.

Missing insulin shots, a clogged insulin pump, or the wrong insulin dose.

Other causes of DKA include:

Heart attack or stroke.

Physical injury, such as from a car accident.

Alcohol or drug use.

Certain medicines, such as some diuretics (water pills) and corticosteroids (used to treat inflammation in the body).

Test for Ketones

Anytime you're sick or your blood sugar is 240 mg/dL or above, use an over-the-counter ketone test kit to check your urine or a meter to test your blood for ketones every 4 to 6 hours. You should also test for ketones if you have any of the symptoms of DKA. Call your doctor if your ketones are moderate or high. Elevated ketones are a sign of DKA, which is a medical emergency and needs to be treated immediately.

Go to the emergency room or call 911 right away if you can't get in touch with your doctor and are experiencing any of the following:

Your blood sugar stays at 300 mg/dL or above.

Your breath smells fruity.

You are vomiting and can't keep food or drinks down.

You're having trouble breathing.

You have multiple signs and symptoms of DKA.

Treatment for DKA

If you have DKA, you'll be treated in the emergency room or admitted to the hospital. Your treatment will likely include:

Replacing fluids you lost through frequent urination and to help dilute excess sugar in your blood.

Replacing electrolytes (minerals in your body that help your nerves, muscles, heart, and brain work the way they should). Too little insulin can lower your electrolyte levels.

Receiving insulin. Insulin reverses the conditions that cause DKA.

Taking medicines for any underlying illness that caused DKA, such as antibiotics for an infection.

Prevent DKA

DKA is a serious condition, but you can take steps to help prevent it:

Check your blood sugar often, especially if you're sick.

Keep your blood sugar levels in your target range as much as possible.

Take medicines as prescribed, even if you feel fine.

Talk to your doctor about how to adjust your insulin based on what you eat, how active you are, or if you're sick.

If you're concerned about DKA or have questions about how to manage your diabetes, be sure to meet with your diabetes care team and ask for a referral to diabetes self-management education and support (DSMES) services for individual guidance. DSMES services are a vital tool to help you manage and live well with diabetes while protecting your health.

# data[].attributes.attachment_link.description
Diabetic ketoacidosis (DKA) is a serious complication of diabetes that can be life-threatening. DKA is most common among people with type 1 diabetes. People with type 2 diabetes can also develop DKA. DKA develops when your body doesn't have enough insulin to allow blood sugar into your cells for use as energy.

# data[].attributes.attachment_link.authors[].name
Cynthia M. Ripsin|Helen Kang|Randall J. Urban

# data[].attributes.attachment_link.title
Management of Blood Glucose in Type 2 Diabetes Mellitus

# data[].attributes.attachment_link.description
Evidence-based guidelines for the treatment of type 2 diabetes mellitus focus on three areas: intensive lifestyle intervention that includes at least 150 minutes per week of physical activity, weight loss with an initial goal of 7 percent of baseline weight, and a low-fat, reduced-calorie diet; aggressive management of cardiovascular risk factors (i.e., hypertension, dyslipidemia, and microalbuminuria) with the use of aspirin, statins, and angiotensin-converting enzyme inhibitors; and normalization of blood glucose levels (hemoglobin A1C level less than 7 percent).

# data[].attributes.attachment_link.title
Is a functional cure for Type 1 Diabetes on the horizon? | Paul Laikind | TEDxSanDiegoSalon

# data[].attributes.body
Chiasson, J., Aris-Jilwan, N., Bélanger, R., Bertrand, S., Beauregard, H., Ekoé, J., Fournier, H., & Havrankova, J. (2003). Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state. Canadian Medical Association Journal (CMAJ), 168(7), 859-866.

# data[].attributes.attachment_link.readable_text
A Prophecy Fulfilled?

Last year, I reported on the highlights of the diabetic neuropathy reports presented at the 61st Scientific Sessions of the American Diabetes Association. I pointed out that the new buzzwords in neuropathy were "oxidative and nitrative stress," and that evidence had accrued that there was overproduction of reactive oxygen species (ROS) that were potentially harmful to nerve function. I also showed that the ROS could bind to nitric oxide (NO) -- an important vasodilator -- and convert it to peroxynitrite, culminating in depletion of NO and formation of yet another "toxic compound" (peroxynitrite) that could further cause nerve damage.

The prediction was that if we could find the ways and means of abrogating this process, we might be able to affect disease progression, or even slow it down sufficiently to allow the body to repair itself. At this year's meeting, this prophecy appeared to be fulfilled in part.

A Look Back

But before we explore where we are going, we should review where we have been. Dan Ziegler, MD, Heinrich Heine University, Dusseldorf, Germany, gave a lecture on the trials that have been conducted on neuropathy, showing in essence that all the agents that have had promise -- the aldose reductase inhibitors (ARIs), inhibitors of advanced glycation end products (AGEs), and the neurotrophic factors -- have either not worked or have shown some success but have proven to be hepato-, nephro- or dermatotoxic. This sense of gloom was relieved only by data from a Russian study supporting the notion that antioxidants, for example alpha lipoic acid, may be beneficial. Since there are 2 major ongoing studies on alpha lipoic acid in the United States, we await their results with bated breath.

The Role of Oxidative Stress

Pursuing the notion that oxidative stress at the mitochondrial level might be important, Irina Obrosova, PhD, University of Michigan, Ann Arbor, and colleagues examined the consequence of oxidative stress via poly ADP ribosylation, ie, transfer of NAD to nuclear protein by the enzyme poly ADP ribose synthetase (PARS). Inhibitors of this enzyme have been shown to improve nerve function in rats. In this study, the investigators showed that creation of transgenic animals deficient in PARS restored endothelial function, repleted the stores of the potent endogenous antioxidant GSH, and protected the animals from galactose-induced nerve damage.

The Role of Protein Kinase C (PKC) Beta

PKC beta is one type of the group of enzymes found in tissues that are targeted by diabetes complications, such as the nerve, kidney, and eye. Current theories of the pathogenesis of diabetic neuropathy suggest that activation of PKC beta may be key in the process that leads to microvascular dysfunction, impairment of endoneurial blood flow, and, ultimately, damage of nerves. While hyperglycemia may be the major stimulus to de novo synthesis of diacylglycerol (DAG), which in turn stimulates the activation of PKC beta, other factors, such as oxidative stress, accumulation of advanced glycation end products, and, possibly, other metabolites that are deranged in diabetes (eg, free fatty acids), may contribute.

Increased activity of PKC beta, is known to stimulate the actions of the potent vasoconstrictors endothelin and angiotensin and to decrease the actions of the vasodilators NO, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Figure 1 illustrates the mechanism whereby hyperglycemia via production of ROS from the mitochondria stimulates PKC beta, which depletes NADPH and enhances the formation of peroxynitrite by the combination of ROS with NO, thus reducing the bioavailability of NO. PKC beta also impairs endothelial function, increases permeability, activates a variety of factors that increase the tendency to vascular occlusion (eg, plasminogen-activator inhibitor-1 [PAI-1], platelets, and cell adhesion molecules), and stimulates the proliferation of smooth muscle cells, culminating in small-vessel occlusion.

Figure 1. Effect of glucose on bioavailability of nitric oxide. (Courtesy of Dr. Vinik.)

Identifying Treatable Patients

Vera Bril, MD, University Health Network, Toronto, Ontario, Canada, and colleagues reported that patients with early diabetic peripheral neuropathy, identified by vibration detection threshold (VDT) and electrophysiology testing, appear to be the group of patients most responsive to therapy. The investigators concluded that detectable sural nerve conduction, or sural nerve action potential (SNAP), identified an earlier degree of diabetic peripheral neuropathy and a greater likelihood of responding to therapy. In addition, the duration of neuropathy was identified as the only factor that might contribute to the difference in ability to detect SNAP ( P = .0043; odds ratio = 0.896). These findings should prove useful in the evaluation of novel agents, such as LY333531, for the treatment of diabetic neuropathy.

PKC Beta Inhibition in the Treatment of Diabetic Neuropathy

LY333531 is a specific inhibitor of PKC beta (Figure 2) currently undergoing phase 3 clinical trials. Several studies of this investigational agent in the treatment of neuropathy were presented at the ADA meeting.

Figure 2. PKC beta activation and action of LY333531. (Courtesy of Dr. Vinik.)

In a 1-year, double-blind, placebo-controlled, parallel trial, LY333531 treatment was found to improve diabetic peripheral neuropathy, as assessed by neurologic examination, objective measures of nerve function, and physician assessment. A total of 205 type 1 or 2 diabetes patients with diabetic peripheral neuropathy received either 32 mg of LY333531, 64 mg of LY333531, or placebo. Treatment with the 32-mg dose of LY333531 produced overall improvement in neurologic examination ( P = .076 vs placebo), most notably in the lower limbs ( P = .049 vs placebo) -- sites most affected by diabetic peripheral neuropathy -- and reflexes ( P = .033 vs placebo). Similar improvements in 2 composite scores, which include components of the neurologic exam and electrophysiologic and quantitative sensory tests, were seen in the 32-mg LY333531 group ( P = .046 and 0.72 for the 2 composite scores vs placebo). Investigator global assessment of patient improvement corroborated these findings.

There were no significant differences in clinical improvement between patients receiving 64-mg of LY333531 and placebo. However, people receiving the lower dose had milder neuropathy of shorter duration than patients receiving the higher dose. When subsets of the entire population who had milder neuropathy were evaluated, both doses were effective (see below). Indeed, these preliminary observations have helped design the phase 3 study.

Of the 205 patients in the study, only 3 withdrew, 1 from the placebo group and 1 each from the 32-mg and 64-mg dose groups. The most common side effect was diarrhea, but in general the drug was well tolerated. There were no effects on glycemic control or hepatic, renal, or bone marrow function.

In an abstract that presented other data from the same study,, Aaron I. Vinik, MD, PhD, Eastern Virginia Medical School, Norfolk, Virginia, and colleagues reported that LY333531 improved the symptoms of diabetic peripheral neuropathy and vibratory sensation (Figure 3). The Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire was used to measure symptomatic improvement in 83 patients. The NTSS-6 measures the frequency and intensity of 6 diabetic peripheral neuropathy symptoms: numbness, allodynia, prickling, and 3 types of pain (aching, burning, and lancinating). Previously used instruments to measure the symptoms of diabetic peripheral neuropathy focused on only 4 symptoms: pain, burning, numbness, and prickling. The addition of 2 more symptoms to the NTSS-6 is believed to produce a more thorough assessment.

Figure 3. Improvements in NTSS-6. (Courtesy of Dr. Vinik.)

Patients in both LY333531 dose groups (32 mg and 64 mg) had improvements in NTSS-6 scores (Figure 3) compared with placebo ( P = .064 for 32 mg; P = .014 for 64 mg). In a subset of 49 patients with early diabetic peripheral neuropathy and symptoms, a significant change in VDT was noted in the 32-mg LY333531 group ( P = .006 vs placebo) and in the 64-mg group ( P = .028 vs placebo). The change in VDT in this subset correlated with improvement in the NTSS-6.

The investigators concluded that the NTSS-6 is a valid instrument to characterize and follow changes in neuropathic symptoms. This conclusion was supported by tests that assessed the reliability and validity of the NTSS-6, as well as correlations with neurologic examination. Significant correlations were observed between change in NTSS-6 score and changes in assessed neurologic parameters.

References

1. Vinik AI. Diabetic neuropathy: a small fiber disease. Medscape Conference Coverage: 61st Scientific Sessions of the American Diabetes Association; June 22-26, 2001; Philadelphia, Pennsylvania. Available at:
http://www.medscape.com/viewarticle/418568. Accessed July 8, 2002.

2. Ziegler D. Neuropathy: recent and potential new treatments of microangiopathy including neuropathy. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association. June 14-18, 2002; San Francisco, California. Diabetes, Volume 51, Supplement 2.

3. Obrosova I, Li F, White L, et al. Poly (ADP-ribose) synthase-knockout mice are protected from functional and biochemical deficits associated with early diabetes-like neuropathy. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association. June 14-18, 2002; San Francisco, California. Abstract 316-OR. Diabetes, Volume 51, Supplement 2.

4. Litchy W, Dyck P, Tesfaye S, Zhang D, Bastyr E. Diabetic peripheral neuropathy (DPN) assessed by neurological examination (NE) and composite scores (CS) is improved with LY333531 treatment. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association. June 14-18, 2002; San Francisco, California. Poster 800-P. Diabetes, Volume 51, Supplement 2.

5. Vinik A, Tesfaye S, Zhang D, Bastyr E. LY333531 treatment improves diabetic peripheral neuropathy with symptoms. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association. June 14-18, 2002; San Francisco, California. Abstract 321-OR. Diabetes, Volume 51, Supplement 2.

6. Bril V, Vinik A, Litchy W, Zhang D, Bastyr E. Detectable sural nerve action potential (SNAP) identifies patients with early diabetic peripheral neuropathy. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association. June 14-18, 2002; San Francisco, California. Poster 799-P. Diabetes, Volume 51, Supplement 2.

# data[].attributes.attachment_link.title
New Developments in the Treatment of Neuropathy

# data[].attributes.attachment_link.description
Last year, I reported on the highlights of the diabetic neuropathy reports presented at the 61st Scientific Sessions of the American Diabetes Association. I pointed out that the new buzzwords in neuropathy were "oxidative and nitrative stress," and that evidence had accrued that there was overproduction of reactive oxygen species (ROS) that were potentially harmful to nerve function.

# data[].attributes.body
https://youtu.be/99KimaS6tTU

# data[].attributes.headline
Pathophysiology of hyperglycemia induced nerve damage.

# data[].attributes.subject
Pathophysiology of hyperglycemia induced nerve damage.

# data[].attributes.attachment_link.readable_text
Nerve damage from diabetes is called diabetic neuropathy (new-ROP-uh-thee). About half of all people with diabetes have some form of nerve damage. It is more common in those who have had the disease for a number of years and can lead to many kinds of problems.

If you keep your blood glucose levels on target, you may help prevent or delay nerve damage. If you already have nerve damage, this will help prevent or delay further damage. There are also other treatments that can help.

Peripheral neuropathy

Peripheral neuropathy can cause tingling, pain, numbness, or weakness in your feet and hands.

Autonomic neuropathy

Autonomic neuropathy affects the nerves in your body that control your body systems.

Additional types of neuropathy

Additional types of neuropathy people with diabetes may experience.

Steps to prevent or delay nerve damage

Take these steps to prevent or delay nerve damage.

# data[].attributes.attachment_link.description
Nerve damage from diabetes is called diabetic neuropathy (new-ROP-uh-thee). About half of all people with diabetes have some form of nerve damage. It is more common in those who have had the disease for a number of years and can lead to many kinds of problems. If you keep your blood glucose levels on target, you may help prevent or delay nerve damage.

# data[].attributes.attachment_link.title
Pathomechanisms of Type 2 Diabetes Genes

# data[].attributes.attachment_link.readable_text
Access options

Subscribe to Journal

Get full journal access for 1 year

$59.00

only $59.00 per issue

All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.

Rent or Buy article

Get time limited or full article access on ReadCube.

All prices are NET prices.

Additional access options:

References

1. 20
International Diabetes Federation. IDF Diabetes Atlas 6th Edition. IDF[online], (2013).

2. 89
Honka, H. et al. Validation of [ ¹⁸F]fluorodeoxyglucose and positron emission tomography (PET) for the measurement of intestinal metabolism in pigs, and evidence of intestinal insulin resistance in patients with morbid obesity. Diabetologia 56, 893-900 (2013).

3. 119
Choi, C. S. et al. Suppression of diacylglycerol acyltransferase-2 ( DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J. Biol. Chem. 282, 22678-22688 (2007).

4. 145
Nishimura, S. et al. CD8⁺ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914-920 (2009).

5. 182
World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. report of a WHO consultation. Part 1: diagnosis and classification of diabetes mellitus (WHO, 1999).

6. 212
[No authors listed.] Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 854-865 (1998).

7. 226
[No authors listed.] Takeda announces completion of the post-marketing commitment to submit data to the FDA, the EMA and the PMDA for pioglitazone containing medicines including ACTOS. Takeda[online], (2014).

8. 244
Richter, B., Bandeira-Echtler, E., Bergerhoff, K. & Lerch, C. L. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst. Rev. 2, CD006739 (2008).

Google Scholar

9. 281
Engel, S. S. Glycemic and lipid effects of the short-acting glucagon receptor antagonist MK-3577 in patients with type 2 diabetes. Diabetes Abstr. 61, A266 (2012).

Google Scholar

10. 303
Harrima, G., Greenwood, J. & Bhar, S. Acetyl-CoA carboxylase inhibition by NDI-630 inhibits fatty acid synthesis stimulates fatty acid oxidative, reduces body weight, improvise insulin sensitivity, and modulates dyslipidemia in rats. Diabetes Abstr. 62, A161 (2013).

Google Scholar

11. 310
Cellitti, S. A novel GLP-1-FGF21 fusion protein for the treatment of diabetes and obesity. Keystone Symp. Obes. (2014).

Download references

Acknowledgements

The authors acknowledge grants from: the South Texas Veterans Healthcare System to R.A.D.; the National Institutes of Health (grants R01DK24092 to R.A.D.; DK58845 and P30 DK46200 to F.B.H.; R01 DK-040936, R01 DK-049230, R24 DK-085836, UL1 RR-045935, R01 DK-082659 and R24 DK085610 to G.I.S.; P30 DK036836 to C.R.K. Novo Nordisk Foundation for Basic Metabolic Research and the University of Copenhagen to G.I.S. and C.R.K.; DVA-Merit Review grant and VA San Diego Healthcare System to R.H.; National Institute for Diabetes and Digestive and Kidney Disease (grant P30DK092926) to W.H.; the Swedish Research Council (grants 2010-3490 and 2008-6589) and European Council (grants GA269045) to L.G.; Italian Ministry of University & Research (MIUR 2010329EKE) to E.F.; the Patient-Centered Outcomes Research Institute (PCORI) Program Award (CE1304-6756) to D.C.S. and M.A.T.; NovoNordisk Foundation to the NNF Center for Basic Metabolic Research to J.H. W.H. acknowledges the Michigan Center for Diabetes Translational Research and I.R. thanks R. Sprung for editorial assistance.

Author information

Affiliations

1. Diabetes Division, Department of Medicine, University of Texas Health Science Center, South Texas Veterans Health Care System and Texas Diabetes Institute, 701 S. Zarzamoro, San Antonio, 78207, Texas, USA

Ralph A. DeFronzo

2. CNR Institute of Clinical Physiology, Pisa, Italy

Ele Ferrannini

3. Department of Clinical Science Malmoe, Diabetes & Endocrinology, Lund University Diabetes Centre, Lund, Sweden

Leif Groop

4. University of California, San Diego, Section of Diabetes, Endocrinology & Metabolism, Center for Metabolic Research, VA San Diego Healthcare System, San Diego, California, USA

Robert R. Henry

5. University of Michigan, Ann Arbor, Michigan, USA

William H. Herman

6. University of Copenhagen, Kobenhavn, Denmark

Jens Juul Holst

7. Department of Nutrition, Harvard T.H. Chan School of Public Health and Department of Epidemiology, Harvard T.H. Chan School of Public Health and Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Frank B. Hu

8. Harvard Medical School and Joslin Diabetes Center, Boston, Massachusetts, USA

C. Ronald Kahn

9. Division of Internal Medicine, Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel

Itamar Raz

10. Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA

Gerald I. Shulman

11. Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Donald C. Simonson

12. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA

Marcia A. Testa

13. Department of Human Metabolism and Nutrition, Braun School of Public Health, Hebrew University, Jerusalem, Israel

Ram Weiss

Contributions

Introduction (R.R.H.); Epidemiology (F.B.H.); Mechanisms/pathophysiology (L.C.G., C.R.K., E.F., G.I.S. and R.A.D.); Diagnosis, screening and prevention (W.H.H.); Management (R.A.D.); Quality of life (D.C.S. and M.A.T.); Outlook (I.R., J.J.H. and R.W.); overview of Primer (R.A.D.).

Corresponding author

Correspondence to Ralph A. DeFronzo.

Ethics declarations

Competing interests

The authors declare the following potential COI: (1) R.A.D.: Research Grant Support - AstraZeneca, Bristol Myers Squibb, Janssen; Speaker's Bureau - AstraZeneca, Novo Nordisk, Advisory Board/Consultant - AstraZeneca, Janssen, Novo Nordisk, Boehringer Ingelheim, Lexicon, Intarcia; (2) E.F.: Research Grant Support - Boehringer Ingelheim, Eli Lilly; Consultant/Speaker Bureau-Boehringer Ingelheim, Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Takeda, Medtronic, Intarcia; (3) C.R.K. serves as a consultant for Medimmune, Merck, Five Prime Therapeutics, CohBar, Antriabio, and Catabasis; (4) L.G. has no conflict of interest; (5) R.H. has received grant support from Hitachi, Janssen, Eli Lilly, Sanofi-Aventis and Viacyte and is a consultant/advisory board member for Alere, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clin Met, Eisai, Elcelyx, Gilead, Intarcia, Isis, Janssen, Merck, Novo Nordisk, Sanofi-Aventis, and Vivus; (6) W.H.H. has no conflict of interest; (7) J.J.H. has received grant support from Novartis and Merck and is a consultant/advisory board member for Glaxo, Smith, Kline, Novo Nordisk, and Zealand Pharmaceuticals; (8) M.A.T. has no conflict of interest; (9) R.W. serves as a consultant for Medtronics and Kamada and is on the speaker's bureau for Medtronics and Novo Nordisk; (10) F.H. has received research support from California Walnut Commission and Metegenics; (11) G.I.S. serves on scientific advisory boards for Merck and Novartis and he has received research grant support from Gilead Pharmaceuticals; (12) D.C.S. has no conflict of interest; (13) I.R. - Advisory Board: Novo Nordisk, Astra Zeneca/BMS, MSD, Eli Lilly, Sanofi, Medscape Cardiology; Consultant: Astra Zeneca/BMS, Insuline; Speaker's Bureau: Eli Lilly, Novo Nordisk, Astra Zeneca/BMS, J&J, Sanofi, MSD, Novartis, Teva; Shareholder: Insuline, Labstyle.

About this article

Cite this article

DeFronzo, R., Ferrannini, E., Groop, L. et al. Type 2 diabetes mellitus. Nat Rev Dis Primers 1, 15019 (2015). https://doi.org/10.1038/nrdp.2015.19
Download citation

Further reading

International Journal of Biological Macromolecules (2021)

Plants (2021)

Journal of Biomedical Informatics (2021)

PLOS ONE (2021)

# data[].attributes.attachment_link.description
Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome.

# data[].attributes.attachment_link.title
Diabetes Complication and Pathophysiology of the complication

# data[].attributes.body
Standards of Medical care in diabetes

# data[].attributes.attachment_link.readable_text
American Diabetes Association

The American Diabetes Association (ADA) Standards of Medical Care in Diabetes is updated and published annually in a supplement to the January issue of Diabetes Care. The Standards are developed by the ADA's multidisciplinary Professional Practice Committee, which comprises physicians, diabetes educators, and other expert diabetes health care professionals. The Standards include the most current evidence-based recommendations for diagnosing and treating adults and children with all forms of diabetes. ADA's grading system uses A, B, C, or E to show the evidence level that supports each recommendation.

A -Clear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered

B -Supportive evidence from well-conducted cohort studies

C -Supportive evidence from poorly controlled or uncontrolled studies

E -Expert consensus or clinical experience

This is an abridged version of the current Standards containing the evidence-based recommendations most pertinent to primary care. The recommendations tables and figures included here retain the same numbering used in the full Standards and so are not numbered sequentially. All of the recommendations included here are substantively the same as in the full Standards. The abridged version does not include references. The complete 2021 Standards of Care, including all supporting references, is available at professional.diabetes.org/standards.

1. Improving Care and Promoting Health in Populations

Diabetes and Population Health

Clinical practice recommendations can improve health across populations; however, for optimal outcomes, diabetes care must also be individualized for each patient. Thus, efforts to improve population health will require a combination of policy-level, system-level, and patient-level approaches. Patient-centered care is defined as care that considers individual patient comorbidities and prognoses; is respectful of and responsive to patient preferences, needs, and values; and ensures that patient values guide all clinical decisions. Further, social determinants of health (SDOH)-often out of direct control of the individual and potentially representing lifelong risk-contribute to medical and psychosocial outcomes and must be addressed to improve all health outcomes.

Six Core Elements

The CCM includes six core elements to optimize the care of patients with chronic disease:

1. Delivery system design (moving from a reactive to a proactive care delivery system where planned visits are coordinated through a team-based approach)

2. Self-management support

3. Decision support (basing care on evidence-based, effective care guidelines)

4. Clinical information systems (using registries that can provide patient-specific and population-based support to the care team)

5. Community resources and policies (identifying or developing resources to support healthy lifestyles)

6. Health systems (to create a quality-oriented culture)

Strategies for System-Level Improvement

Care Teams

Collaborative, multidisciplinary teams are best suited to provide care for people with chronic conditions such as diabetes and to facilitate patients' self-management. The care team should avoid therapeutic inertia and prioritize timely and appropriate intensification of lifestyle and/or pharmacologic therapy for patients who have not achieved the recommended metabolic targets.

Telemedicine

Telemedicine is a growing field that may increase access to care for patients with diabetes. Increasingly, evidence suggests that various telemedicine modalities may be effective at reducing A1C in patients with type 2 diabetes compared with usual care or in addition to usual care.

Behaviors and Well-Being

Successful diabetes care also requires a systematic approach to supporting patients' behavior-change efforts, including high-quality diabetes self-management education and support (DSMES).

2. Classification and Diagnosis of Diabetes

Classification

Diabetes can be classified into the following general categories:

1. Type 1 diabetes (due to autoimmune β-cell destruction, usually leading to absolute insulin deficiency, including latent autoimmune diabetes of adulthood)

2. Type 2 diabetes (due to a progressive loss of β-cell insulin secretion frequently on the background of insulin resistance)

3. Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young), diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), and drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS, or after organ transplantation)

4. Gestational diabetes mellitus (GDM; diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation)

It is important for providers to realize that classification of diabetes type is not always straightforward at presentation, and misdiagnosis may occur. ​ Children with type 1 diabetes typically present with polyuria/polydipsia, and approximately one-third present with diabetic ketoacidosis (DKA). Adults with type 1 diabetes may not present with classic symptoms and may have a temporary remission from the need for insulin. The diagnosis may become more obvious over time and should be reevaluated if there is concern.

Screening and Diagnostic Tests for Prediabetes and Type 2 Diabetes

The diagnostic criteria for diabetes and prediabetes are shown in Table 2.2/2.5. Screening criteria are listed in Table 2.3.

3. Prevention or Delay of Type 2 Diabetes

Pharmacologic Interventions

Recommendation

3.6 Metformin therapy for prevention of type 2 diabetes should be considered in those with prediabetes, especially for those with BMI ≥35 kg/m ², those aged <60 years, and women with prior GDM. A

Metformin has the strongest evidence base and demonstrated long-term safety as a pharmacologic therapy for diabetes prevention. Other medications have been studied; no pharmacologic agent has been approved by the U.S. Food and Drug Administration (FDA) specifically for diabetes prevention.

Prevention of Vascular Disease and Mortality

4. Comprehensive Medical Evaluation and Assessment of Comorbidities

Patient-Centered Collaborative Care

A successful medical evaluation depends on beneficial interactions between the patient and a coordinated interdisciplinary team. Individuals with diabetes must assume an active role in their care. The patient, family or support people, physicians, and health care team should together formulate the management plan, which includes lifestyle management.

The goals of treatment for diabetes are to prevent or delay complications and optimize quality of life ( Figure 4.1). Treatment goals and plans should be created with patients based on their individual preferences, values, and goals.

Recommendations

The use of empowering language can help to inform and motivate people, yet language that shames and judges may undermine this effort.

Use language that is neutral, nonjudgmental, and based on facts, actions, or physiology/biology.

Use language free from stigma.

Use language that is strength based, respectful, and inclusive and that imparts hope.

Use language that fosters collaboration between patients and providers.

Use language that is person centered (e.g., "person with diabetes" is preferred over "diabetic").

Comprehensive Medical Evaluation

Recommendations

* Confirm the diagnosis and classify diabetes. A

* Evaluate for diabetes complications and potential comorbid conditions. A

* Review previous treatment and risk factor control in patients with established diabetes. A

* Begin patient engagement in the formulation of a care management plan. A

* Develop a plan for continuing care. A

Immunizations

The importance of routine vaccinations for people living with diabetes has been elevated by the coronavirus disease 2019 (COVID-19) pandemic. Preventing avoidable infections not only directly prevents morbidity but also reduces hospitalizations, which may additionally reduce risk of acquiring infections such as COVID-19. Children and adults with diabetes should receive vaccinations according to age-appropriate recommendations.

Assessment of Comorbidities

Cognitive Impairment/Dementia

See "12. OLDER ADULTS."

Nonalcoholic Fatty Liver Disease

Cancer

Patients with diabetes should be encouraged to undergo recommended age- and sex-appropriate cancer screenings and to reduce their modifiable cancer risk factors (obesity, physical inactivity, and smoking).

5. Facilitating Behavior Change and Well-Being to Improve Health Outcomes

Effective behavior management and psychological well-being are foundational to achieving treatment goals for people with diabetes. Essential to achieving these goals are DSMES, medical nutrition therapy (MNT), routine physical activity, smoking cessation counseling when needed, and psychosocial care.

DSMES

MNT

All providers should refer people with diabetes for individualized MNT provided by a registered dietitian nutritionist (RD/RDN) who is knowledgeable and skilled in providing diabetes-specific MNT at diagnosis and as needed throughout the life span, similar to DSMES. MNT delivered by an RD/RDN is associated with A1C absolute decreases of 1.0-1.9% for people with type 1 diabetes and 0.3 - 2.0% for people with type 2 diabetes.

Eating Patterns and Meal Planning

Evidence suggests that there is not an ideal percentage of calories from carbohydrate, protein, and fat for people with diabetes. Therefore, macronutrient distribution should be based on an individualized assessment of current eating patterns, personal preferences (e.g., tradition, culture, religion, health beliefs and goals, and economics), and metabolic goals.

Weight Management

Lifestyle intervention programs should be intensive and have frequent follow-up to achieve significant reductions in excess body weight and improve clinical indicators.

For many individuals with overweight and obesity with type 2 diabetes, 5% weight loss is needed to achieve beneficial outcomes in glycemic control, lipids, and blood pressure. The clinical benefits of weight loss are progressive, and more intensive weight-loss goals (i.e., 15%) may be appropriate to maximize benefit depending on need, feasibility, and safety.

Physical Activity

Exercise in the Presence of Microvascular Complications

Retinopathy

If proliferative diabetic retinopathy or severe nonproliferative diabetic retinopathy is present, then vigorous-intensity aerobic or resistance exercise may be contraindicated because of the risk of triggering vitreous hemorrhage or retinal detachment. Consultation with an ophthalmologist prior to engaging in an intense exercise regimen may be appropriate.

Peripheral Neuropathy

Decreased pain sensation and a higher pain threshold in the extremities can result in an increased risk of skin breakdown, infection, and Charcot joint destruction with some forms of exercise. All individuals with peripheral neuropathy should wear proper footwear and examine their feet daily to detect lesions early. Anyone with a foot injury or open sore should be restricted to non-weight-bearing activities.

Autonomic Neuropathy

Individuals with diabetic autonomic neuropathy should undergo cardiac investigation before beginning physical activity more intense than that to which they are accustomed.

Diabetic Kidney Disease

Physical activity can acutely increase urinary albumin excretion. However, there is no evidence that vigorous-intensity exercise accelerates the rate of progression of diabetic kidney disease (DKD), and there appears to be no need for specific exercise restrictions for people with DKD in general.

Smoking Cessation: Tobacco and E-Cigarettes

6. Glycemic Targets

Assessment of Glycemic Control

Glycemic control is assessed by the A1C measurement, continuous glucose monitoring (CGM), and self-monitoring of blood glucose (SMBG). Clinical trials primarily use A1C as the metric to demonstrate the benefits of improved glycemic control. CGM serves an important role in assessing the effectiveness and safety of treatment in many patients with type 1 diabetes, including prevention of hypoglycemia, and in patients with type 2 diabetes on intensive insulin regimens and with hypoglycemia. Patient SMBG can be used with self-management and medication adjustment, particularly in individuals taking insulin.

Glycemic Assessment

Glucose Assessment by CGM

Recommendations

For many people with diabetes, glucose monitoring is key for achieving glycemic targets. It allows patients to evaluate their individual response to therapy and assess whether glycemic targets are being safely achieved.

CGM technology has grown rapidly and is more accessible and accurate. The Glucose Management Indicator (GMI) and data on TIR, hypoglycemia, and hyperglycemia are available to providers and patients via standardized reports such as the AGP ( Figure 6.1). Visual cues and recommendations are offered to assist in data interpretation and treatment decision-making.

Glycemic Goals

Recommendations

Reassess glycemic targets over time based on patient and disease factors. (See Figure 6.2 and Table 12.1 in the complete 2021 Standards of Care.) Table 6.3 summarizes glycemic recommendations for many nonpregnant adults. For specific guidance, see "6. Glycemic Targets," "13. Children and Adolescents," and "14. Management of Diabetes in Pregnancy" in the complete 2021 Standards of Care.

Hypoglycemia

The classification of hypoglycemia level is defined in Table 6.4.

7. Diabetes Technology

Diabetes technology describes the devices, software, and hardware used to manage diabetes. It includes delivery systems such as insulin pumps, pens, and syringes as well as CGM devices and glucose meters. Newer forms of diabetes technology include hybrid devices that both monitor glucose and deliver insulin, sometimes via automated algorithms. Mobile applications and software provide diabetes self-management support. Increased patient interest has increased the use of diabetes technology in the primary care setting.

SMBG

CGM Devices

See Table 7.3 for definitions of types of CGM devices.

Recommendations

Data derived by CGM allows providers to analyze patient data using new metrics for glycemic targets. These metrics include average blood glucose, percentage of TIR (70-180 mg/dL), glycemic variability, and percentage of time spent above and below range.

Combined Insulin Pump and Sensor Systems

See "7. Diabetes Technology" in the complete 2021 Standards of Care for more information.

The Future

Diabetes technology must be adapted for the individual needs of the patient. Education is essential to ensure that patients can appropriately engage with their diabetes devices to reap the potential health benefits. Both patients and providers must have realistic expectations and understand the capabilities of these new technologies.

8. Obesity Management for the Treatment of Type 2 Diabetes

Strong evidence exists that treatment of obesity can slow the progression of prediabetes to diabetes and benefit those with type 2 diabetes. Modest and sustained weight loss has been shown to improve glycemic control and reduce the need for glucose-lowering medications.

Diet, Physical Activity, and Behavioral Therapy

Metabolic Surgery

9. Pharmacologic Approaches to Glycemic Treatment

Pharmacologic Therapy for Type 2 Diabetes

Figure 9.1, Figure 9.2, and Table 9.1 provide details for informed decision-making on pharmacologic agents for type 2 diabetes.

10. CVD and Risk Management

ASCVD-defined as coronary heart disease (CHD), cerebrovascular disease, or peripheral arterial disease (PAD) presumed to be of atherosclerotic origin-is the leading cause of morbidity and mortality for people with diabetes. HF is another major cause of morbidity and mortality from CVD. For prevention and management of both ASCVD and HF, CV risk factors should be assessed at least annually in all patients with diabetes. These risk factors include obesity/overweight, hypertension, dyslipidemia, smoking, a family history of premature coronary disease, chronic kidney disease (CKD), and the presence of albuminuria.

The Risk Calculator

The American College of Cardiology/American Heart Association ASCVD risk calculator (Risk Estimator Plus) is a useful tool to estimate 10-year ASCVD risk ( tools.acc.org/ASCVD-Risk-Estimator-Plus).

Hypertension/Blood Pressure Control

Hypertension, defined as a sustained blood pressure ≥140/90 mmHg, is common among patients with either type 1 or type 2 diabetes.

Treatment Strategies

Lifestyle Intervention

Recommendation

Pharmacologic Interventions

Lipid Management

Lifestyle Intervention

Recommendations

10.15 Lifestyle modification focusing on weight loss (if indicated); application of a Mediterranean style or DASH eating pattern; reduction of saturated fat and trans fat; increase of dietary n-3 fatty acids, viscous fiber, and plant stanols/sterols intake; and increased physical activity should be recommended to improve the lipid profile and reduce the risk of developing ASCVD in patients with diabetes. A

Ongoing Therapy and Monitoring With Lipid Panel

Statin Treatment

Primary Prevention

Secondary Prevention

Treatment of Other Lipoprotein Fractions or Targets

Other Combination Therapy

Diabetes Risk With Statin Use

A meta-analysis of 13 randomized statin trials with 91,140 participants showed an odds ratio of 1.09 for a new diagnosis of diabetes, so that (on average) treatment of 255 patients with statins for 4 years resulted in one additional case of diabetes while simultaneously preventing 5.4 vascular events among those 255 patients.

Lipid-Lowering Agents and Cognitive Function

The most recent systematic review of the FDA's post-marketing surveillance databases, randomized controlled trials, and cohort, case-control, and cross-sectional studies evaluating cognition in patients receiving statins found that published data do not reveal an adverse effect of statins on cognition.

Antiplatelet Agents

Risk Reduction

Aspirin is effective in reducing CV morbidity and mortality in high-risk patients with previous myocardial infarction (MI) or stroke (secondary prevention) and is strongly recommended.

In primary prevention, however, the benefit is more controversial. The use of aspirin needs to be carefully considered in the context of shared decision-making, weighing the CV benefits with the fairly comparable increase in risk of bleeding; generally, it may not be recommended. Aspirin may be considered in the context of high CV risk with low bleeding risk, but generally not in older adults. Aspirin is not recommended for those at low risk of ASCVD (such as men and women aged <50 years with diabetes with no other major ASCVD risk factors) as the low benefit is likely to be outweighed by the risks of bleeding. The risks and benefits of dual antiplatelet or antiplatelet plus anticoagulant treatment strategies should be thoroughly discussed with eligible patients.

CVD

Recommendations

Treatment

CV outcomes trials (CVOTs) of dipeptidyl peptidase 4 (DPP-4) inhibitors have all, so far, not shown CV benefits relative to placebo. Numerous large randomized controlled trials have reported statistically significant reductions in CV events for three of the FDA-approved SGLT2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) and four FDA-approved GLP-1 receptor agonists (liraglutide, albiglutide [although that agent was removed from the market for business reasons], semaglutide [lower risk of CV events in a moderate-sized clinical trial but one not powered as a CVOT], and dulaglutide). SGLT2 inhibitors also appear to reduce risk of HF hospitalization and progression of kidney disease in patients with established ASCVD, multiple risk factors for ASCVD, or DKD.

In patients with type 2 diabetes and established ASCVD, multiple ASCVD risk factors, or DKD, an SGLT2 inhibitor with demonstrated CV benefit is recommended to reduce the risk of MACE and/or HF hospitalization. In patients with type 2 diabetes and established ASCVD or multiple risk factors for ASCVD, a GLP-1 receptor agonist with demonstrated CV benefit is recommended to reduce the risk of MACE. For many patients, use of either an SGLT2 inhibitor or a GLP-1 receptor agonist to reduce CV risk is appropriate. It is unknown whether use of both classes of drugs will provide an additive CV outcomes benefit. In patients with type 2 diabetes and established HFrEF, an SGLT2 inhibitor with proven benefit in this patient population is recommended to reduce the risk of worsening HF and CV death.

11. Microvascular Complications and Foot Care

CKD

Recommendations

Treatment

11.3a For patients with type 2 diabetes and DKD, consider use of an SGLT2 inhibitor in patients with an eGFR ≥30 mL/min/1.73 m ² and urinary albumin >300 mg/g creatinine. A

11.3b In patients with type 2 diabetes and DKD, consider use of SGLT2 inhibitors additionally for CV risk reduction when eGFR and urinary albumin creatinine are ≥30 mL/min/1.73 m ² or >300 mg/g, respectively. A

11.3c In patients with CKD who are at increased risk for CV events, use of a GLP-1 receptor agonist reduces renal end points, primarily albuminuria, progression of albuminuria, and CV events ( Table 9.1). A

11.6 For people with nondialysis-dependent CKD, dietary protein intake should be ∼0.8 g/kg body weight per day (the recommended daily allowance). A For patients on dialysis, higher levels of dietary protein intake should be considered, since malnutrition is a major problem in some dialysis patients. B

11.7 In nonpregnant patients with diabetes and hypertension, either an ACE inhibitor or an ARB is recommended for those with modestly elevated UACR (30 -299 mg/g creatinine) B and is strongly recommended for those with UACR ≥300 mg/g creatinine and/or eGFR <60 mL/min/1.73 m ². A

11.10 Patients should be referred for evaluation by a nephrologist if they have an eGFR <30 mL/min/1.73 m ². A

Epidemiology of Diabetes and CKD

CKD is diagnosed by the persistent presence of elevated urinary albumin excretion (albuminuria), low eGFR, or other manifestations of kidney damage ( Figure 11.1). Among people with type 1 or type 2 diabetes, the presence of CKD markedly increases CV risk and health care costs.

Selection of Glucose-Lowering Medications for Patients With CKD

For patients with type 2 diabetes and established CKD, special considerations for the selection of glucose-lowering medications include limitations to available medications when eGFR is diminished and a desire to mitigate high risks of CKD progression, CVD, and hypoglycemia. Drug dosing may require modification with eGFR <60 mL/min/1.73 m ².

Metformin is contraindicated in patients with an eGFR <30 mL/min/1.73 m ²; eGFR should be monitored while taking metformin; the benefits and risks of continuing treatment should be reassessed when eGFR falls to <45 mL/min/1.73 m ²; metformin should not be initiated for patients with an eGFR <45 mL/min/1.73 m ²; and metformin should be temporarily discontinued at the time of or before iodinated contrast imaging procedures in patients with eGFR of 30-60 mL/min/1.73 m ².

SGLT2 inhibitors and GLP-1 receptor agonists should be considered for patients with type 2 diabetes and CKD who require another drug added to metformin to attain target A1C or cannot use or tolerate metformin. SGLT2 inhibitors reduce risks of CKD progression, CVD events, and hypoglycemia. GLP-1 receptor agonists are suggested because they reduce risks of CVD events and hypoglycemia and appear to possibly slow CKD progression.

For patients with type 2 diabetes and CKD, the selection of specific agents may depend on comorbidity and CKD stage. SGLT2 inhibitors may be more useful for patients at high risk of CKD progression (i.e., with albuminuria or a history of documented eGFR loss) ( Figure 9.1) because they appear to have large beneficial effects on CKD incidence. The SGLT2 inhibitors empagliflozin and dapagliflozin are approved by the FDA for use with eGFR ≥45 mL/min/1.73 m ².

CVD and Blood Pressure

Hypertension is a strong risk factor for the development and progression of CKD. Two clinical trials studied the combinations of ACE inhibitors and ARBs and found no benefits on CVD or CKD, and the drug combination had higher adverse event rates (hyperkalemia and/or acute kidney injury). Therefore, the combined use of ACE inhibitors and ARBs should be avoided.

Neuropathy

Recommendations

Treatment

11.28 Optimize glucose control to prevent or delay the development of neuropathy in patients with type 1 diabetes A and to slow the progression of neuropathy in patients with type 2 diabetes. B

11.29 Assess and treat patients to reduce pain related to diabetic peripheral neuropathy B and symptoms of autonomic neuropathy and to improve quality of life. E

Foot Care

12. Older Adults

Recommendations

More than one-fourth of people over the age of 65 years have diabetes and one-half of older adults have prediabetes. Diabetes management in older adults requires regular assessment of medical, psychological, functional, and social domains. Older adults with diabetes have higher rates of premature death, functional disability, accelerated muscle loss, and coexisting illnesses, such as hypertension, CHD, and stroke, than older adults without diabetes. Screening for diabetes complications in older adults should be individualized and periodically revisited, as the results of screening tests may impact targets and therapeutic approaches.

Neurocognitive Function

Recommendation

Older adults with diabetes are at higher risk of institutionalization and cognitive impairment, which can make it challenging for clinicians to help their patients reach individualized glycemic, blood pressure, and lipid targets. People with diabetes have higher incidences of all-cause dementia, Alzheimer disease, and vascular dementia than people with normal glucose tolerance.

Hypoglycemia

Recommendations

Older adults are at higher risk of hypoglycemia for many reasons, including insulin deficiency necessitating insulin therapy and progressive renal insufficiency. Glycemic targets and pharmacologic regimens may need to be adjusted to minimize the occurrence of hypoglycemic events. Patients and their caregivers should be routinely queried about hypoglycemia and hypoglycemia unawareness.

Treatment Goals

Recommendations

Providers caring for older adults with diabetes must take clinical, cognitive, and functional heterogeneity into consideration when setting and prioritizing treatment goals. (See Table 12.1 in the complete 2021 Standards of Care.) Patients who can be expected to live long enough to reap the benefits of long-term intensive diabetes management, who have good cognitive and physical function, and who choose to do so via shared decision-making may be treated using therapeutic interventions and goals similar to those for younger adults with diabetes.

Lifestyle Management

Pharmacologic Therapy

Recommendations

Special care is required in prescribing and monitoring pharmacologic therapies in older adults. Metformin is the first-line agent for older adults with type 2 diabetes. See Figure 9.1 for general recommendations regarding glucose-lowering treatment for adults with type 2 diabetes and Table 9.1 for patient- and drug-specific factors to consider when selecting glucose-lowering agents.

The needs of older adults with diabetes and their caregivers should be evaluated to construct a tailored care plan.

Due in part to the success of modern diabetes management, patients with type 1 diabetes are living longer, and the population of these patients >65 years of age is growing. Some of these patients may be using insulin pumps and/or CGM systems. To avoid DKA, older adults with type 1 diabetes need some form of basal insulin even when they are unable to ingest meals.

Treatment in Skilled Nursing Facilities and Nursing Homes

Recommendations

Management of diabetes is unique in the LTC setting. Special management considerations include the need to avoid both hypoglycemia and the complications of hyperglycemia. Older adults with diabetes in LTC are especially vulnerable to hypoglycemia.

An older adult residing in an LTC facility may have irregular and unpredictable meal consumption, undernutrition, anorexia, and impaired swallowing. Diets tailored to patients' culture, preferences, and personal goals may increase quality of life, satisfaction with meals, and nutrition status.

End-of-Life Care

Recommendations

Overall, palliative medicine promotes comfort, symptom control and prevention (pain, hypoglycemia, hyperglycemia, and dehydration), and preservation of dignity and quality of life in patients with limited life expectancy. Strict glucose and blood pressure control may not be consistent with achieving comfort and quality of life. Glucose targets should aim to prevent hypoglycemia and hyperglycemia. Different patient categories, including stable patients, patients with organ failure, and dying patients, have been proposed for diabetes management in those with advanced disease.

13. Children and Adolescents

The management of diabetes in children and adolescents cannot simply be derived from care routinely provided to adults with diabetes. The epidemiology, pathophysiology, developmental considerations, and response to therapy in pediatric-onset diabetes are different from adult diabetes.

See "13. Children and Adolescents" in the complete 2021 Standards of Care for specific recommendations regarding the treatment of type 1 diabetes in this group, as well as the comprehensive treatment of children with type 2 diabetes, including screening, prevention and management of CV risk factors, microvascular complications, and other associated conditions. See "7. Diabetes Technology" in the complete 2021 Standards of Care for more information on the use of blood glucose meters, CGM, and insulin pumps. The ADA position statements "Type 1 Diabetes in Children and Adolescents" and "Evaluation and Management of Youth-Onset Type 2 Diabetes" offer additional information.

Type 1 Diabetes

Type 1 diabetes is the most common form of diabetes in youth. The provider must consider the unique aspects of care and management of children and adolescents with type 1 diabetes. A multidisciplinary team of specialists trained in pediatric diabetes management and sensitive to the challenges of children and adolescents with type 1 diabetes and their families should provide care for this population.

Type 2 Diabetes

Type 2 diabetes in youth has increased over the past 20 years, and recent estimates suggest an incidence of ∼5,000 new cases per year in the U.S. Evidence suggests that type 2 diabetes in youth is different not only from type 1 diabetes, but also from type 2 diabetes in adults.

Management

Treatment of youth-onset type 2 diabetes by a multidisciplinary team should include lifestyle management, diabetes self-management education, and pharmacologic treatment. Current pharmacologic treatment options for youth-onset type 2 diabetes are limited to three approved drugs: insulin, metformin, and liraglutide.

Most youth with type 2 diabetes come from racial/ethnic minority groups, have low socioeconomic status, and often experience multiple psychosocial stressors. Consideration of the sociocultural context and efforts to personalize diabetes management are of critical importance to minimize barriers to care, enhance adherence, and maximize response to treatment.

Glycemic Targets

Pharmacologic Management

14. Management of Diabetes in Pregnancy

The prevalence of diabetes in pregnancy has been increasing in the U.S. in parallel with the worldwide epidemic of obesity. In general, specific risks of diabetes in pregnancy include spontaneous abortion, fetal anomalies, preeclampsia, fetal demise, macrosomia, neonatal hypoglycemia, hyperbilirubinemia, and neonatal respiratory distress syndrome, among others. In addition, diabetes in pregnancy may increase the risk of obesity, hypertension, and type 2 diabetes in offspring later in life.

Pregnancy and Drug Considerations

Postpartum Care

15. Diabetes Care in the Hospital

Among hospitalized patients, hyperglycemia, hypoglycemia, and glucose variability are associated with adverse outcomes, including death. Therefore, careful management of inpatients with diabetes has direct and immediate benefits. When caring for hospitalized patients with diabetes, consult with a specialized diabetes or glucose management team when possible.

Hospital Care Delivery Standards

Considerations on Admission

Initial orders should state the type of diabetes, if known. Because inpatient treatment and discharge planning are more effective if based on preadmission glycemia, an A1C should be measured on all patients with diabetes or hyperglycemia if the test has not been performed in the previous 3 months.

Glycemic Targets in Hospitalized Patients

Recommendations

Hyperglycemia in hospitalized patients is defined as blood glucose levels >140 mg/dL (7.8 mmol/L). Glucose levels persistently above this level should receive prompt conservative interventions to correct the hyperglycemia, such as changes to diet or medications causing hyperglycemia.

Hypoglycemia in the hospital is classified the same as in any setting. (See "6. GLYCEMIC TARGETS.")

Bedside Blood Glucose Monitoring

In patients who are eating, bedside glucose monitoring should be performed before meals; in those not eating, glucose monitoring is advised every 4-6 hours. More frequent bedside glucose testing, every 30 minutes to every 2 hours, is required for intravenous insulin infusion.

Although CGM has theoretical advantages over point-of-care glucose testing in detecting and reducing the incidence of hypoglycemia, it has not been approved by the FDA for inpatient use. However, some hospitals with established glucose management teams allow the use of CGM in selected patients.

Glucose-Lowering Treatment in Hospitalized Patients

Recommendations

15.6 Basal insulin or a basal plus bolus correction insulin regimen is the preferred treatment for noncritically ill hospitalized patients with poor oral intake or those who are taking nothing by mouth. A

15.7 An insulin regimen with basal, prandial, and correction components is the preferred treatment for noncritically ill hospitalized patients with good nutritional intake. A

15.8 Use of only a sliding-scale insulin regimen in the inpatient hospital setting is strongly discouraged. A

In certain circumstances, it may be appropriate to continue home regimens including oral glucose-lowering medications. If oral medications are held in the hospital, there should be a protocol for resuming them 1-2 days before discharge.

Insulin Therapy

In the critical care setting, continuous intravenous insulin infusion is the best method for achieving glycemic targets. Outside of critical care units, scheduled insulin regimens as described above are recommended.

For patients who are eating, insulin injections should align with meals. In patients with unpredictable oral intake, a safer procedure is to administer prandial insulin immediately after the patient eats with the dose adjusted for the amount ingested.

An insulin regimen with basal and correction components is necessary for all hospitalized patients with type 1 diabetes, with the addition of prandial insulin if patients are eating. A transition protocol from insulin infusion to subcutaneous insulin with the administration of basal insulin 2 hours before discontinuing the intravenous insulin drip is recommended.

Noninsulin Therapies

The safety and efficacy of noninsulin glucose-lowering therapies in the hospital setting is an area of active research. See "15. Diabetes Care in the Hospital" in the complete 2021 Standards of Care for a comprehensive review of the inpatient use of these medications.

Hypoglycemia

Recommendations

Patients with or without diabetes may experience hypoglycemia in the hospital setting. Insulin is one of the most common drugs causing adverse events in hospitalized patients, and insulin dosing/administration errors occur relatively frequently.

While hypoglycemia is associated with increased mortality, it may be a marker of underlying disease rather than the cause of fatality. Recently, several groups have developed algorithms to predict episodes of hypoglycemia among inpatients. Models such as these are potentially important and, once validated for general use, could provide a valuable tool to reduce rates of hypoglycemia in hospitalized patients.

MNT in the Hospital

The goals of MNT in the hospital are to provide adequate calories to meet metabolic demands, optimize glycemic control, address personal food preferences, and facilitate creation of a discharge plan. The ADA does not endorse any single meal plan.

Self-Management in the Hospital

Diabetes self-management in the hospital may be appropriate for specific patients. Sufficient cognitive and physical skills, adequate oral intake, proficiency in carbohydrate estimation, and knowledge of sick-day management are some of the requirements. Self-administered insulin with a stable MDI regimen or insulin pump therapy may be considered. A protocol should exist for these situations.

Standards for Special Situations

See "15. Diabetes Care in the Hospital" in the complete 2021 Standards of Care for guidance on enteral/parenteral feedings, glucocorticoid therapy, perioperative care, and DKA and hyperosmolar hyperglycemic state.

Transition From the Acute Care Setting

Medication Reconciliation

The patient's medications must be cross-checked to ensure that no chronic medications were stopped and to ensure the safety of new prescriptions.

Prescriptions for new or changed medication should be filled and reviewed with the patient and family at or before discharge.

Discharge planning should begin at admission and be updated as patient needs change. An outpatient follow-up visit 1 month after discharge is recommended. An earlier appointment (in 1-2 weeks) is preferred, and frequent contact may be needed to avoid hyperglycemia and hypoglycemia.

Structured Discharge Communication

Information on medication changes, pending tests and studies, and follow-up needs must be accurately and promptly communicated to outpatient providers, including transmission of the discharge summary to the primary care provider as soon as possible after discharge.

Scheduling follow-up appointments prior to discharge increases the likelihood that patients will attend.

It is important that patients be provided with appropriate durable medical equipment, medications, supplies, and prescriptions along with education at the time of discharge.

Preventing Admissions and Readmissions

Strategies aimed at reducing readmission include targeted interventions for insulin treatment of patients with admission A1C >9% (75 mmol/mol) and collaborative patient-centered medical homes for people with DKD.

Age is also an important risk factor in hospitalization and readmission among patients with diabetes.

16. Diabetes Advocacy

For a list of ADA advocacy position statements, including "Diabetes and Driving" and "Diabetes and Employment," see "16. Diabetes Advocacy" in the complete 2021 Standards of Care.

Article Information

Acknowledgments

This abridged version of the Standards of Medical Care in Diabetes-2021 was created by the ADA's Primary Care Advisory Group (PCAG), with special thanks to PCAG chair Eric L. Johnson, MD, of Grand Forks, ND, vice-chair Hope Feldman, CRNP, FNP-BC, of Philadelphia, PA, Amy Butts, PA-C, CDCES, BC-ADM, of Wheeling, WV, James Chamberlain, MD, of Salt Lake City, UT, CDR Billy Collins, DHSc, PA-C, of Bethesda, MD, Kacie Doyle-Delgado, DNP, NP-C, of Salt Lake City, UT, Joy Dugan-Moverley, MPH, DHS(c), PA-C, of Vallejo, CA, RaShaye Freeman, DNP, FNP-BC, CDCES, ADM-BC, of Nashville, TN, Sandra Leal, PharmD, MPH, FAPhA, CDCES, of Tucson, AZ, CDR Parmjeet Saini, DHSc, MPA, PA-C, of New York, NY, Jay H. Shubrook, DO, of Vallejo, CA, and Jennifer Trujillo, PharmD, FCCP, BCPS, CDCES, BC-ADM, of Aurora, CO, with ADA staff support from Sarah Bradley.

The complete Standards of Medical Care in Diabetes-2021 was developed by the ADA's Professional Practice Committee: Boris Draznin, MD, PhD (Chair), Vanita R. Aroda, MD, George Bakris, MD, Gretchen Benson, RDN, LD, CDCES, Florence M. Brown, MD, RaShaye Freeman, DNP, FNP-BC, CDCES, ADM-BC, Jennifer Green, MD, Elbert Huang, MD, MPH, FACP, Diana Isaacs, PharmD, BCPS, BC-ADM, CDCES, Scott Kahan, MD, MPH, Christine G. Lee, MD, MS, Jose Leon, MD, MPH, Sarah K. Lyons, MD, Anne L. Peters, MD, Jane E.B. Reusch, MD, and Deborah Young-Hyman, PhD, CDCES. ADA staff support includes Mindy Saraco, MHA, Malaika I. Hill, MA, Matthew P. Petersen, Shamera Robinson, MPH, RDN, Jo Mandelson, MS, RDN, and Robert A. Gabbay, MD, PhD.

# data[].attributes.attachment_link.title
Standards of Medical Care in Diabetes-2021 Abridged for Primary Care Providers

# data[].attributes.attachment_link.description
The American Diabetes Association (ADA) Standards of Medical Care in Diabetes is updated and published annually in a supplement to the January issue of Diabetes Care . The Standards are developed by the ADA's multidisciplinary Professional Practice Committee, which comprises physicians, diabetes educators, and other expert diabetes health care professionals.

# data[].attributes.attachment_link.readable_text
The management of type 1 and 2 diabetes mellitus (DM) requires addressing multiple goals, with the primary goal being glycemic control. Maintaining glycemic control in patients with diabetes prevents many of the microvascular and macrovascular complications associated with diabetes. This chapter presents a review of the prevalence, screening, diagnosis, and management of these complications.

Prevalence

Retinopathy. In patients with type 1 DM, 13% have retinopathy at 5 years and 90% have retinopathy after 10 to 15 years; approximately 25% will develop proliferative retinopathy after 15 years.[1]

In patients with type 2 DM, 40% of patients taking insulin and 24% of patients taking oral hypoglycemic agents will develop retinopathy at 5 years. After 15 to 19 years, the percentages increase to 84% and 53%, respectively. Proliferative retinopathy develops in 2% of patients with type 2 DM for longer than 5 years and in 25% of patients with diabetes for 25 years or longer.[2]

Nephropathy. The prevalence of nephropathy in diabetes has not been determined. Approximately 30% of patients with type 1 DM─and 5% to 10% of those with type 2 DM─become uremic. [3] Diabetic nephropathy is a leading cause of end-stage renal disease.

Neuropathy. The prevalence of neuropathy in patients with diabetes is 7% at 1 year, increasing to 50% at 25 years for both type 1 and type 2 DM.[4]

Macrovascular. Macrovascular complications in patients with diabetes cause an estimated two- to four-fold increased risk of coronary artery disease (CAD), peripheral arterial disease, and cerebrovascular disease.[5] An estimated 37% to 42% of all ischemic strokes in Americans are attributable to the effects of diabetes, alone or in combination with hypertension.[6] The prevalence of CAD or stroke in patients with diabetes is approximately 34% in both men and women. The prevalence of peripheral vascular disease in patients with diabetes aged 30 years or older is 26%.[7]

Pathophysiology

Retinopathy. Microaneurysm formation is the earliest manifestation of diabetic retinopathy. Microaneurysms may form due to the release of vasoproliferative factors, weakness in the capillary wall, or increased intra-luminal pressures. Microaneurysms can cause vascular permeability in the macula, which can lead to macular edema that threatens central vision. Obliteration of retinal capillaries can lead to intraretinal microvascular abnormalities. As capillary closure becomes extensive, intraretinal hemorrhages develop.

Proliferative retinopathy develops due to ischemia and release of vasoactive substances, such as vascular endothelial growth factor, which stimulate new blood vessel formation as a progression of nonproliferative retinopathy. These vessels may erupt through the surface of the retina and grow on the posterior surface of the vitreous humor. These vessels are very friable and can lead to vitreous hemorrhages. The vitreous humor can contract and lead to retinal detachment.

Nephropathy. Two pathophysiologic pathways for diabetic nephropathy have been identified. First, diabetic nephropathy can result from increased glomerular capillary flow that, in turn, results in increased extracellular matrix production and endothelial damage. This leads to increased glomerular permeability to macromolecules. Mesangial expansion and interstitial sclerosis can ensue, which have the potential to cause glomerular sclerosis. A second pathway termed nonalbuminuric renal impairment is due to macrovascular and/or repeated unresolved episodes of acute kidney injury. Reduced glomerular filtration rate (GFR) and albuminuria are risk factors for cardiovascular events whereas albuminuria predicted death and progression to end stage renal disease better than GFR loss.

Neuropathy. The pathophysiology of neuropathy is complex. Diabetes is associated with dyslipidemia, hyperglycemia, and low insulin and growth factor abnormalities. These abnormalities are associated with glycation of blood vessels and nerves. In addition, autoimmunity may affect nerve structure. Trauma and nerve entrapment can lead to structural nerve damage including segmental demyelination, axonal atrophy and loss, and progressive demyelination. These effects cause neuropathy.

Macrovascular. The macrovascular complications of diabetes result from hyperglycemia, excess free fatty acid, and insulin resistance. These cause increased oxidative stress, protein kinase activation, and activation of the receptor for advanced glycation end products, factors that act on the endothelium.

First, decreased nitric oxide, increased endothelin, and increased angiotensin II cause vasoconstriction that results in hypertension and vascular smooth muscle cell growth.

Second, decreased nitric oxide, activated nuclear factor-KB, increased angiotensin II, and activation of activated protein-1 increase inflammation, which results in the release of chemokines, cytokines, and expression of cellular adhesion molecules.

Third, decreased nitric oxide, increased tissue factor, increased plasminogen activator inhibitor-1, and decreased prostacyclin result in thrombosis, hypercoagulation, platelet activation, and decreased fibrinolysis.

These pathways ultimately lead to atherosclerosis, the cause of the macrovascular complications of diabetes.

Signs and Symptoms

Retinopathy. Symptoms of retinopathy are minimal until advanced disease ensues with loss or blurring of vision. Signs of nonproliferative retinopathy include microaneurysms, venous loops, retinal hemorrhages, hard exudates, and soft exudates. Proliferative retinopathy can include new vessels in the eyes or vitreous hemorrhage.

Nephropathy. The earliest sign of nephropathy is hypertension, which often coincides with the development of microalbuminuria. As nephropathy worsens, patients can develop edema, arrhythmias associated with hyperglycemia, or symptoms related to renal failure.

Neuropathy. Signs and symptoms of neuropathy depend on the type of neuropathy that develops. Most commonly, patients develop symptomatic distal polyneuropathy. Signs include decreased or total loss of ankle jerk reflexes and vibratory sensation, with hyperalgesia and calf pain in some patients. These usually present in a "stocking and glove" distribution. Wasting of the small muscle of the hands and feet also can occur.

Patients may present with focal neuropathies due to either mononeuritis or entrapment syndromes. These produce focal neurologic deficits confined to a single nerve. A rare but severe form of diabetic neuropathy is diabetic amyotrophy, which begins with pain followed by severe weakness and spreads from unilateral to bilateral. It resolves spontaneously in 18 to 24 months.

Macrovascular. Patients with diabetes-associated CVD can present with stable or unstable angina pectoris, MI, or dysrhythmias; however, many patients have unrecognizable symptoms. Patients with cerebral vascular disease can present with a sudden onset of a focal neurologic deficit such as facial droop, hemiparesis, or isolated weakness of an arm or leg. Dizziness, slurred speech, gait difficulties, and visual loss also can be the presenting symptoms.

Peripheral vascular disease is recognized by exertional leg pain that can progress to pain at rest and ischemic ulcers. Most cases are asymptomatic.

Screening

Patients with diabetes should be screened regularly, at least every 6 months, for retinopathy, nephropathy, and neurology complications ( Table 1). Those with uncontrolled diabetes should be examined more frequently.

Table 1. Screening for micro- and macrovascular complications in patients with diabetes.

Retinopathy

Dilated eye examinations by an ophthalmologist or optometrist should be performed within 5 years of onset in type 1 DM and at the time of diagnosis in type 2 DM, because the actual date of onset is hard to determine in type 2 DM. Follow-up eye examinations should be performed annually in patients with no or minimal background retinopathy. More frequent follow-up examinations are needed in those who have more advanced retinopathy.

Handheld ophthalmoscopy may be able to detect diabetic retinopathy, but it offers limited view of the retina and has difficulty detecting diabetic macular edema, a significant cause of vision loss in diabetes. Retinopathy is easier to detect with binocular vision. In difficult cases, IV fluorescein angiography and confocal microscopy are used. Technology is available for screening with fundus photographs obtained in the practitioner's office and then read by an expert. However, these do not show a complete view of the retina and do not include other aspects of the eye examination, such as eye pressure, and, thus, cannot replace yearly eye evaluations.

Nephropathy

The hallmark of early diabetic nephropathy is albumin excretion. Sensitive assays to detect very low levels of albumin, or microalbuminuria, have been available for many years. The simplest screening measure is a spot urine test adjusted for the urine creatinine level. Timed overnight collections or 24-hour collections also may be used.

In general, microalbuminuria is defined as more than 30 mg albumin per gram of creatinine (spot urine test) or 30 to 299 mg per 24 hours and more than 300 mg gram of creatinine (or 24 hours) as albuminuria. Serum creatinine determinations should be performed at least annually in patients with albuminuria. When estimated glomerular filtration rate (eGFR) values are declining, more specific measures of GFR (most commonly, creatinine clearance) should be used.

Peripheral Neuropathy

Monofilament testing performed in the office is the easiest way to check for the insensate foot. The 5.07 mm monofilament is applied to the bottoms of the feet ( Figure 1). Any loss of sensation is associated with an increased risk for ulcer formation. A patient who has had a foot ulcer is at increased risk for additional foot ulcers.

Patients should be instructed to examine their feet daily. Patients who have difficulty examining their feet should seek assistance, especially if they have impaired vision. The use of a mirror can help patients see the bottoms of their feet (see the chapter, " Prevention and Treatment of Leg and Foot Ulcers in Diabetes Mellitus").

Cardiovascular Disease

Careful questioning about symptoms of ischemic coronary disease is still one of the most important ways to screen for CVD. Many patients with diabetes do not have typical exertional chest pain. Consequently, clinicians must ask about reduced exercise tolerance, dyspnea, or exercise-induced nausea.

Various studies have considered the issue of screening for CVD. The guidelines and individual recommendations are not entirely concordant. Whereas nearly every group suggests stress tests for patients with symptoms of CVD or electrocardiographic changes suggesting ischemia, recommendations on screening for asymptomatic disease are less consistent.

The American Diabetes Association (ADA) considers that candidates for cardiac stress testing should include those with a history of peripheral or carotid occlusive disease; those with a sedentary lifestyle who are older than 55 years and who plan to begin a vigorous exercise program; and those with two or more risk factors for CVD.[8]

The American Association of Clinical Endocrinologists (AACE) guidelines state the following:

Screening for asymptomatic coronary artery disease with various stress tests in patients with T2D has not been clearly demonstrated to improve cardiac outcomes and is therefore not recommended.[9]

The American Heart Association (AHA) consensus group created the following approach to screening for CAD in patients with diabetes:

Screening is defined as the detection of disease in asymptomatic persons. Because screening tests are intended for widespread application, they should be rapid and inexpensive. In addition, to be useful, the results of testing should lead to a change in management, and the results of testing should improve outcomes.[10]

The American College of Cardiology (ACC)/AHA Guidelines for Exercise Testing give screening by exercise treadmill testing in patients with diabetes a data quality rating of IIb, meaning that its usefulness or efficacy is less well established by evidence or opinion.[11] They note that exercise testing might be useful in people with heightened pretest risk.

Most consensus statements and guidelines on diabetes and CAD have suggested that noninvasive cardiac testing be performed in patients with diabetes and one additional criterion: peripheral arterial disease, cerebrovascular disease, rest changes on the electrocardiogram (ECG), or the presence of two or more major CVD risk factors.

According to these guidelines, risk assessment begins with a medical history, including special attention to symptoms of atherosclerotic disease, such as angina, claudication, or erectile dysfunction. Electrocardiographic changes showing left ventricular hypertrophy and ST-T changes suggest increased CVD risk. Data from the ongoing DIAD study (Detection of Ischemia in Asymptomatic Diabetics),[12] which is designed to determine risk factors associated with clinically silent myocardial disease using stress tests with cardiac imaging, has suggested that the presence of neuropathy may be one of the most important predictors of CVD risk.

It is not yet clear how results from noninvasive testing can change risk management strategies in patients with diabetes, because diabetes is already considered a CVD risk equivalent. Thus, noninvasive testing should be targeted as much as possible to identify patients who might have CVD that is amenable to surgical intervention. Whereas noninvasive screening in asymptomatic patients might detect disease amenable to percutaneous intervention or coronary artery bypass grafting, the cost effectiveness and effects on long-term outcomes are still uncertain.

Careful attention to a patient's history of changes in exercise tolerance, atypical symptoms that suggest angina, or suggestive ECG abnormalities are reasons to consider stress testing. In addition, dyslipidemia, obesity, hypertension, albuminuria, and a family history of CVD may be reasons to consider stress testing in patients who do not have clinical symptoms of CVD. This approach is most consistent with the AACE guidelines and should select patients at highest risk for CVD. In the absence of robust evidence, as noted by the AHA, practitioners need to make decisions about patients who might have silent myocardial disease.

Diagnosis

Retinopathy

The diagnosis of retinopathy is based on the findings of eye exams to determine if the patient has clinically significant macular edema, proliferative retinopathy, or severe nonproliferative retinopathy. The progressive changes in the retina that occur in patients with diabetes include the following:

1. Formation of retinal capillary microaneurysms;

2. Development of abnormal vascular permeability;

3. Ischemia;

4. New vessel and fibrous tissue proliferation of the surface of the retina and optic disk;

5. Contraction of the fibrovascular proliferations and the vitreous.[13]

Nephropathy

The diagnosis of nephropathy is initially based on development of microalbuminuria. Microalbuminuria is defined as an albumin excretion rate 20 to 200 mcg/min. Because the average daily albumin excretion rate varies by up to 40% between those with diabetes and those without, it is recommended that three urine collections be taken over several weeks before making this diagnosis. Overt nephropathy is defined as an albumin excretion rate >300 mg/24 hours. This is associated with a linear decline in GFR ranging from 0.1 to 2.4 mL/min/month.

The following are the stages of chronic kidney disease:[14]

Stage 1: GFR >90 mg/24 hours.

Stage 2: GFR is mildly decreased at 60 to 89 mg/24 hours.

Stage 3: GFR is 30 to 59 mg/24 hours.

Stage 4: GFR is 15 to 29 mg/24 hours.

Stage 5: End-stage nephropathy with a GFR <15 mg/24 hours.

Neuropathy

The diagnosis of neuropathy, defined by loss of ankle jerk reflexes, is based on finding focal (individual root) or diffuse (entire limb) involvement. Findings can be asymmetric (mononeuritis multiplex) or symmetric conforming to a distal-to-proximal gradient of involvement (most common). Electrodiagnostic studies can confirm peripheral nerve disease and define the pattern of disease. Autonomic neuropathy is diagnosed in patients with gastroparesis or orthostatic hypotension.

Cardiovascular Disease

The diagnosis of CVD can be confirmed by several diagnostic and imaging studies. A resting 12-lead ECG is not sensitive enough to identify disease in patients with stable angina. Cardiovascular stress testing can be assessed with ECG assessment during exercise, dobutamine, dipyridamole, or adenosine. Echocardiography can enhance the sensitivity of the test. Alternatively, nuclear stress testing with thallium 201 or technetium 99m in association with dipyridamole or adenosine can be used. Significant CAD is identified by relative hypoperfusion in peak stress images. Coronary arteriography can confirm CAD.

The diagnosis of a stroke is based on a patient developing symptoms of focal neurologic deficit and can be confirmed by a CT scan or MRI. CT angiography can be used to identify the location of vascular occlusion and assess for salvageable brain tissue.

The diagnosis of peripheral arterial disease is diagnosed by determining the ankle brachial index (ABI). This is the ratio of the Doppler-determined systolic ankle pressure over the systolic brachial pressure. An ABI less than 0.9 has a sensitivity of 95% and a specificity of 100% in detecting peripheral arterial disease. An ABI greater than 1.4 reflects calcified arteries. It is associated with increased risk of foot ulcers and CVD. If revascularization is being considered, other tests including duplex ultrasonography, MR angiography, and CT angiography can be used to determine specific sites of surgical intervention.

Management: Lifestyle

Appropriate management of the microvascular and macrovascular complications of diabetes requires practitioners to treat a comprehensive range of factors that focus on several areas including nutritional intake, control of blood glucose, lifestyle and activity, blood pressure, and lipids.

Medical-Nutrition Therapy

Guidelines for medical-nutrition therapy have been established by the ADA and are summarized in Table 2.[15] The primary focus of these guidelines is to improve outcomes by improving glycemic control, reducing weight (as appropriate), and controlling blood pressure and lipids. There is clear evidence that excess saturated fat in the diet has a detrimental effect on lipid profiles; therefore, restriction of saturated fat is recommended. Data supporting absolute restriction of carbohydrates are not robust, so the ADA guidelines allow flexibility in intake of carbohydrates. The ADA has published separate guidelines for the carbohydrate content and composition of the diet.[16]

The most important variable in prandial glycemic excursion is total carbohydrate intake. Consumption of low glycemic index foods results in lower prandial glucose excursion than consuming high glycemic index foods. In the context of a mixed meal, however, differences between low and high glycemic index foods are attenuated.

The amount and source of carbohydrates are important determinants of postprandial glucose levels. In studies of the relative impact of the glycemic index and total carbohydrate content of individual foods on glycemic load-the product of glycemic index and total grams of carbohydrates-carbohydrate content (total grams) explained 68% of the variation in glycemic load and the glycemic index of the food explained 49%.[17,18] When total carbohydrate content and glycemic index were both included in the regression analysis, the glycemic index accounted for 32% of the variation.

Restriction of alcohol and sodium is generally advised. Nutritional supplements are not necessary in patients who are consuming a well-balanced diet. Many recommendations for weight management propose calorie restriction based on the degree of obesity along with 30 to 45 minutes of exercise 3 to 5 days a week. Exercise is an important component of any regimen for weight reduction and glycemic control. Other nutritional guidelines for patients with diabetes are generally consistent with the ADA guidelines.

Table 2. Goals of medical-nutrition therapy for patients with diabetes.

1. Blood glucose levels in the normal range or as close to normal as is safely possible

2. Lipid and lipoprotein profiles that reduce risk for macrovascular disease

3. Blood pressure levels that reduce risk for vascular disease

4. Modify nutrient intake and lifestyle as appropriate to prevent and treat obesity, dyslipidemia, CVD, hypertension, and nephropathy

Specific patient populations

Children and adolescents with type 1 DM

Provide adequate energy to ensure normal growth and development.
Integrate insulin regimens into usual eating and physical activity habits.

Children and adolescents with type 2 DM

Facilitate changes in eating and physical activity habits that reduce insulin resistance and improve metabolic status.

Pregnant and lactating women

Provide adequate energy and nutrients needed for optimal outcomes.

Provide for the nutritional and psychosocial needs of aging adults.

Patients treated with insulin or insulin secretagogues

Provide self-management education for treatment (and prevention) of hypoglycemia, acute illnesses, and exercise-related blood glucose problems.

Population at risk for diabetes

Decrease risk by encouraging physical activity and promoting food choices that facilitate moderate weight loss or at least prevent weight gain.

Source: Bantle JP Diabetes Care 2006. [15]

Exercise

Guidelines for exercise have not always been specific with regard to exact exercise prescriptions, especially regarding aerobic and resistance exercises. The commonly proposed recommendation is for 150 minutes of moderate-intensity (or 90 minutes of vigorous) aerobic exercise per week to achieve benefits on glycemic control and reduce CVD risk. It is supported by ADA/AHA recommendations.[19]

Regular exercise is encouraged, but complications of diabetes need to be taken into account. For example, patients with loss of sensation in their feet should limit weight-bearing exercise. Because of the CVD risk in patients with diabetes, appropriate screening for CVD should be performed before patients engage in an exercise program. Benefits of exercise include weight control and improved glycemic control, often due to reduced insulin resistance.

Smoking

All diabetes and CVD-related guidelines recommend smoking cessation.

Management: Microvascular Risks

Prevention is the optimal approach to managing the microvascular complications of diabetes. The two main approaches to preventing retinopathy and nephropathy are intensive glycemic control and aggressive control of hypertension. Intensive glycemic control has been the most effective approach to preventing neuropathic complications of diabetes.

The Wisconsin Epidemiologic Study demonstrated that in patients with diabetes, higher baseline hemoglobin A1c (HbA1c) levels correlated with increased incidence of retinopathy, progression of retinopathy, and progression of proliferative retinopathy.[1,2]

The Diabetes Control and Complications Trial [20] (DCCT) compared intensive insulin therapy (insulin pump or multiple daily injections) versus conventional therapy (one or two injections per day) in 1,441 patients with type 1 DM (615 with mild to moderate retinopathy). After a mean of 6.5 years, intensive therapy effectively slowed or delayed the onset of diabetic retinopathy, nephropathy, and neuropathy in insulin-dependent patients. In a 4-year follow-up after the study ended,[21] the reduced risks of progressive retinopathy (proliferative retinopathy, macular edema, and need for laser therapy) and nephropathy (incidence of albuminuria) persisted despite a narrowing of the HbA1c levels in the two groups.

The Kumamoto Trial,[22] which included 110 patients with type 2 DM, showed that intensive therapy with multiple daily injections (preprandial, regular, and bedtime intermediate acting insulin) compared with once or twice daily insulin injections decreased HbA1c from 9.4% to 7.1%. In addition, two-step progression of retinopathy decreased by 69%, nephropathy progression decreased by 70%, and nerve conduction velocities improved, supporting the efficacy of intensive therapy.

The UK Prospective Diabetes Study (UKPDS) Group [23,24] evaluated 5,102 patients with type 2 DM. Patients using intensive treatment (metformin;[23] sulphonylureas or insulin [24]) versus conventional treatment had lower average HbA1c (7.0% vs 7.9%) and 12-year risk reductions of 27% for retinal photo coagulation, 33% for microalbuminuria, and 74% for doubling of creatinine levels. These results further support the importance of intensive therapy in reducing the microvascular complications of diabetes.

Hypertension control has been shown to reduce the risk for both retinopathy and nephropathy. The Hypertension and Diabetes Study,[25,26] which was part of the UKPDS, enrolled 1,148 patients with type 2 DM and coexisting hypertension. Patients in the tight-control group had a blood pressure goal of <150/85 mm Hg on treatment. They were randomized to either captopril (angiotensin-converting enzyme [ACE] inhibitor) or atenolol (beta blocker). The comparator group had a higher blood pressure goal of <180/105 mm Hg; they were not randomized to the active treatments.

On average, patients in the tight-control group maintained an average blood pressure of 144/82 mm Hg versus 154/87 mm Hg in the comparator group. After 9 years of follow-up, tight control resulted in a 35% reduction in retinal photo coagulation ( P <0.025), a 34% reduction in two-step deterioration of retinopathy, and a 47% risk reduction in visual acuity deterioration by three lines in the early treatment of diabetic retinopathy study (ETDRS) chart ( P <0.005).[26]

The Euclid Trial,[27] which included 354 normotensive patients with type 1 diabetes aged 20 to 59 years, demonstrated that lisinopril treatment resulted in a 50% reduction in retinopathy progression, 73% reduction in 2-grade retinopathy progression, and an 82% reduction in development of proliferative retinopathy.

Several studies have assessed the effects of hypertension control on nephropathy in patients with type 1 and type 2 DM have been performed assessing effects. A 1983 study [28] showed that effective blood pressure control in patients with diabetes and nephropathy decreased albumin excretion rate by 50% and slowed the rate of GFR decline from 0.29 to 0.1 mL/min/month.

A 2001 meta-analysis [29] of 12 trials demonstrated that ACE inhibitors can delay progression to overt nephropathy by 62% in patients with type 1 CM with microalbuminuria. Many of these patients also experienced decreased albumin excretion rates. No studies in patients with type 1 DM have shown that starting ACE inhibitors when the albumin excretion rate is normal delays the development of microalbuminuria.

The Collaborative Study Group [30] studied the effect of an ACE inhibitor (captopril) in 409 patients with type 1 DM with overt nephropathy (protein excretion >500 mg/d and creatinine <2.5 mg/dL). Creatinine doubled in 12.1% of the patients receiving captopril and in 21.3% of patients receiving placebo (a 48% reduction in risk).

Several studies in patients with type 2 DM with microalbuminuria-with or without hypertension-have found that ACE inhibitors can delay progression to overt nephropathy, decrease the albumin excretion rate, and diminish the decline in GFR. Another study demonstrated that in patients with type 2 DM who were normotensive and normoalbuminuric, treatment with enalapril attenuated the increase in the albumin excretion rate and decreased the likelihood of development of microalbuminuria (a 12.5% risk reduction). In other studies in patients with type 2 DM, there is a slowing of progression of microalbuminuria to overt nephropathy when angiotensin II-receptor blockers are administered.

Recommendations

Glucose, BP control. Based on these studies, the ADA recommends a preprandial plasma glucose goal of 80 to 130 mg/dL and a postprandial goal of <180 mg/dL. The ADA goal for HbA1c is <7% (normal HbA1c is <6%) and the BP goal is <140/90 mm Hg.[31]

The AACE recommends preprandial glucose targets of <110 mg/dL and <140 mg/dL postprandial.[9] The HbA1c goal is <6.5% and the BP goal of <130/85 mm Hg. Both the ADA and AACE recommend HbA1c measurements every 3 months.

Self-administered glucose testing in patients with type 1 DM or in pregnant women with diabetes is recommended at least three times a day. The frequency of glucose monitoring for type 2 DM should be sufficient to facilitate achievement of the glucose goals.

In hypertensive patients with microalbuminuria or albuminuria, therapy with ACE inhibitors or angiotensin II-receptor blockers should be strongly considered. The UKPDS found that intensive blood pressure control decreased microvascular complications by 37% with both ACE inhibitors and beta blockers.[26]

Retinopathy. Patients with type 1 DM should have an initial dilated and comprehensive eye exam within 5 years of the onset of diabetes. Patients with type 2 DM should have an eye exam shortly after diagnosis. Patient with either type 1 or type 2 DM should have subsequent eye exams annually, performed by an ophthalmologist or optometrist knowledgeable and experienced in diagnosing retinopathy.

Visual loss in nonproliferative diabetic retinopathy occurs primarily through development of macular edema. When clinically significant macular edema is present, intraviteral anti vascular endothelial growth factor (VGEF) or focal laser photocoagulation are initial treatment options.

Once retinopathy is established, the best treatment to prevent blindness in those with high-risk and severe proliferative retinopathy is laser photocoagulation. The Diabetic Retinopathy Study found that a 50% reduction in severe visual loss could be achieved by using photocoagulation to treat eyes with neovascularization associated with vitreous hemorrhage or neovascularization on or near the optic disc, and for eyes with proliferative retinopathy or very severe nonproliferative retinopathy.[32,33] Anti-VGEF inhibitors can be used as adjunct therapy to prevent photocoagulation for selected cases of diabetic retinopathy. The Diabetic Retinopathy Clinical Research Network found that 0.5 mg intravitreous ranibizumab was noninferior to panretinal photocoagulation at 2 years in regards to visual acuity outcomes.[34] Long-term data, however, are not available. If vitreous hemorrhage occurs and does not resolve, vitrectomy may restore vision.

Nephropathy. Early nephropathy is associated with microalbuminuria, hypertension, and, possibly, elevated creatinine. First-line therapy is directed toward controlling hypertension. Generally, ACE inhibitors are first-line agents. Patients who develop a severe cough, a common side effect of ACE inhibitors, can be switched to an angiotensin II-receptor blocker. These agents have shown similar efficacy at decreasing microalbuminuria, lowering blood pressure, and preventing worsening renal function. Some calcium channel blockers (diltiazem and verapamil) have been shown to decrease microalbuminuria and may be added to the medications, if necessary. If creatinine increases above 2 or 3 mg/dL, ACE inhibitors should be avoided because overt renal failure can result, which can lead to a need for dialysis or kidney transplant.

Neuropathy. The Diabetes Control and Complications trial found some improvement in neuropathy with intensive diabetes control.[20] If this is not successful, further treatment should focus on analgesia. The most common neuropathy is bilateral distal polyneuropathy. Increasing doses of tricyclic antidepressants, gabapentin, phenytoin, carbamazepine, and benzodiazepines have been used with varying degrees of success. Several agents have shown promise for restoring the structural nerve damage that can cause neuropathy including laminin B2, immunoglobulin FI and FII, nerve growth factor, insulin, and neurotrophin-3. Gastroparesis is treated with metoclopramide.

Management: Macrovascular Risks

Patients with diabetes are at increased risk for the macrovascular complications of CVD. Compared with a nondiabetic population, patients with diabetes have a two- to four-fold increased risk of CVD, and more than half of patients with diabetes die from CVD complications.[35,36] The increased CVD risks include coronary ischemia, stroke, MI, and angina pectoris. Guidelines from the United States and Europe consider type 2 DM to be a CVD equivalent, thereby elevating it to the highest category.[36,37]

Table 3 lists the common CVD risk factors associated with diabetes and recommended therapeutic goals. Practitioners should note that not all patients with diabetes have an elevated risk of a cardiac event, so some discretion may be used with the guidelines.

Table 3. Goals for managing CVD risk factors in patients with diabetes.

Risk Factor

Goal of Therapy

Hyperlipidemia

LDL cholesterol, pts with CVD+DM

LDL <70 mg/dL

LDL cholesterol level elevated

LDL <70 mg/dL

Triglyceride level 200-499 mg/dL

Non-HDL cholesterol level <130 mg/dL

HDL cholesterol level <40 mg/dL

Raise HDL (no specific goal)

Hypertension

BP <140/90 mmHg (ADA, JNC 8)

Prothrombotic state (elevated plasminogen activator inhibitor)

Low-dose aspirin therapy (patients with CVD and other risk factors)

Overweight (BMI 25-29.9 kg/m ²)
Obese (BMI ≥30 kg/m ²)

Decrease BMI to healthy weight

Physical inactivity

Exercise prescription depending on patient's status

Cigarette smoking

Complete cessation

Adverse nutrition

Achieve, maintain goals for plasma glucose, lipids, BP

Abbreviations: ADA=American Diabetes Association; BMI=body mass index; BP=blood pressure; CVD=cardiovascular disease; HDL=high-density lipoprotein; JNC VI=Sixth Report of the Joint National Committee on Prevention, Evaluation, and Treatment of High Blood Pressure; LDL=low-density lipoprotein.

Adapted from ADA and JNC 8.[31, 42].

Dyslipidemia

Guidelines for the management of dyslipidemia have been published by the National Cholesterol Education Program and by expert panels from the AACE, ACP, ADA, ACC, and AHA. The guidelines are generally consistent in recommending aggressive lipid-lowering management in diabetes.

The proposed LDL cholesterol level targets are as follows:[37,39]

The LDL cholesterol level is <100 mg/dL for any patient with diabetes.

If the LDL cholesterol level is <100 mg/dL but triglyceride (and very LDL [VLDL] cholesterol) levels are elevated, then the non-high-density lipoprotein (HDL) cholesterol level should be <130 mg/dL.

For patients at very high risk, such as diabetic patients with a prior MI, the recommended LDL cholesterol level is <70 mg/dL; the non-HDL cholesterol level is <100 mg/dL.

Patients who have an LDL cholesterol level <100 mg/dL without medication should be treated to achieve a >30% reduction in the LDL cholesterol level.

These guidelines are based on findings from lipid-lowering trials that included diabetic patients and were confirmed by subsequent trials.[37]

Post-hoc analyses of diabetic patients who were included in lipid-lowering trials have supported the notion that these patients have comparable relative reductions (or perhaps greater absolute reductions) in the risk for CVD events than their nondiabetic counterparts. These data are summarized in the ACP guidelines.[40] The ADA and AHA guidelines [19] suggest an LDL cholesterol level target of <100 mg/dL for patients with diabetes and an optional target of <70 mg/dL for patients with diabetes and CVD.

In addition, these guidelines recommend that in patients with elevated triglyceride levels and a corresponding increase in VLDL cholesterol levels, that the non-HDL cholesterol value (LDL plus VLDL cholesterol level) be set at 30 mg/dL higher than the LDL target-that is, a non-HDL cholesterol level <130 mg/dL, with an optional target of <100 mg/dL. These guidelines are still recommended by the AACE.

The ACC/AHA guidelines also recommend that patients with diabetes aged 40 to 75 years and an LDL level of 70 to 189 mg/dL should be treated with a high-intensity statin without a target cholesterol level.[41]

Hypertension

In patients with diabetes, large clinical trials have demonstrated favorable effects of BP control on reducing CVD risks. The ADA guidelines recommend BP targets of 140/90 mm Hg.[31, 42] Multidrug regimens (often three or more drugs) are usually required to reach BP targets. Based on studies in patients with diabetes showing favorable cardiovascular results with the ACE inhibitors ramipril (HOPE [43]) and perindopril (EUROPA study [44]), these agents should be considered part of initial therapy in patients with hypertension and type 2 DM.

The large ONTARGET study (N=25,620; 38% with diabetes) evaluated CVD outcomes in three treatment arms: ramipril, telmisartan, and both drugs combined.[45] There were no differences among the three arms. The beneficial effects could not be entirely attributed to BP reduction in these trials. The ACCORD trial showed no benefit in decreasing BP <120 mm Hg versus <140 mm Hg.[46]

Glycemic Control

Intervention trials have shown a somewhat modest relationship between glycemic control and CVD risk. In the UKPDS trial, an HbA1c reduction of 0.9% was associated with a 14% reduction in the MI risk ( P = .052) in the intention-to-treat analyses and a 16% reduction for every 1% HbA1c level change in a post hoc observational analysis.[24, 47] The metformin arm in obese patients in the UKPDS had a 39% reduction in MI risk compared with the conventional arm ( P = .010).[23] The ACCORD (N=10,251) and ADVANCE (N=11,140) trials did not demonstrate beneficial effects of intensive control (HbA1c <7.0%) on CVD events.[48,49]

The Diabetes Control and Complications Trial (DCCT) showed no CV benefits from intensive glucose-control therapy during the initial trial.[50] The Epidemiology of Diabetes Interventions and Complications (EDIC) study, the DCCT long-term follow-up study, found a 42% reduction in risk of any cardiac event during the duration of the DCCT/EDIC study and a 57% reduction in nonfatal myocardial infarction or death from CVD during a 17-year follow-up of the patients in the DCCT.[51]

Two studies published in 2012 suggest that patients with a BMI ≥35 may benefit from gastric bypass surgery as treatment for obesity and diabetes. Mingrone et al [52] found that in patients with a BMI ≥35, 95% of those treated with biliopancreatic diversion and 75% of those treated with gastric bypass had remission of diabetes. Schauer et al [53] found that in obese patients with type 2 DM, the percentage who achieved glycemic control (HbA1c ≤6% at 1 year) was statistically significantly greater in those treated with Roux-en-Y gastric bypass (42%) or sleeve gastrectomy (37%) compared with patients medically managed (12%).

Recommendation. A patient with diabetes should be referred to an endocrinologist if targets for glycemic control cannot be achieved or if the patient is experiencing severe hypoglycemia. It is important to refer patients early in the disease stage to help them avoid long-term complications. Also, patients who develop complications should be referred to an endocrinologist to see if glycemic control can be improved or simply to treat the complications.

Aspirin

Aspirin therapy is recommended in the ADA guidelines for primary prevention of CVD in patients with diabetes.[8, 54] Aspirin is recommended for all adults with a 10-year Framingham CVD risk >10%, for most men ≥50 years old, for most women ≥60 years old, and for those with any of the following risk factors: tobacco use, microalbuminuria, family history of premature CVD, hypertension, and dyslipidemia. Aspirin is recommended for adults with a 10-year risk of a coronary event below 5%, for men younger than 50, and for women younger than 60 with no additional risk factors.

In men aged ≥50 years and in women aged ≥60 years with type 1 or type 2 DM plus an additional risk factor, aspirin should be used for secondary prevention. Aspirin should be used in combination with clopidogrel for up to 1 year in these patients following acute coronary syndrome.

Conclusion

The watchword of the ADA is that diabetes is a serious disease associated with significant morbidity and mortality related to microvascular and macrovascular complications. Careful screening for these complications provides clinicians with opportunities to reduce the risk for their development and progression. Aggressive interventions with glycemic control, as well as management of lipids and blood pressure, seem to have favorable effects on many complications of diabetes. Aspirin therapy has been shown to reduce the CVD risk in these patients. These screening and intervention strategies are supported by robust observational and intervention trial data and, in turn, are endorsed by the various organizations that have written disease management guidelines.

Summary Points

Diabetes is a leading cause of retinopathy, nephropathy, and neuropathy.

Diabetes increases the CVD risk by 2- to 5-fold.

Glycemic control is associated with a reduced risk for both microvascular and macrovascular complications of diabetes.

Treatment of CVD risk factors, especially dyslipidemia, is associated with a reduced risk for CVD events.

Early detection of microvascular complications and implementation of appropriate treatment strategies, such as laser therapy (retinopathy), ACE inhibitors or angiotensin receptor blockers, and proper footwear (neuropathy), can reduce the risk for adverse outcomes from these complications.

Blood pressure goals for patients with diabetes should be <140/90 mm Hg.

Goals for LDL are <100 mg/dL in patients with diabetes; the LDL goal is <70 mg/dL for patients with concomitant coronary heart disease or in patients 40 to 75 years old treated with high-intensity statin.

References

1. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of Diabetic retinopathy: II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1984; 102:520-526.

2. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of Diabetic retinopathy: II. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984; 102:527-532.

3. Friedman EA. Diabetic Renal Disease. In Rifkin H, Porte D, Eds. Diabetes Mellitus/Theory and Practice 1990; 684-709.

4. Vinik AI, Mitchell BD, Leichter SB, Wagner AL, O'Brian IT, Georges LP. Epidemiology of the complications of diabetes. In: Leslie RDG, Robbins DC, eds. Diabetes: Clinical Science in Practice Cambridge, MA: Cambridge University Press; 1995:221.

5. Vinik AI, Pittenger GL, McNitt P, Stansberry KB. Diabetic neuropathies: an overview of clinical aspects, pathogenesis, and treatment. In: LeRoith D, Taylor SI, Olefsky JM, eds. Diabetes Mellitus: A Fundamental and Clinical Text 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:911-934.

6. Kissela BM, Khoury J, Kleindorfer D, et al. Epidemiology of ischemic stroke in patients with diabetes: the greater Cincinnati/Northern Kentucky Stroke Study. Diabetes Care 2005;28:355-359.

7. Melton LJ 3rd, Macken KM, Palumbo PJ, Elveback LR. Incidence and prevalence of clinical peripheral vascular disease in a population-based cohort of diabetic patients. Diabetes Care 1980; 3:650-654.

8. Bax JJ, Young LH, Frye RL, Bonow RO, Steinberg HO, Barrett EJ. Screening for coronary artery disease in patients with diabetes. Diabetes Care 2007; 30:2729-2736.

9. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocr Pract 2015; 21(Suppl 1):1-87.

10. Vinik AI. Diagnosis and management of diabetic neuropathy. Clin Geriatr Med 1999; 15:293-320.

11. Gibbons RJ, Balady GJ, Beasley JW, et al. ACC/AHA guidelines for exercise testing: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). Circulation 1997; 96:345-354.

12. Young LH, Wackers FJ, Chyun DA, et al; DIAD Investigators. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA 2009; 301:1547-55.

13. Jindal V. Neurodegeneration as a primary change and role of neuroprotection in diabetic retinopathy. Mol Neurobiol 2015; 51:878-884.

14. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39(2 Suppl 1):S1-266.

15. Bantle JP, Wylie-Rosett J, Albright AL, et al. Nutrition recommendations and interventions for diabetes-2006: a position statement of the American Diabetes Association. Diabetes Care 2006; 29:2140-2157.

16. Sheard NF, Clark NG, Brand-Miller JC, et al. Dietary carbohydrate (amount and type) in the prevention and management of diabetes: a statement by the American Diabetes Association. Diabetes Care 2004; 27:2266-2271.

17. Foster-Powell K, Holt SH, Brand-Miller JC. International table of glycemic index and glycemic load values: 2002. Am J Clin Nutr 2002;76:5-56.

18. Brand-Miller JC, Holt SHA. Reply to R Mendoza. Glycemic load values [Letters to the Editor]. Am J Clin Nutr 2003; 77:994-995.

19. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2007; 30:162-172.

20. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-986.

21. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000; 342:381-389.

22. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995; 28:103-117.

23. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352:854-865.

24. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). [Erratum 1999; 354:602] Lancet 1998; 352:837-853.

25. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317:713-720.

26. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:703-713.

27. Chautervedi N, Sjolie AK, Stephenson JM, et al, and the EUCLID Study Group. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 1998; 351:28-31.

28. Parving HH, Andersen AR, Smidt UM, Svendsen PA. Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1983; 1(8335):1175-1179.

29. ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001; 134:370-379.

30. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. Collaborative Study Group. N Engl J Med 1993; 329:1456-1462.

31. American Diabetes Association. Standards of medical care in diabetes-2016: position statement. Diabetes Care 2016; 39(Suppl 1):S4-S119.

32. Diabetic Retinopathy Study Research Group: Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. Ophthalmology 1981; 88:583-600.

33. Diabetic Retinopathy Study Research Group. Indications of photocoagulation treatment of diabetic retinopathy: DRS Report No. 14. Int Ophthalmol Clin 1987; 27:239-253.

34. Writing Committee for the Diabetic Retinopathy Clinical Research Network. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA 2015; 314:2137-46.

35. Laing S, Swerdlow AJ, Slater SD, et al. Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes. Diabetologia 2003; 46:760-765.

36. Juutilainen A1, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Type 2 diabetes as a "coronary heart disease equivalent": an 18-year prospective population-based study in Finnish subjects. Diabetes Care 2005; 28:2901-7.

37. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106:3143-421.

38. De Backer G, Ambrosioni E, Borch-Johnsen K, et al; European Society of Cardiology Committee for Practice Guidelines. European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil 2003; 10:S1-S10.

39. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol 2004; 24:e149-e161.

40. Snow V, Aronson MD, Hornbake ER, et al. Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2004; 140:644-649.

41. Stone NJ, Robinson JG, Lichtenstein AH, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129(25 Suppl 2):S1-S45.

42. James P, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507-520.

43. Yusuf S, Sleight P, Pogue J, et al, for the Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342:145-153.

44. Daly CA, Fox KM, Remme WJ, et al. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Eur Heart J 2005; 26:1369-1378.

45. Yusuf S, Teo KK, Pogue J, et al; for the ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547-1559.

46. Soliman EZ, Byington RP, Bigger JT, et al. Effect of intensive blood pressure lowering on left ventricular hypertrophy in patients with diabetes mellitus: Action to Control Cardiovascular Risk in Diabetes Blood Pressure Trial. Hypertension 2015; 66:1123-1129.

47. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321:405-412.

48. Gerstein HC, Miller ME, Byington RP, et al; for the Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545-2559.

49. Patel A, MacMahon S, Chalmers J, et al; for the ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358:2560-2572.

50. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000; 342:381-9.

51. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643-2653.

52. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery verses conventional medical therapy for type 2 diabetes. N Engl J Med 2012; 266:1577-1585.

53. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery verses intensive medical management therapy in obese patients with diabetes. N Engl J Med 2012; 366:1567-1576.

54. Colwell JA. Aspirin therapy in diabetes. Diabetes Care 2004; 27:(Suppl 1)S72-S73.

Suggested Readings

Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321:412-419.

American Association of Diabetes Educators. Position statement. Diabetes education and public health. Diabetes Educ 2000; 26:607-609.

Grundy SM, Howard B, Smith S Jr, et al. Prevention Conference VI: Diabetes and Cardiovascular Disease: Executive summary: Conference proceeding for health care professionals from a special writing group of the American Heart Association. Circulation 2002; 105:2231-2239.

Krauss RM, Eckel RH, Howard B, et al. AHA Dietary Guidelines: Revision 2000: A statement for health care professionals from the Nutrition Committee of the American Heart Association. Circulation 2000; 102:2284-2299.

Lebovitz HE, Austin MM, Blonde L, et al. ACE/AACE consensus conference on the implementation of outpatient management of diabetes mellitus: consensus conference recommendations. Endocr Pract 2006; 12:(Suppl 1)6-12.

Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation 2006; 114:82-96.

Pugliese G. Updating the natural history of diabetic nephropathy. Acta Diabetol 2014; 51:905-915.

Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006; 113:2363-2372.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 2003; 290:2159-2167.

Acknowledgement

This chapter is updated from two previous Disease Management chapters: "Diabetes Mellitus: Disease Management," by Byron J. Hoogwerf, MD, and "Microvascular Complications of Diabetes," by Robert S. Zimmerman, MD.

# data[].attributes.attachment_link.title
Diabetes Mellitus: Management of Microvascular and Macrovascular Complications

# data[].attributes.attachment_link.description
The management of type 1 and 2 diabetes mellitus (DM) requires addressing multiple goals, with the primary goal being glycemic control. Maintaining glycemic control in patients with diabetes prevents many of the microvascular and macrovascular complications associated with diabetes. This chapter presents a review of the prevalence, screening, diagnosis, and management of these complications.

# data[].attributes.body
Discusses other neuropathies such as digestion, urinary, sexual dysfunction.

# data[].attributes.attachment_link.readable_text
Diabetic neuropathies are a family of nerve disorders caused by diabetes. People with diabetes can, over time, develop nerve damage throughout the body. Some people with nerve damage have no symptoms. Others may have symptoms such as pain, tingling, or numbness-loss of feeling-in the hands, arms, feet, and legs. Nerve problems can occur in every organ system, including the digestive tract, heart, and sex organs.

About 60 to 70 percent of people with diabetes have some form of neuropathy. People with diabetes can develop nerve problems at any time, but risk rises with age and longer duration of diabetes. The highest rates of neuropathy are among people who have had diabetes for at least 25 years. Diabetic neuropathies also appear to be more common in people who have problems controlling their blood glucose, also called blood sugar, as well as those with high levels of blood fat and blood pressure, and those who are overweight.

Causes

The causes are probably different for different types of diabetic neuropathy. Researchers are studying how prolonged exposure to high blood glucose causes nerve damage. Nerve damage is likely due to a combination of factors:

Metabolic factors, such as high blood glucose, long duration of diabetes, abnormal blood fat levels, and possibly low levels of insulin

Neurovascular factors, leading to damage to the blood vessels that carry oxygen and nutrients to nerves

Autoimmune factors that cause inflammation in nerves

Mechanical injury to nerves, such as carpal tunnel syndrome

Inherited traits that increase susceptibility to nerve disease

Lifestyle factors, such as smoking or alcohol use

Symptoms

Symptoms depend on the type of neuropathy and which nerves are affected. Some people with nerve damage have no symptoms at all. For others, the first symptom is often numbness, tingling, or pain in the feet. Symptoms are often minor at first, and because most nerve damage occurs over several years, mild cases may go unnoticed for a long time. Symptoms can involve the sensory, motor, and autonomic-or involuntary-nervous systems. In some people, mainly those with focal neuropathy, the onset of pain may be sudden and severe.

Symptoms of nerve damage may include

Numbness, tingling, or pain in the toes, feet, legs, hands, arms, and fingers

Wasting of the muscles of the feet or hands

Indigestion, nausea, or vomiting

Diarrhea or constipation

Dizziness or faintness due to a drop in blood pressure after standing or sitting up

Problems with urination

Erectile dysfunction in men, or vaginal dryness in women

Weakness

Symptoms that are not due to neuropathy, but often accompany it, include weight loss and depression.

Types of Diabetic Neuropathy

Diabetic neuropathy can be classified as peripheral, autonomic, proximal, or focal. Each affects different parts of the body in various ways.

Peripheral neuropathy, the most common type of diabetic neuropathy, causes pain or loss of feeling in the toes, feet, legs, hands, and arms.

Autonomic neuropathy causes changes in digestion, bowel and bladder function, sexual response, and perspiration. It can also affect the nerves that serve the heart and control blood pressure, as well as nerves in the lungs and eyes. Autonomic neuropathy can also cause hypoglycemia unawareness, a condition in which people no longer experience the warning symptoms of low blood glucose levels.

Proximal neuropathy causes pain in the thighs, hips, or buttocks and leads to weakness in the legs.

Focal neuropathy results in the sudden weakness of one nerve or a group of nerves, causing muscle weakness or pain. Any nerve in the body can be affected.

What is peripheral neuropathy?

Peripheral neuropathy, also called distal symmetric neuropathy or sensorimotor neuropathy, is nerve damage in the arms and legs. Feet and legs are likely to be affected before hands and arms. Many people with diabetes have signs of neuropathy that a doctor could note but feel no symptoms themselves. Symptoms of peripheral neuropathy may include:

Numbness or insensitivity to pain or temperature

A tingling, burning, or prickling sensation

Sharp pains or cramps

Extreme sensitivity to touch, even light touch

Loss of balance and coordination

These symptoms are often worse at night.

Peripheral neuropathy may also cause muscle weakness and loss of reflexes, especially at the ankle, leading to changes in the way a person walks. Foot deformities, such as hammertoes and the collapse of the midfoot, may occur. Blisters and sores may appear on numb areas of the foot because pressure or injury goes unnoticed. If an infection occurs and is not treated promptly, the infection may spread to the bone, and the foot may then have to be amputated. Many amputations are preventable if minor problems are caught and treated in time.

What is autonomic neuropathy?

Autonomic neuropathy affects the nerves that control the heart, regulate blood pressure, and control blood glucose levels. Autonomic neuropathy also affects other internal organs, causing problems with digestion, respiratory function, urination, sexual response, and vision. In addition, the system that restores blood glucose levels to normal after a hypoglycemic episode may be affected, resulting in loss of the warning symptoms of hypoglycemia.

Hypoglycemia Unawareness

Normally, symptoms such as shakiness, sweating, and palpitations occur when blood glucose levels drop below 70 mg/dL. In people with autonomic neuropathy, symptoms may not occur, making hypoglycemia difficult to recognize. Problems other than neuropathy can also cause hypoglycemia unawareness.

Heart and Blood Vessels

The heart and blood vessels are part of the cardiovascular system, which controls blood circulation. Damage to nerves in the cardiovascular system interferes with the body's ability to adjust blood pressure and heart rate. As a result, blood pressure may drop sharply after sitting or standing, causing a person to feel light-headed or even to faint. Damage to the nerves that control heart rate can mean that the heart rate stays high, instead of rising and falling in response to normal body functions and physical activity.

Digestive System

Nerve damage to the digestive system most commonly causes constipation. Damage can also cause the stomach to empty too slowly, a condition called gastroparesis. Severe gastroparesis can lead to persistent nausea and vomiting, bloating, and loss of appetite. Gastroparesis can also make blood glucose levels fluctuate widely, due to abnormal food digestion.

Nerve damage to the esophagus may make swallowing difficult, while nerve damage to the bowels can cause constipation alternating with frequent, uncontrolled diarrhea, especially at night. Problems with the digestive system can lead to weight loss.

Urinary Tract and Sex Organs

Autonomic neuropathy often affects the organs that control urination and sexual function. Nerve damage can prevent the bladder from emptying completely, allowing bacteria to grow in the bladder and kidneys and causing urinary tract infections. When the nerves of the bladder are damaged, urinary incontinence may result because a person may not be able to sense when the bladder is full or control the muscles that release urine.

Autonomic neuropathy can also gradually decrease sexual response in men and women, although the sex drive may be unchanged. A man may be unable to have erections or may reach sexual climax without ejaculating normally. A woman may have difficulty with arousal, lubrication, or orgasm.

Sweat Glands

Autonomic neuropathy can affect the nerves that control sweating. When nerve damage prevents the sweat glands from working properly, the body cannot regulate its temperature as it should. Nerve damage can also cause profuse sweating at night or while eating.

Eyes

Finally, autonomic neuropathy can affect the pupils of the eyes, making them less responsive to changes in light. As a result, a person may not be able to see well when a light is turned on in a dark room or may have trouble driving at night.

What is proximal neuropathy?

Proximal neuropathy, sometimes called lumbosacral plexus neuropathy, femoral neuropathy, or diabetic amyotrophy, starts with pain in the thighs, hips, buttocks, or legs, usually on one side of the body. This type of neuropathy is more common in those with type 2 diabetes and in older adults with diabetes. Proximal neuropathy causes weakness in the legs and the inability to go from a sitting to a standing position without help. Treatment for weakness or pain is usually needed. The length of the recovery period varies, depending on the type of nerve damage.

What is focal neuropathy?

Focal neuropathy appears suddenly and affects specific nerves, most often in the head, torso, or leg. Focal neuropathy may cause

Inability to focus the eye

Double vision

Aching behind one eye

Paralysis on one side of the face, called Bell's palsy

Severe pain in the lower back or pelvis

Pain in the front of a thigh

Pain in the chest, stomach, or side

Pain on the outside of the shin or inside of the foot

Chest or abdominal pain that is sometimes mistaken for heart disease, a heart attack, or appendicitis

Focal neuropathy is painful and unpredictable and occurs most often in older adults with diabetes. However, it tends to improve by itself over weeks or months and does not cause long-term damage.

People with diabetes also tend to develop nerve compressions, also called entrapment syndromes. One of the most common is carpal tunnel syndrome, which causes numbness and tingling of the hand and sometimes muscle weakness or pain. Other nerves susceptible to entrapment may cause pain on the outside of the shin or the inside of the foot.

Prevention

The best way to prevent neuropathy is to keep blood glucose levels as close to the normal range as possible. Maintaining safe blood glucose levels protects nerves throughout the body.

Diagnosis

Doctors diagnose neuropathy on the basis of symptoms and a physical exam. During the exam, the doctor may check blood pressure, heart rate, muscle strength, reflexes, and sensitivity to position changes, vibration, temperature, or light touch.

Foot Exams

Experts recommend that people with diabetes have a comprehensive foot exam each year to check for peripheral neuropathy. People diagnosed with peripheral neuropathy need more frequent foot exams. A comprehensive foot exam assesses the skin, muscles, bones, circulation, and sensation of the feet. The doctor may assess protective sensation or feeling in the feet by touching them with a nylon monofilament-similar to a bristle on a hairbrush-attached to a wand, or by pricking them with a pin. People who cannot sense pressure from a pinprick or monofilament have lost protective sensation and are at risk for developing foot sores that may not heal properly. The doctor may also check temperature perception or use a tuning fork, which is more sensitive than touch pressure, to assess vibration perception.

Other Tests

The doctor may perform other tests as part of the diagnosis.

Nerve conduction studies or electromyography are sometimes used to help determine the type and extent of nerve damage. Nerve conduction studies check the transmission of electrical current through a nerve. Electromyography shows how well muscles respond to electrical signals transmitted by nearby nerves. These tests are rarely needed to diagnose neuropathy.

A check of heart rate variability shows how the heart responds to deep breathing and to changes in blood pressure and posture.

Ultrasound uses sound waves to produce an image of internal organs. An ultrasound of the bladder and other parts of the urinary tract, for example, can be used to assess the structure of these organs and show whether the bladder empties completely after urination.

Treatment

The first treatment step is to bring blood glucose levels within the normal range to help prevent further nerve damage. Blood glucose monitoring, meal planning, physical activity, and diabetes medicines or insulin will help control blood glucose levels. Symptoms may get worse when blood glucose is first brought under control, but over time, maintaining lower blood glucose levels helps lessen symptoms. Good blood glucose control may also help prevent or delay the onset of further problems. As scientists learn more about the underlying causes of neuropathy, new treatments may become available to help slow, prevent, or even reverse nerve damage.

As described in the following sections, additional treatment depends on the type of nerve problem and symptom.

Pain Relief

Doctors usually treat painful diabetic neuropathy with oral medications, although other types of treatments may help some people. People with severe nerve pain may benefit from a combination of medications or treatments and should consider talking with a health care provider about treatment options.

Medications used to help relieve diabetic nerve pain include

Tricyclic antidepressants, such as amitriptyline, imipramine, and desipramine (Norpramin, Pertofrane)

Other types of antidepressants, such as duloxetine (Cymbalta), venlafaxine, bupropion (Wellbutrin), paroxetine (Paxil), and citalopram (Celexa)

Anticonvulsants, such as pregabalin (Lyrica), gabapentin (Gabarone, Neurontin), carbamazepine, and lamotrigine (Lamictal)

Opioids and opioidlike drugs, such as controlled-release oxycodone, an opioid; and tramadol (Ultram), an opioid that also acts as an antidepressant

Duloxetine and pregabalin are approved by the U.S. Food and Drug Administration specifically for treating painful diabetic peripheral neuropathy.

People do not have to be depressed for an antidepressant to help relieve their nerve pain. All medications have side effects, and some are not recommended for use in older adults or those with heart disease. Because over-the-counter pain medicines such as acetaminophen and ibuprofen may not work well for treating most nerve pain and can have serious side effects, some experts recommend avoiding these medications.

Treatments that are applied to the skin-typically to the feet-include capsaicin cream and lidocaine patches (Lidoderm, Lidopain). Studies suggest that nitrate sprays or patches for the feet may relieve pain. Studies of alpha-lipoic acid, an antioxidant, and evening primrose oil suggest they may help relieve symptoms and improve nerve function in some patients.

A device called a bed cradle can keep sheets and blankets from touching sensitive feet and legs. Acupuncture, biofeedback, or physical therapy may help relieve pain in some people. Treatments that involve electrical nerve stimulation, magnetic therapy, and laser or light therapy may be helpful but need further study. Researchers are also studying several new therapies in clinical trials.

Gastrointestinal Problems

To relieve mild symptoms of gastroparesis-indigestion, belching, nausea, or vomiting-doctors suggest eating small, frequent meals; avoiding fats; and eating less fiber. When symptoms are severe, doctors may prescribe erythromycin to speed digestion, metoclopramide to speed digestion and help relieve nausea, or other medications to help regulate digestion or reduce stomach acid secretion.

To relieve diarrhea or other bowel problems, doctors may prescribe an antibiotic such as tetracycline, or other medications as appropriate.

Dizziness and Weakness

Sitting or standing slowly may help prevent the light-headedness, dizziness, or fainting associated with blood pressure and circulation problems. Raising the head of the bed or wearing elastic stockings may also help. Some people benefit from increased salt in the diet and treatment with salt-retaining hormones. Others benefit from high blood pressure medications. Physical therapy can help when muscle weakness or loss of coordination is a problem.

Urinary and Sexual Problems

To clear up a urinary tract infection, the doctor will probably prescribe an antibiotic. Drinking plenty of fluids will help prevent another infection. People who have incontinence should try to urinate at regular intervals-every 3 hours, for example-because they may not be able to tell when the bladder is full.

To treat erectile dysfunction in men, the doctor will first do tests to rule out a hormonal cause. Several methods are available to treat erectile dysfunction caused by neuropathy. Medicines are available to help men have and maintain erections by increasing blood flow to the penis. Some are oral medications and others are injected into the penis or inserted into the urethra at the tip of the penis. Mechanical vacuum devices can also increase blood flow to the penis. Another option is to surgically implant an inflatable or semirigid device in the penis.

Vaginal lubricants may be useful for women when neuropathy causes vaginal dryness. To treat problems with arousal and orgasm, the doctor may refer women to a gynecologist.

Foot Care

People with neuropathy need to take special care of their feet. The nerves to the feet are the longest in the body and are the ones most often affected by neuropathy. Loss of sensation in the feet means that sores or injuries may not be noticed and may become ulcerated or infected. Circulation problems also increase the risk of foot ulcers. Smoking increases the risk of foot problems and amputation. A health care provider may be able to provide help with quitting smoking.

More than 60 percent of all nontraumatic lower-limb amputations in the United States occur in people with diabetes. Nontraumatic amputations are those not caused by trauma, such as severe injuries from an accident. In 2004, about 71,000 nontraumatic amputations were performed in people with diabetes. Comprehensive foot care programs can reduce amputation rates by 45 to 85 percent.

Careful foot care involves:

Cleaning the feet daily using warm-not hot-water and a mild soap. Soaking the feet should be avoided. A soft towel can be used to dry the feet and between the toes.

Inspecting the feet and toes every day for cuts, blisters, redness, swelling, calluses, or other problems. Using a mirror-handheld or placed on the floor-may be helpful in checking the bottoms of the feet, or another person can help check the feet. A health care provider should be notified of any problems.

Using lotion to moisturize the feet. Getting lotion between the toes should be avoided.

Filing corns and calluses gently with a pumice stone after a bath or shower.

Cutting toenails to the shape of the toes and filing the edges with an emery board each week or when needed.

Always wearing shoes or slippers to protect feet from injuries. Wearing thick, soft, seamless socks can prevent skin irritation.

Wearing shoes that fit well and allow the toes to move. New shoes can be broken in gradually by first wearing them for only an hour at a time.

Looking shoes over carefully before putting them on, and feeling the insides to make sure the shoes are free of tears, sharp edges, or objects that might injure the feet.

People who need help taking care of their feet should consider making an appointment to see a foot doctor, also called a podiatrist.

Points to Remember

Diabetic neuropathies are nerve disorders caused by many of the abnormalities common to diabetes, such as high blood glucose.

Neuropathy can affect nerves throughout the body, causing numbness and sometimes pain in the hands, arms, feet, or legs, and problems with the digestive tract, heart, sex organs, and other body systems.

Treatment first involves bringing blood glucose levels within the normal range. Good blood glucose control may help prevent or delay the onset of further problems.

Foot care is an important part of treatment. People with neuropathy need to inspect their feet daily for any injuries. Untreated injuries increase the risk of infected foot sores and amputation.

Treatment also includes pain relief and other medications as needed, depending on the type of nerve damage.

Smoking increases the risk of foot problems and amputation. A health care provider may be able to provide help with quitting.

# data[].attributes.attachment_link.description
Diabetic neuropathies are a family of nerve disorders caused by diabetes. People with diabetes can, over time, develop nerve damage throughout the body. Some people with nerve damage have no symptoms. Others may have symptoms such as pain, tingling, or numbness-loss of feeling-in the hands, arms, feet, and legs.

# data[].attributes.attachment_link.readable_text
There are two main types of complications of diabetes, which are called microvascular and macrovascular. Macrovascular, referring to the term macro, involves issues with macro circulation, which is the circulatory system itself, in other words causing disease in the cardiovascular system itself, while the micro kind involves micro circulation, involving things such as the eyes, the kidneys, and the nerves.

For the most part, the concerns about diabetic complications are focused a lot on the microvascular system, things like retinopathy, a disease of the retina, neuropathy, which affects the nerves, most notably the nerves in the perhiphery such as the feet and hands, and nephropathy, which affects the kidneys.

It is true that we are at particular risk for microvascular complications, since we are talking about more delicate systems that are more easily disturbed, but for the most part this is more of a focus because of the much higher risk that diabetics are subject to with these particular conditions.

High blood sugar is actually a big culprit here, this is why you see such strong correlations between A1C and these complications, and the higher the A1C, and therefore the higher the blood sugar, the more oxidative stress one is subject to, which ends up damaging one's microcirculation and nerve fibers to the extent that one experiences damage and symptoms.

Technically speaking, neuropathy isn't really a microcirculation disorder, it's a disorder of the nerves themselves, but it gets thrown into this category, and it actually makes sense to because the pathologies are pretty similar to things like retinopathy and nephropathy, which do involve microcirculation.

So the focus with the micro stuff we'll call it is almost exclusively on blood sugar levels, and while blood sugar levels are important here, when we focus too much on this we end up neglecting the fact that there is another major component of this that plays a very critical role in this disease process, which is oxidation.

So you need both, high blood sugar and too much oxidation of it, to be out of hand to get damage, and while the higher your blood sugar is the more oxidative stress you have, the body does have defences to this process which do vary. So we should not only be looking to improve our blood sugar here and reduce the oxidative load, we should also be focused on minimizing the damage from oxidation, by focusing on enhancing the body's antioxidant capacity.

So there are a bunch of things you can take for this, and this stuff has been shown to have a big impact on not only preventing oxidative damage from high blood sugar, but actually correcting and healing it, although people tend to not pay much attention to this until they get the complications, and even then, may not make enough of an effort to bolster the body's natural response to such things.

Most people though don't have a clue about this and if you asked 100 diabetics what role oxidation and glycation plays in diabetes, or what the best things to take to help this was, few would know. Your doctor probably wouldn't know either, this isn't stuff they are taught.

This is because our system is so focused on drugs, but they have no drugs to prevent this and really don't have much to help you when you get this stuff either, they can give you an anti epileptic drug to dull the pain of neuropathy for instance to provide some relief as the disease ravages on, until even that isn't enough to relieve your suffering much.

So this is dysfunctional medicine after all, so they aren't interested in improving the body's function, and they certainly aren't interested in recommending natural medicines. I'll have much more to say on this in future articles, including some good things you can take to both prevent and treat microvascular complications of diabetes.

It's not just high blood sugar levels we need to be concerned about with microvascular complications, high insulin levels are harmful to this as well. Normal insulin levels are perfectly fine and safe, but the body isn't designed to handle the toxic levels we see in diabetics, and since insulin is pro inflammatory in excess, it can cause quite a bit of oxidative stress itself when too high, as high blood sugar does.

As far as the other type of complication goes, macrovascular complications, high insulin is at the forefront of this and may actually be even worse than high blood sugar in causing this. We know this is the case actually from the ACCORD study alone where people's blood sugar was decreased, and their insulin levels were increased, and they got more macrovascular complications.

We have a lot of evidence to show this, for instance I picked a particular study for you to look at if you like which shows that we can test people's insulin levels and the people with high levels are at more risk for macrovascular complications, as well as other conditions including obesity, and it's probably the obesity that is behind most of the added risk here.

All we have to do is look at what obesity tends to cause, including diabetes, to get an idea of what we're talking about here, and the relationship between obesity and cardiovascular disease is one that is beyond any doubt. The relationship between high insulin and obesity is another link that we can be certain of, and there's lots of evidence showing this as well.

There is more to it than that though as high insulin itself has also been shown to advance cardiovascular disease risk independent of obesity, and it's not hard to imagine how. Once again, excessive insulin causes excess inflammation, and this excess insulin flows around the blood stream, and it's clear that inflammation to the circulatory system plays a big role in cardiovascular disease.

So the bottom line here is that we need to be worrying about a lot more than high blood sugar when we are looking to manage the risks of diabetic complications, I personally am more worried about high insulin than I am about high blood sugar, from everything I've read, and there are others that feel the same way.

The people who just worry about blood sugar on the other hand are the people that haven't really looked into the risks of high insulin, and just assume that if our blood sugar is high, we need more insulin, and blood sugar levels are the only thing that matter, but that's a mistake. We instead need to account for both of these conditions and find a solution that minimizes our risks here overall, which also includes taking things that help this, as we aren't as helpless here as conventional medicine would lead you to believe.

# data[].attributes.attachment_link.title
Microvascular And Macrovascular Complications - Understanding Type 2 Diabetes

# data[].attributes.attachment_link.description
There are two main types of complications of diabetes, which are called microvascular and macrovascular. Macrovascular, referring to the term macro, involves issues with macro circulation, which is the circulatory system itself, in other words causing disease in the cardiovascular system itself, while the micro kind involves micro circulation, involving things such as the eyes, the kidneys, and the nerves.

# data[].attributes.headline
Occurs from lack of insulin. Noncompliance, infection, or other event, such as an MI, increases the need for insulin. DKA is largely preventable with  proper diabetes management (Kreider, 2018).

# data[].attributes.subject
Occurs from lack of insulin. Noncompliance, infection, or other event, such as an MI, increases the need for insulin. DKA is largely preventable with  proper diabetes management (Kreider, 2018).

# data[].attributes.body
Increased glucose levels (>250 mg/dL), metabolic acidosis, and ketosis.

Can occur at any age, most commonly 11-15 years of age.

Females are at higher risk.

References:
Kreider, K. E. (2018). Updates in the management of diabetic ketoacidosis. The Journal of Nurse Practitioners, 14(8), 591-597. https://doi.org/10.1016/j.nurpra.2018.06.013

# data[].attributes.body
Main cause is insulin deficiency and an increase in counter regulatory hormones. The lack of insulin free fatty acids, from adipocytes increases the production of ketone bodies at a rate faster than they're used (McCance & Huether, 2019)

# data[].attributes.attachment_link.readable_text
Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis

INTRODUCTION

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also known as hyperosmotic hyperglycemic nonketotic state [HHNK]) are two of the most serious acute complications of diabetes. DKA is characterized by ketoacidosis and hyperglycemia, while HHS usually has more severe hyperglycemia but no ketoacidosis ( table 1). Each represents an extreme in the spectrum of hyperglycemia.

The precipitating factors, clinical features, evaluation, and diagnosis of DKA and HHS in adults will be reviewed here. The epidemiology, pathogenesis, and treatment of these disorders are discussed separately. DKA in children is also reviewed separately.

●(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis".)

●(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment".)

●(See "Diabetic ketoacidosis in children: Clinical features and diagnosis".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription.

Literature review current through: Apr 2021. | This topic last updated: Mar 29, 2020.

The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of UpToDate content is governed by the UpToDate Terms of Use. ©2021 UpToDate, Inc. All rights reserved.

REFERENCES

1. Kitabchi AE, Razavi L.Hyperglycemic Crises: Diabetic Ketoacidosis (DKA), And Hyperglycemic Hyperosmolar State (HHS). In: http://www.endotext.org/diabetes/diabetes24/diabetesframe24.htm (Accessed on January 30, 2013).

2. Randall L, Begovic J, Hudson M, et al. Recurrent diabetic ketoacidosis in inner-city minority patients: behavioral, socioeconomic, and psychosocial factors. Diabetes Care 2011; 34:1891.

3. Wachtel TJ, Tetu-Mouradjian LM, Goldman DL, et al. Hyperosmolarity and acidosis in diabetes mellitus: a three-year experience in Rhode Island. J Gen Intern Med 1991; 6:495.

4. Wachtel TJ. The diabetic hyperosmolar state. Clin Geriatr Med 1990; 6:797.

5. Wachtel TJ, Silliman RA, Lamberton P. Prognostic factors in the diabetic hyperosmolar state. J Am Geriatr Soc 1987; 35:737.

6. Kitabchi AE, Murphy MB. Consequences of insulin deficiency. In: Atlas of Diabetes, 4th, Skyler J (Ed), Springer US, New York 2012. p.39.

7. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19 Suppl 1:1.

8. Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab 2015; 100:2849.

9. Warner EA, Greene GS, Buchsbaum MS, et al. Diabetic ketoacidosis associated with cocaine use. Arch Intern Med 1998; 158:1799.

10. Nyenwe EA, Loganathan RS, Blum S, et al. Active use of cocaine: an independent risk factor for recurrent diabetic ketoacidosis in a city hospital. Endocr Pract 2007; 13:22.

11. Polonsky WH, Anderson BJ, Lohrer PA, et al. Insulin omission in women with IDDM. Diabetes Care 1994; 17:1178.

12. Peden NR, Braaten JT, McKendry JB. Diabetic ketoacidosis during long-term treatment with continuous subcutaneous insulin infusion. Diabetes Care 1984; 7:1.

13. Pańkowska E, Błazik M, Dziechciarz P, et al. Continuous subcutaneous insulin infusion vs. multiple daily injections in children with type 1 diabetes: a systematic review and meta-analysis of randomized control trials. Pediatr Diabetes 2009; 10:52.

14. Daugirdas JT, Kronfol NO, Tzamaloukas AH, Ing TS. Hyperosmolar coma: cellular dehydration and the serum sodium concentration. Ann Intern Med 1989; 110:855.

15. Fulop M, Tannenbaum H, Dreyer N. Ketotic hyperosmolar coma. Lancet 1973; 2:635.

16. Kitabchi AE, Fisher JN. Insulin therapy of diabetic ketoacidosis: Physiologic versus pharmacologic doses of insulin and their routes of administration. In: Handbook of Diabetes Mellitus, Brownlee M (Ed), Garland ATPM Press, New York 1981. p.95.

17. Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am 1995; 79:39.

18. Maccario M. Neurological dysfunction associated with nonketotic hyperglycemia. Arch Neurol 1968; 19:525.

19. Guisado R, Arieff AI. Neurologic manifestations of diabetic comas: correlation with biochemical alterations in the brain. Metabolism 1975; 24:665.

20. Lavin PJ. Hyperglycemic hemianopia: a reversible complication of non-ketotic hyperglycemia. Neurology 2005; 65:616.

21. Harden CL, Rosenbaum DH, Daras M. Hyperglycemia presenting with occipital seizures. Epilepsia 1991; 32:215.

22. Nyenwe EA, Razavi LN, Kitabchi AE, et al. Acidosis: the prime determinant of depressed sensorium in diabetic ketoacidosis. Diabetes Care 2010; 33:1837.

23. Malone ML, Gennis V, Goodwin JS. Characteristics of diabetic ketoacidosis in older versus younger adults. J Am Geriatr Soc 1992; 40:1100.

24. Umpierrez G, Freire AX. Abdominal pain in patients with hyperglycemic crises. J Crit Care 2002; 17:63.

25. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009; 32:1335.

26. Barrett EJ, DeFronzo RA. Diabetic ketoacidosis: diagnosis and treatment. Hosp Pract (Off Ed) 1984; 19:89.

27. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care 2001; 24:131.

28. Arieff AI, Carroll HJ. Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine (Baltimore) 1972; 51:73.

29. Munro JF, Campbell IW, McCuish AC, Duncan LJ. Euglycaemic diabetic ketoacidosis. Br Med J 1973; 2:578.

30. Burge MR, Hardy KJ, Schade DS. Short-term fasting is a mechanism for the development of euglycemic ketoacidosis during periods of insulin deficiency. J Clin Endocrinol Metab 1993; 76:1192.

31. Eisenbarth GS, Polonsky KS, Buse JB. Type 1 diabetes mellitus: Acute diabetic emergencies: Diabetic ketoacidosis. In: Williams Textbook of Endocrinology, Larsen PR, Kronenberg HM, Melmed S, Polonsky KS (Eds), Elsevier Science, Philadelphia 2003. p.1500.

32. Qiu H, Novikov A, Vallon V. Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: Basic mechanisms and therapeutic perspectives. Diabetes Metab Res Rev 2017; 33.

33. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999; 15:412.

34. Sheikh-Ali M, Karon BS, Basu A, et al. Can serum beta-hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes Care 2008; 31:643.

35. Wiggam MI, O'Kane MJ, Harper R, et al. Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management. A randomized controlled study. Diabetes Care 1997; 20:1347.

36. Porter WH, Yao HH, Karounos DG. Laboratory and clinical evaluation of assays for beta-hydroxybutyrate. Am J Clin Pathol 1997; 107:353.

37. Fulop M, Murthy V, Michilli A, et al. Serum beta-hydroxybutyrate measurement in patients with uncontrolled diabetes mellitus. Arch Intern Med 1999; 159:381.

38. Smith SW, Manini AF, Szekely T, Hoffman RS. Bedside detection of urine beta-hydroxybutyrate in diagnosing metabolic acidosis. Acad Emerg Med 2008; 15:751.

39. Bektas F, Eray O, Sari R, Akbas H. Point of care blood ketone testing of diabetic patients in the emergency department. Endocr Res 2004; 30:395.

40. DeFronzo RA, Matzuda M, Barret E. Diabetic ketoacidosis: a combined metabolic-nephrologic approach to therapy. Diabetes Rev 1994; 2:209.

41. Adrogué HJ, Lederer ED, Suki WN, Eknoyan G. Determinants of plasma potassium levels in diabetic ketoacidosis. Medicine (Baltimore) 1986; 65:163.

42. Khardori R, Soler NG. Hyperosmolar hyperglycemic nonketotic syndrome. Report of 22 cases and brief review. Am J Med 1984; 77:899.

43. Phillips PA, Bretherton M, Johnston CI, Gray L. Reduced osmotic thirst in healthy elderly men. Am J Physiol 1991; 261:R166.

44. Kaminska ES, Pourmotabbed G. Spurious laboratory values in diabetic ketoacidosis and hyperlipidemia. Am J Emerg Med 1993; 11:77.

45. Rumbak MJ, Hughes TA, Kitabchi AE. Pseudonormoglycemia in diabetic ketoacidosis with elevated triglycerides. Am J Emerg Med 1991; 9:61.

46. Emmett M. Case 6: Diabetes and Acidosis. In: NephSAP: Nephrology Self-Assessment Program: Fluid, Electrolyte, and Acid-Base Disturbances, Sterns RH, Emmett M (Eds), The American Society of Nephrology 2013. Vol 12, No 3, p.191.

47. Graber ML, Quigg RJ, Stempsey WE, Weis S. Spurious hyperchloremia and decreased anion gap in hyperlipidemia. Ann Intern Med 1983; 98:607.

48. Kreisberg RA. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment. Ann Intern Med 1978; 88:681.

49. Abramson E, Arky R. Diabetic acidosis with initial hypokalemia. Therapeutic implications. JAMA 1966; 196:401.

50. Murthy K, Harrington JT, Siegel RD. Profound hypokalemia in diabetic ketoacidosis: a therapeutic challenge. Endocr Pract 2005; 11:331.

51. Arora S, Cheng D, Wyler B, Menchine M. Prevalence of hypokalemia in ED patients with diabetic ketoacidosis. Am J Emerg Med 2012; 30:481.

52. Atchley DW, Loeb RF, Richards DW, et al. ON DIABETIC ACIDOSIS: A Detailed Study of Electrolyte Balances Following the Withdrawal and Reestablishment of Insulin Therapy. J Clin Invest 1933; 12:297.

53. Kebler R, McDonald FD, Cadnapaphornchai P. Dynamic changes in serum phosphorus levels in diabetic ketoacidosis. Am J Med 1985; 79:571.

54. Shen T, Braude S. Changes in serum phosphate during treatment of diabetic ketoacidosis: predictive significance of severity of acidosis on presentation. Intern Med J 2012; 42:1347.

55. Molitch ME, Rodman E, Hirsch CA, Dubinsky E. Spurious serum creatinine elevations in ketoacidosis. Ann Intern Med 1980; 93:280.

56. Kemperman FA, Weber JA, Gorgels J, et al. The influence of ketoacids on plasma creatinine assays in diabetic ketoacidosis. J Intern Med 2000; 248:511.

57. Yadav D, Nair S, Norkus EP, Pitchumoni CS. Nonspecific hyperamylasemia and hyperlipasemia in diabetic ketoacidosis: incidence and correlation with biochemical abnormalities. Am J Gastroenterol 2000; 95:3123.

58. Warshaw AL, Feller ER, Lee KH. On the cause of raised serum-amylase in diabetic ketoacidosis. Lancet 1977; 1:929.

59. Vinicor F, Lehrner LM, Karn RC, Merritt AD. Hyperamylasemia in diabetic ketoacidosis: sources and significance. Ann Intern Med 1979; 91:200.

60. Vantyghem MC, Haye S, Balduyck M, et al. Changes in serum amylase, lipase and leukocyte elastase during diabetic ketoacidosis and poorly controlled diabetes. Acta Diabetol 1999; 36:39.

61. Kjaergaard JJ, Salling N, Magid E, Ditzel J. Serum amylase during recovery from diabetic ketoacidosis. Diabete Metab 1984; 10:25.

62. Nair S, Yadav D, Pitchumoni CS. Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA. Am J Gastroenterol 2000; 95:2795.

63. Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE. Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes 2004; 53:2079.

64. Nematollahi LR, Taheri E, Larijani B, et al. Catecholamine-induced leukocytosis in acute hypoglycemic stress. J Investig Med 2007; 55:S262.

65. Slovis CM, Mork VG, Slovis RJ, Bain RP. Diabetic ketoacidosis and infection: leukocyte count and differential as early predictors of serious infection. Am J Emerg Med 1987; 5:1.

66. Weidman SW, Ragland JB, Fisher JN Jr, et al. Effects of insulin on plasma lipoproteins in diabetic ketoacidosis: evidence for a change in high density lipoprotein composition during treatment. J Lipid Res 1982; 23:171.

67. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th, McGraw-Hill, New York 2001. p.809-815.

68. Morris LR, Kitabchi AE. Efficacy of low-dose insulin therapy for severely obtunded patients in diabetic ketoacidosis. Diabetes Care 1980; 3:53.

69. Szeto CC, Li KY, Ko GT, et al. Acromegaly in a woman presenting with diabetic ketoacidosis and insulin resistance. Int J Clin Pract 1997; 51:476.

70. Shah P, Isley WL. Ketoacidosis during a low-carbohydrate diet. N Engl J Med 2006; 354:97.

71. Reichard GA Jr, Owen OE, Haff AC, et al. Ketone-body production and oxidation in fasting obese humans. J Clin Invest 1974; 53:508.

72. Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006; 26:1.

73. Mahoney CA. Extreme gestational starvation ketoacidosis: case report and review of pathophysiology. Am J Kidney Dis 1992; 20:276.

74. Wrenn KD, Slovis CM, Minion GE, Rutkowski R. The syndrome of alcoholic ketoacidosis. Am J Med 1991; 91:119.

# data[].attributes.attachment_link.title
Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis - UpToDate

# data[].attributes.attachment_link.description
Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis INTRODUCTION Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also known as hyperosmotic hyperglycemic nonketotic state [HHNK]) are two of the most serious acute complications of diabetes. DKA is characterized by ketoacidosis and hyperglycemia, while HHS usually has more severe hyperglycemia but no ketoacidosis ( table 1).

# data[].attributes.attachment_link.readable_text
Uncontrolled diabetes can cause metabolic imbalance leading to acute complications that may require immediate medical attention. Hyperglycemia (high levels of glucose in blood) sets the stage for protein glycation, which in turn may lead to chronic conditions requiring constant monitoring and treatment. Individuals with diabetes may also develop high cholesterol and high blood pressure, which require medical management.
Acute Complications - Require Immediate Medical Intervention

Ketoacidosis: Despite high blood glucose levels, the body cells (muscle and lipid cells) may be starved for glucose due to absence or improper function of insulin. Cells may also starve for glucose if the amount of food intake is low (such as during illness) or if the dosage of insulin is too high. Under these conditions cells start using fats as a source of energy. Liver cells produce ketone bodies from fatty acids. When the glucose levels are low, brain cells can use ketone bodies, but not free fatty acids, for energy. High concentrations of ketones can make the urine acidic and cause fruity-smelling breath. If not managed, this condition can progress to coma (prolonged unconsciousness) and even death.

Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNS): High blood glucose level triggers increased urination. If liquids are not replaced, the individual can become severely dehydrated. High blood glucose levels can lead to altered mental states, confusion, seizures, coma, and even death.

Chronic Complications - Long-term Side Effects of Diabetes

Microvascular complications affect the smaller blood vessels, such as in the eyes (leading to retinopathy), kidneys (leading to nephropathy), and neurons (leading to neuropathy). Individuals with poorly managed blood glucose levels may suffer from one or more of these complications in advanced stages of the disease. Thus, besides monitoring the health of eyes and kidneys, diabetics also require foot care. Interestingly, several large population studies have shown that aggressive management of blood glucose levels (i.e., keeping blood glucose levels within a narrow range) can avoid, or at least delay, the onset of these complications (Nathan et al., 2014). Regular monitoring and management of blood glucose levels is of critical importance in maintaining metabolic balance and avoiding microvascular complications.

Macrovascular complications affect larger blood vessels, such as those supplying the heart, brain, and extremities. The causes of these complications stem from narrowing of blood vessels due to glycation, inflammation, lipid deposition and other factors. Complications resulting from large vessel damage may lead to cardiomyopathy, stroke, rheumatoid arthritis, osteoporosis, and the degenerative process of aging (Singh et al., 2014). The major concern amongst these complications is myocardial infarction (heart attack). At present, it appears that blood glucose control does not significantly reduce the risks or delay the onset of macrovascular complications. Additional medical management is required.

Figure 1. Major microvascular and macrovascular complications associated with diabetes mellitus. Parts of the image were adapted from Servier Medical Art.
Protein Glycation
When proteins are exposed to high levels of sugar, for long periods of time, they may covalently attach to proteins by a non-enzymatic process, called glycation (Singh et al., 2014). Note that this process differs from the post-translational glycosylation of proteins in rough endoplasmic reticulum and Golgi, where sugars are attached to proteins systematically, by specific enzymes and carrier proteins.

In early stages of glycation, sugars react with free amino groups on the protein to form a Schiff base, which further undergoes rearrangements to form a more stable product called amadori product. Over time, these glycated proteins may be further modified to form advanced glycation products (AGEs). Receptors for AGEs bind to these adducts and initiate an inflammation response, which in turn lead to some of the complications of diabetes.

In poorly managed diabetes, the blood glucose levels may be high and proteins found in the blood, such as albumin, immunoglobulins, and collagen, are often glycated. A glycated product of hemoglobin (an oxygen transporting molecule present in red blood cells), called Hb A1c is used as a measure of overall glucose management in individuals with diabetes.

Diabetes and Foot Care:

Diabetic foot infection (DFI) is a common and complex problem in individuals with diabetes. Due to nerve damage and numbness, individuals with diabetes may not feel any pain and foot ulcers may go undetected for long periods. Infections in these ulcers may also go untreated and even when detected may heal slowly (due to peripheral artery disease). In extreme cases, the ulcers and infections may lead to gangrene and require amputation.

Treating foot ulcers in diabetic patients is challenging. Often, multiple microorganisms infect the ulcers, some of which may be resistant to standard antimicrobial treatments. In order to effectively treat the infection, ideally the ulcer microbiome (genomes of all microorganisms found in the ulcer) should be studied. State of the art treatment protocols use molecular techniques such as polymerase chain reaction (PCR) and gene sequencing to identify key components of the ulcer microbiota and design specific treatments. However, such thorough analysis is currently not the standard of medical care for diabetic patients with foot ulcers.

# data[].attributes.attachment_link.title
PDB101: Global Health: Diabetes Mellitus: Monitoring: Complications

# data[].attributes.attachment_link.description
Uncontrolled diabetes can cause metabolic imbalance leading to acute complications that may require immediate medical attention. Hyperglycemia (high levels of glucose in blood) sets the stage for protein glycation, which in turn may lead to chronic conditions requiring constant monitoring and treatment. Individuals with diabetes may also develop high cholesterol and high blood pressure, which require medical management.

# data[].attributes.attachment_link.readable_text
Key Points

Diabetes is associated with significant microvascular complications: retinopathy, neuropathy and nephropathy

Diabetic retinopathy remains the most common cause of blindness in working-age adults in the developed world.

Early aggressive treatment of microalbuminuria reduces the risk of the development of nephropathy

Neuropathy may manifest in different ways and can be difficult to manage

Prevention and reduction in progression of microvascular complications requires intensive management of glucose, blood pressure and lipids

Diabetes mellitus (DM) is characterised by organ dysfunction arising directly or indirectly from the effects of chronic hyperglycaemia. The chronic complications of diabetes are traditionally classified as macro- or microvascular depending on the underlying pathophysiology. The microvascular triad of retinopathy, nephropathy and neuropathy is unique to diabetes. Most patients with diabetes will have one or more of these as overt or subclinical manifestations during the course of their disease. This review aims to give a broad overview of diabetes-related microvascular disease.

Pathophysiology

The underlying driver of microvascular disease is tissue exposure to chronic hyperglycaemia. Landmark clinical trials such as the UK Prospective Diabetes Study (UKPDS) and Diabetes Control of Complications Trial (DCCT) have established a clear relationship between microvascular disease and glucose control. Microvascular disease tends to occur predominantly in tissues where glucose uptake is independent of insulin activity (eg kidney, retina and vascular endothelium) because these tissues are exposed to glucose levels that correlate very closely with blood glucose levels. The development of disease is the result of a combination of direct glucose-mediated endothelial damage, oxidative stress due to superoxide overproduction, and the production of sorbitol and advanced glycation end-products due to the prevailing state of hyperglycaemia. These metabolic injuries cause altered blood flow and changes in endothelial permeability, extravascular protein deposition and coagulation resulting in organ dysfunction. Current evidence demonstrates a clear relationship between blood pressure (BP) and progression of nephropathy and retinopathy. These are now established as independent risk factors for microvascular disease progression.

Diabetic retinopathy

Diabetic retinopathy is the most common cause of visual loss in working-age adults in the developed world. It occurs following hyperglycaemia-mediated damage within the retinal microvasculature. This damage causes basement membrane thickening, increased capillary permeability and the formation of microaneurysms. These changes lead to intravascular coagulation, resulting in retinal ischaemia which drives the formation of new vessels within the retina (neovascularisation). These new vessels are fragile and may rupture causing retinal bleeds. Furthermore, the lack of lymphatic drainage within the retina causes fluid accumulation in the presence of hyperglycaemia resulting in macular oedema. Macular oedema can be associated with any of the aforementioned stages. The classification of different forms of retinopathy is given in .

Table 1.

The UKPDS trial highlighted that up to 40% of patients with type 2 diabetes (T2DM) have some retinopathy at the time of diagnosis, reflecting late presentation in this group. This contrasts with epidemiological data in which the prevalence varies from 16-95% depending on duration of diabetes. Diabetic retinopathy is rare in newly diagnosed patients with T1DM where the presentation is more acute. Diabetes duration, glycaemic control and BP are the strongest risk factors for the development and progression of retinopathy. There is some evidence that rapid improvements in glycaemic control can cause transient worsening of retinopathy. In patients with advanced retinopathy improvements in glycaemic control should therefore be gradual. Retinopathy is known to deteriorate during pregnancy; these patients need to have retinal assessments soon after their first appointment and again in the 28th week of pregnancy.

Management

Pan-retinal photocoagulation, introduced in the early 1970s, is the treatment of choice for proliferative and pre-proliferative retinopathy. This procedure coagulates the ischaemic retina which acts as the driving factor for new vessel formation (presumably by reducing vascular endothelial growth factor. Focal laser treatment is also used in macular oedema to reduce vascular leakage. Laser treatment can bring down the five-year incidence of blindness from 50% to 5%, but at the expense of losing up to 50% of peripheral vision - with possible implications for driving licence holders.

Nephropathy

Diabetic nephropathy arises from the combination of hyperglycaemia and hypertension driving glomerular damage. The underlying pathological changes involve thickening of basement membrane, atrophy, interstitial fibrosis and arteriosclerosis. This initially results in glomerular hyperfiltration and subsequently progressive loss of renal function. Diabetic nephropathy occurs in 30-40% of patients within 25 years. It is not understood why some individuals with 'poor control' are protected against renal disease.

Microalbuminuria

Increased glomerular filtration pressures result in albuminuria, a driver for ongoing renal damage. Microalbuminuria () is the first step towards developing overt proteinuria, but only 20% of patients with the condition progress towards proteinuric nephropathy. Proteinuric nephropathy continues to have a poor prognosis, with most patients dying from cardiac disease or progressing to end-stage renal failure. Furthermore, proteinuria is a marker of vascular endothelial dysfunction and there is a good correlation between cardiovascular risk and degree of albuminuria. The presence of microalbuminuria should therefore prompt clinicians to manage all cardiovascular risk factors aggressively. Criteria for referrals to nephrology services need to be defined so that these patients can be referred in a timely manner and their care optimised.

Management

Aggressive blood pressure reduction is of vital importance in managing diabetic nephropathy. Individuals with microalbuminuria need to have BP ≤=125/75. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are first line agents for treating hypertension with numerous trials showing their effectiveness in reducing proteinuria and deterioration of renal function, but often multiple blood pressure lowering agents are required. Early studies suggested that combining ACEIs and ARBs was superior to monotherapy in reducing proteinuria,but recent evidence highlights increased side effects (hyperkalemia and renal impairment) of combination therapy with quite modest outcome benefits. Both the UKPDS and the DCCT have demonstrated the importance of glycaemic control in retarding progression of nephropathy, whereas the evidence for positive outcomes with low-density lipoprotein (LDL) cholesterol reduction appears less clear. Patients with worsening proteinuria or deteriorating renal function will need to be seen by nephrologists to ensure that renal replacement therapy can be planned appropriately.

Neuropathy

Diabetic neuropathy refers to a spectrum of various neurological disorders associated with diabetes. Rarely, hyperglycaemia can induce an acute neuropathy that is reversible when glycaemic control is improved, but neuropathy is usually persistent. The most common form is a distal, symmetrical sensorimotor neuropathy which may be asymptomatic in up to 50%. The spectrum can include a wide range of clinical syndromes (), including cranial nerve palsies, mononeuropathies and autonomic dysfunction. The main sequel of neuropathy is foot deformity, ulceration and Charcot arthropathy. The combination of neuropathy, arteriopathy and infection are the driving factors behind most diabetic foot amputations.

Table 2.

Management

The management of neuropathy is predominantly supportive. Good glycaemic control can reduce its progression. However, once neuropathy has been established glycaemic control has little influence in controlling pain which is the main symptom. Simple analgesics suffice in mild cases of painful neuropathy, but opiates may be required in more severe cases. Amitriptyline, duloxetine, gabapentin and pregabalin all have evidence of being superior to placebo. Tricyclic antidepressants such as amitriptyline are first-line agents but pregabalin is particularly useful as therapeutic benefits are seen early. Clinicians need to have empathy with a holistic approach when dealing with these patients and often high doses of analgesics are needed. Patients with neuropathy need to be told of the importance of paying attention to foot care and wearing appropriate footwear as they are at high risk of developing ulcers. Patients also need to have access to podiatry and chiropody services for regular assessment of their feet.

Severe symptoms. Autonomic neuropathy can have devastating effects on patients' lives. Postural hypotension increases the risk of falling. Standard treatments such as fludrocortisone are usually not possible due to coexisting hypertension. Gastroparesis can cause intractable nausea and vomiting in severe cases. Delays in food absorption in mild cases cause severe problems in insulin treated patients where erratic food absorption causes fluctuations in blood glucose levels that are difficult to control with conventional basal bolus regimens. In fact, a large proportion of patients with 'brittle diabetes' have some degree of underlying gastroparesis. Mild cases can be managed with prokinetic agents such as metoclopramide, domperidone, erythromycin and dietary modification. More severe cases may require gastric electrical stimulation where implanted electrodes act as a form of gastric pacemaker and stimulate gastric contractions. Unfortunately, this procedure is performed only in specialist centres. Erectile dysfunction affects up to 50% of men with diabetes and is often multifactorial (a combination of neuropathy, small vessel disease, medication and psychological), requiring a holistic approach.

Preventing microvascular disease

Risk factors

The prevention of microvascular disease involves paying attention to aggravating risk factors and implementing screening programmes to improve early detection. Both the UKPDS and DCCT have clearly demonstrated that progression of retinopathy and nephropathy is linked to glycaemic control and that it is crucial that patients maintain HbA 1c less than or equal to 6.5% to minimise disease progression. In contrast, the association between glycaemic/BP control and neuropathy progression is more tenuous.

Blood pressure

BP needs to be kept below 140/80 mmHg to prevent microvascular disease, but once this has been established it needs to be more aggressively treated with targets below 125/75 mmHg.

Angiotensin-converting enzyme inhibitors (ACEIs)

ACEIs and angiotensin receptor antagonists are first-line agents. Many clinical trials have demonstrated their efficacy in reducing proteinuria and delaying progression of renal failure. In the Heart Outcomes Prevention Evaluation (HOPE) study ramipril reduced overt nephropathy by 24%. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial there was a 25% reduction in retinopathy progression and the risk of end-stage renal disease was reduced by 28%. Angiotensin blockade with ACEI also has a useful role in preventing retinopathy and reducing its progression by 50%.However, these agents are potentially teratogenic which needs to be considered when prescribing them to women of reproductive age.

Statins

Statins are useful in reducing the progression of nephropathy. They reduce proteinuria and have modest effects in improving renal function. Patients with nephropathy need to have their low-density lipoprotein cholesterol levels brought below 2 mmol/l. Statins also have benefits in ameliorating retinopathy in animal models, though the evidence in clinical trials is less robust. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial has shown some positive effects of fibrate therapy on retinopathy.

Screening

Microvascular disease needs to be identified early by robust screening methods. Nationwide screening for retinopathy started in the 1990s and has played a central role in reducing diabetes-related visual loss. Patients with significant retinopathy need to be referred according to national guidelines (). Nephropathy can be picked up early by testing for microalbuminuria, and neuropathy detected by detailed foot examination during annual review of the diabetic patient.

Table 3.

Conclusions

A combined approach of tight glycaemic control, aggressive BP control and cholesterol reduction will help reduce disease progression for both nephropathy and retinopathy, although neuropathy seems to be less affected. Patients with diabetes and their healthcare professionals need to be vigilant and detect microvascular disease at an early stage to avoid potentially devastating complications.

References

1. Goh K, Tooke J. Abnormalities of the microvasculature. In: Wass J, Shalet S, Oxford textbook of endocrinology and diabetes. Oxford: Oxford University Press, 2002:1749-55.10.1001/archneur.65.6.812 [[ CrossRef] Google Scholar]

10. Royal College of Ophthalmologists Guideline for diabetic retinopathy. Executive summary. 2005 [ Google Scholar]

13. National Collaborating Centre for Women's and Children's Health Diabetes in pregnancy: management of diabetes and its complications from pre-conception to the postnatal period. London: NCCWCH, 2008. [ Google Scholar]

15. Williams G, Pickup JC. The handbook of diabetes, 3rd edn. Oxford Blackwell Publishing, 2004. [ Google Scholar]

16. Gnudi L, Gruden G, Viberti GC. Pathogenesis of diabetic nephropathy. In: Pickup JC, Williams G, Textbook of diabetes, 3rd edn. Oxford: Blackwell Publishing, 2003;521-22. [ Google Scholar]

26. The National Collaborating Centre for Chronic Conditions Type 2 diabetes: national clinical guideline for management in primary and secondary care (update). London: Royal College of Physicians, 2008. [ Google Scholar]

# data[].attributes.attachment_link.description
Diabetes is associated with significant microvascular complications: retinopathy, neuropathy and nephropathy Diabetic retinopathy remains the most common cause of blindness in working-age adults in the developed world.

# data[].attributes.attachment_link.readable_text
Highlights

*

Diabetic ketoacidosis (DKA) is an emergency characterized by hyperglycemia, metabolic acidosis, and ketosis.

*

This article reviews updates in DKA diagnosis, management, and patient education.

*

Nurse practitioners are positioned to address education needs for patients at risk for DKA.

*

Nurse practitioners are equipped to provide individualized, evidence-based management in DKA.

Diabetic ketoacidosis (DKA) is an emergency for people with diabetes characterized by hyperglycemia, metabolic acidosis, and ketosis. DKA onset and recurrence can largely be prevented through patient education. Nurse practitioners are well positioned to promote patient education, self-management, and individualized patient care. This article outlines updates in the clinical management of patients with DKA to optimize care and reduce costs.

The Centers for Disease Control and Prevention (CDC) United States Diabetes Surveillance System recently reported an increase in DKA episodes in the US between 2009 and 2014, with an average annual increase of 6.3%.

DKA can occur at any age but primarily occurs in those aged younger than 30 years (36% incidence) and between 30 and 50 years (27% incidence).

The highest incidence of DKA is for those aged between 11 and 15 years.

German Competence Network Diabetes Mellitus and the DPV Initiative
Predictors of diabetic ketoacidosis in children and adolescents with type 1 diabetes. Experience from a large multicentre database.

The diagnosis of DKA is made based on the metabolic triad of high blood glucose (BG) levels (generally > 250 mg/dL), acidosis (pH < 7.2), and the presence of urine or serum ketones ( Table). Inpatient providers commonly rely on laboratory data to confirm DKA, whereas outpatient providers rely on history, presentation, BG levels, and urine ketones.

Euglycemic DKA (euDKA), which occurs when the patient presents with acidosis and ketosis but has a glucose ≤ 200 mg/dL, has become an emerging concern. Causes of euDKA can include recent insulin administration, decreased caloric intake, substantial alcohol consumption, chronic liver disease, or rarely, glycogen storage issues. In addition, there have been increasing reports of euDKA caused by a new class of drugs for diabetes, sodium glucose cotransporter 2 (SGLT-2) inhibitors. In May 2015, the US Food and Drug Administration added a warning about the risk of DKA with use of these drugs. One study suggested that the risk of DKA for patients using SGLT-2 inhibitors was twice as high as those prescribed a dipeptidyl peptidase IV inhibitor, after controlling for other risk factors, although the risk of hospitalization was low. The exact cause of this relationship is unknown, but several theories include reduced insulin doses when SGLT-2 is initiated, an increase in glucagon, or decreased excretion of ketone bodies. Other related factors may be mild infection, increased activity, reduced food intake, or insulin reduction or omission.

Case reports of traditional and euDKA occurring while using SGLT-2 inhibitors has been shown in patients with T1DM and in those with T2DM. Many patients with euDKA present with nausea and vomiting but are misdiagnosed due to the lack of clear glucose elevation.

References

1. Diabetic ketoacidosis: evaluation and treatment.

: 337-346

2. Trends in diabetic ketoacidosis hospitalizations and in-hospital mortality-United States, 2000-2014.

: 362-365

Fritsch M.

Rosenbauer J.

Schober E.

Neu A.

Placzek K.

Holl R.W.

German Competence Network Diabetes Mellitus and the DPV Initiative

Predictors of diabetic ketoacidosis in children and adolescents with type 1 diabetes. Experience from a large multicentre database.

: 307-312

4. Diabetic ketoacidosis: a review and update.

: 10-17 https://doi.org/10.1007/s40138-012-0001-3

5. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition.

: 1687-1693

6. The implementation and evaluation of an evidence-based protocol to treat diabetic ketoacidosis: a quality improvement study.

: 189-198

7. New approaches to the use of insulin in patients with diabetic ketoacidosis.

: 213-216

8. AADE Practice Paper. Continuous subcutaneous insulin infusion (CSII) with and without sensor integration. American Association of Diabetes Educators, 2018. https://www.diabeteseducator.org/practice/practice-documents/practice-papers. Accessed May 17, 2018.

9. Ketoacidosis in diabetes: recognition and avoidance.

: 393-399

10. How to assess diabetes distress: comparison of the Problem Areas in Diabetes Scale (PAID) and the Diabetes Distress Scale (DDS).

: 835-843

Kathryn Evans Kreider, DNP, FNP-BC, is from the Division of Endocrinology, Metabolism & Nutrition, Duke University Medical Center, and is an assistant professor at Duke University School of Nursing, Durham, NC. She is available at

Article Info

Publication History

Footnotes

American Association of Nurse Practitioners (AANP) members may receive 1.0 continuing education contact hours, including 0.25 pharmacology credit, approved by AANP, by reading this article and completing the online posttest and evaluation at aanp.inreachce.com.
In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest.

Identification

DOI: https://doi.org/10.1016/j.nurpra.2018.06.013

ScienceDirect
Access this article on ScienceDirect

Diagnostic Workup

Providers in outpatient settings where laboratory results are not readily available should rely on BG and ketone values for the initial diagnosis. BG values will typically be > 250 mg/dL, although up to 10% of patients in DKA may present with euDKA. For this reason, some experts argue that the cutoff BG value for diagnosing DKA should be decreased to 200 mg/dL.

Some outpatient glucometers, measure β-OHB in addition to BG levels. Several of these types of monitoring systems are available on the market. These meters measuring capillary ketones have been shown to have high sensitivity, specificity, positive predictive value, and negative predictive value in identifying DKA compared with urine ketone testing. Patients with diabetes who have access to β-OHB meters may have reduced emergency department visits, time to recovery from DKA, and the potential for reduced costs. Currently, these systems are not widely used and are expensive but may be beneficial to consider for patients who are at risk for DKA.

Hyperglycemia

BG levels are typically > 250 mg/dL unless euDKA is present. Hyperglycemia is precipitated by an increase in catecholamines, such as growth hormone, cortisol, and epinephrine, that are released during periods of imminent physiologic stress. Catecholamines stimulate the liver to produce more glucose, often making it difficult to reduce BG levels.

An earlier study evaluating SQ vs IV regular insulin used 0.3 U/kg SQ rapid-acting insulin as a loading dose, followed by 0.1 U/kg/h until the BG was < 250 mg/dL. The dose was then reduced to 0.05 U/kg/h until the DKA resolved. Compared with IV insulin, there was no difference in length of stay or total amount of insulin needed. Other more recent studies have supported these findings, including no difference in rates of hypoglycemia when using SQ insulin compared with IV insulin.

, Recommended doses of rapid-acting SQ insulin analogs are between 0.075 and 0.1 U/kg/h. This is similar to the recommended dose of IV insulin that is initiated in the hospital setting. Alternately, 0.1 to 0.2 U/kg can be administered every 2 to 3 hours.

Relevance for NPs

NPs are educated to provide holistic care, considering physical, emotional, and psychosocial needs of the patient. Given that evidence suggests that DKA onset and recurrence may be largely related to education deficits and psychosocial considerations, NPs are well prepared to assess and intervene for high-risk patients. Nurse practitioners should assess patients with diabetes for

Patients with diabetes should also regularly be evaluated for diabetes distress, depression, or other mental health concerns. Multiple validated tools are available to evaluate patients for diabetes distress

and depression. Consider referring patients with complex psychological needs to a mental health specialist.

The incidence of DKA has increased in recent years.

Although mortality levels have decreased, DKA remains a medical emergency that must be managed with precision and timeliness. Providers who understand the pathophysiology of DKA along with critical management principles can more readily provide evidence-based care to patients who present with DKA. NPs are in an excellent position to educate patients about diabetes and sick day rules and to implement individualized patient care plans that emphasize self-management and early detection of illness.

In addition, girls and women and the immigrant population are at higher risk.

# data[].attributes.attachment_link.title
Updates in the Management of Diabetic Ketoacidosis

# data[].attributes.attachment_link.description
Diabetic ketoacidosis (DKA) is an emergency for people with diabetes characterized by hyperglycemia, metabolic acidosis, and ketosis. DKA onset and recurrence can largely be prevented through patient education. Nurse practitioners are well positioned to promote patient education, self-management, and individualized patient care.

# data[].attributes.attachment_link.title
Type 1 Diabetes Mellitus - Genetics and Environmental Factors Study

# data[].attributes.attachment_link.readable_text
HHS is a condition of:

Extremely high blood sugar (glucose) level

Extreme lack of water (dehydration)

Decreased alertness or consciousness (in many cases)

Buildup of ketones in the body (ketoacidosis) may also occur. But it is unusual and is often mild compared with diabetic ketoacidosis.

HHS is more often seen in people with type 2 diabetes who don't have their diabetes under control. It may also occur in those who have not been diagnosed with diabetes. The condition may be brought on by:

Infection

Other illness, such as heart attack or stroke

Medicines that decrease the effect of insulin in the body

Medicines or conditions that increase fluid loss

Running out of, or not taking prescribed diabetes medicines

Normally, the kidneys try to make up for a high glucose level in the blood by allowing the extra glucose to leave the body in the urine. But this also causes the body to lose water. If you do not drink enough water, or you drink fluids that contain sugar and keep eating foods with carbohydrates, you become very dehydrated. When this occurs, the kidneys are no longer able to get rid of the extra glucose. As a result, the glucose level in your blood can become very high, sometimes more than 10 times the normal amount.

The loss of water also makes the blood more concentrated than normal. This is called hyperosmolarity. It is a condition in which the blood has a high concentration of salt (sodium), glucose, and other substances. This draws the water out of the body's other organs, including the brain.

Risk factors include:

A stressful event such as infection, heart attack, stroke, or recent surgery

Heart failure

Impaired thirst

Limited access to water (especially in people with dementia or who are bedbound)

Older age

Poor kidney function

Poor management of diabetes, not following the treatment plan as directed

Stopping or running out of insulin or other medicines that lower glucose level

# data[].attributes.attachment_link.description
HHS is a condition of: Extremely high blood sugar (glucose) level Extreme lack of water (dehydration) Decreased alertness or consciousness (in many cases) Buildup of ketones in the body (ketoacidosis) may also occur. But it is unusual and is often mild compared with diabetic ketoacidosis.

# data[].attributes.attachment_link.readable_text
doi: 10.2174/1570161117666190405165151.

Affiliations

¹ Centre of Cardiology, North Estonia Medical Centre, Tallinn, Estonia; Institute of Health Technologies, Tallinn University of Technology, Tallinn, Estonia.

² 2nd Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece.

doi: 10.2174/1570161117666190405165151.

Affiliations

¹ Centre of Cardiology, North Estonia Medical Centre, Tallinn, Estonia; Institute of Health Technologies, Tallinn University of Technology, Tallinn, Estonia.

² 2nd Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece.

Abstract

Background: Type 2 diabetes mellitus (T2DM) has emerged as a pandemic. It has different complications, both microvascular and macrovascular.

Objective: The purpose of this review is to summarize the different types of macrovascular complications associated with T2DM.

Methods: A comprehensive review of the literature was performed to identify clinical studies, which determine the macrovascular complications associated with T2DM.

Results: Macrovascular complications of T2DM include coronary heart disease, cardiomyopathy, arrhythmias and sudden death, cerebrovascular disease and peripheral artery disease. Cardiovascular disease is the primary cause of death in diabetic patients. Many clinical studies have shown a connection between T2DM and vascular disease, but almost always other risk factors are present in diabetic patients, such as hypertension, obesity and dyslipidaemia.

Conclusion: T2DM causes a variety of macrovascular complications through different pathogenetic pathways that include hyperglycaemia and insulin resistance. The association between T2DM and cardiovascular disease is clear, but we need more clinical studies in order to identify the pure effect of T2DM.

Keywords: Type 2 diabetes mellitus; cerebrovascular disease; coronary heart disease; heart failure; hyperglycaemia; macrovascular complications..

Similar articles

Asymptomatic peripheral arterial disease in type 2 diabetes patients: a 10-year follow-up study of the utility of the ankle brachial index as a prognostic marker of cardiovascular disease.

Bundó M, Muñoz L, Pérez C, Montero JJ, Montellà N, Torán P, Pera G. Bundó M, et al. Ann Vasc Surg. 2010 Nov;24(8):985-93. doi: 10.1016/j.avsg.2010.06.001. Ann Vasc Surg. 2010. PMID: 21035692

# data[].attributes.attachment_link.keywords[]
peripheral arterial disease / physiopathology

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Macrovascular Complications of Type 2 Diabetes Mellitus - PubMed

# data[].attributes.attachment_link.description
T2DM causes a variety of macrovascular complications through different pathogenetic pathways that include hyperglycaemia and insulin resistance. The association between T2DM and cardiovascular disease is clear, but we need more clinical studies in order to identify the pure effect of T2DM.

# data[].attributes.attachment_link.readable_text
Overview

Diabetic neuropathy is a type of nerve damage that can occur if you have diabetes. High blood sugar (glucose) can injure nerves throughout your body. Diabetic neuropathy most often damages nerves in your legs and feet.

Depending on the affected nerves, diabetic neuropathy symptoms can range from pain and numbness in your legs and feet to problems with your digestive system, urinary tract, blood vessels and heart. Some people have mild symptoms. But for others, diabetic neuropathy can be quite painful and disabling.

Diabetic neuropathy is a serious diabetes complication that may affect as many as 50% of people with diabetes. But you can often prevent diabetic neuropathy or slow its progress with consistent blood sugar management and a healthy lifestyle.

Products & Services

Symptoms

There are four main types of diabetic neuropathy. You can have one type or more than one type of neuropathy.

Your symptoms will depend on the type you have and which nerves are affected. Usually, symptoms develop gradually. You may not notice anything is wrong until considerable nerve damage has occurred.

Peripheral neuropathy

This type of neuropathy may also be called distal symmetric peripheral neuropathy. It's the most common type of diabetic neuropathy. It affects the feet and legs first, followed by the hands and arms. Signs and symptoms of peripheral neuropathy are often worse at night, and may include:

Numbness or reduced ability to feel pain or temperature changes

Tingling or burning sensation

Sharp pains or cramps

Increased sensitivity to touch - for some people, even a bedsheet's weight can be painful

Serious foot problems, such as ulcers, infections, and bone and joint pain

Autonomic neuropathy

The autonomic nervous system controls your heart, bladder, stomach, intestines, sex organs and eyes. Diabetes can affect nerves in any of these areas, possibly causing:

A lack of awareness that blood sugar levels are low (hypoglycemia unawareness)

Bladder or bowel problems

Slow stomach emptying (gastroparesis), causing nausea, vomiting and loss of appetite

Changes in the way your eyes adjust from light to dark

Decreased sexual response

Proximal neuropathy (diabetic polyradiculopathy)

This type of neuropathy - also called diabetic amyotrophy - often affects nerves in the thighs, hips, buttocks or legs. It can also affect the abdominal and chest area. Symptoms are usually on one side of the body, but may spread to the other side. You may have:

Severe pain in a hip and thigh or buttock

Eventual weak and shrinking thigh muscles

Difficulty rising from a sitting position

Severe stomach pain

Mononeuropathy (focal neuropathy)

There are two types of mononeuropathy - cranial and peripheral. Mononeuropathy refers to damage to a specific nerve. Mononeuropathy may also lead to:

Difficulty focusing or double vision

Aching behind one eye

Paralysis on one side of your face (Bell's palsy)

Numbness or tingling in your hand or fingers, except your pinkie (little finger)

Weakness in your hand that may cause you to drop things

When to see a doctor

Call your doctor for an appointment if you have:

A cut or sore on your foot that is infected or won't heal

Burning, tingling, weakness or pain in your hands or feet that interferes with daily activities or sleep

Changes in digestion, urination or sexual function

Dizziness and fainting

The American Diabetes Association recommends that screening for diabetic neuropathy begin immediately after someone is diagnosed with type 2 diabetes, and five years after diagnosis for someone with type 1 diabetes. After that, screening is recommended annually.

Causes

The exact cause of each type of neuropathy is unknown. Researchers think that over time, uncontrolled high blood sugar damages nerves and interferes with their ability to send signals, leading to diabetic neuropathy. High blood sugar also weakens the walls of the small blood vessels (capillaries) that supply the nerves with oxygen and nutrients.

Risk factors

Anyone who has diabetes can develop neuropathy. But these risk factors make you more likely to get nerve damage:

Poor blood sugar control. Uncontrolled blood sugar puts you at risk of every diabetes complication, including nerve damage.

Diabetes history. Your risk of diabetic neuropathy increases the longer you have diabetes, especially if your blood sugar isn't well controlled.

Kidney disease. Diabetes can damage the kidneys. Kidney damage sends toxins into the blood, which can lead to nerve damage.

Being overweight. Having a body mass index (BMI) of 25 or more may increase your risk of diabetic neuropathy.

Smoking. Smoking narrows and hardens your arteries, reducing blood flow to your legs and feet. This makes it more difficult for wounds to heal and damages the peripheral nerves.

Complications

Diabetic neuropathy can cause a number of serious complications, including:

Hypoglycemia unawareness. Blood sugar levels below 70 milligrams per deciliter (mg/dL) normally cause shakiness, sweating and a fast heartbeat. But if you have autonomic neuropathy, you may not notice these warning signs.

Loss of a toe, foot or leg. Nerve damage can make you lose feeling in your feet, so even minor cuts can turn into sores or ulcers without your realizing it. In severe cases, an infection can spread to the bone or lead to tissue death. Removal (amputation) of a toe, foot or even the lower leg may be necessary.

Urinary tract infections and urinary incontinence. If the nerves that control your bladder are damaged, you may be unable to fully empty your bladder. Bacteria can build up in the bladder and kidneys, causing urinary tract infections. Nerve damage can also affect your ability to feel when you need to urinate or to control the muscles that release urine, leading to leakage (incontinence).

Sharp drops in blood pressure. Damage to the nerves that control blood flow can affect your body's ability to adjust blood pressure. This can cause a sharp drop in pressure when you stand after sitting, which may lead to dizziness and fainting.

Digestive problems. If nerve damage strikes your digestive tract, you can have constipation or diarrhea, or both. Diabetes-related nerve damage can lead to gastroparesis, a condition in which the stomach empties too slowly or not at all, which causes bloating and indigestion.

Sexual dysfunction. Autonomic neuropathy often damages the nerves that affect the sex organs. Men may experience erectile dysfunction. Women may have difficulty with lubrication and arousal.

Increased or decreased sweating. Nerve damage can disrupt how your sweat glands work and make it difficult for your body to control its temperature properly.

Prevention

You can prevent or delay diabetic neuropathy and its complications by closely managing your blood sugar and taking good care of your feet.

Blood sugar management

The American Diabetes Association recommends that people with diabetes have an A1C test at least twice a year. This test estimates your average blood sugar level for the past two to three months.

A1C goals may need to be individualized, but for many adults, the American Diabetes Association recommends an A1C of less than 7%. If your blood sugar levels are higher than your goal, you may need changes in your daily management, such as adding or adjusting your medications or changing your diet.

Foot care

Foot problems, including sores that don't heal, ulcers and even amputation, are common complications of diabetic neuropathy. But you can prevent many of these problems by having a thorough foot exam at least once a year, having your doctor check your feet at each office visit and taking good care of your feet at home.

Follow your doctor's recommendations for good foot care. To protect the health of your feet:

Check your feet every day. Look for blisters, cuts, bruises, cracked and peeling skin, redness, and swelling. Use a mirror or ask a friend or family member to help examine parts of your feet that are hard to see.

Keep your feet clean and dry. Wash your feet every day with lukewarm water and mild soap. Avoid soaking your feet. Dry your feet and between your toes carefully.

Moisturize your feet. This helps prevent cracking. But don't get lotion between your toes, because it might encourage fungal growth.

Trim your toenails carefully. Cut your toenails straight across. File the edges carefully to avoid sharp edges.

Wear clean, dry socks. Look for socks made of cotton or moisture-wicking fibers that don't have tight bands or thick seams.

Wear cushioned shoes that fit well. Always wear shoes or slippers to protect your feet. Make sure your shoes fit properly and allow your toes to move. A foot doctor can teach you how to buy properly fitted shoes and to prevent problems such as corns and calluses. If you qualify for Medicare, your plan may cover the cost of at least one pair of shoes each year.

# data[].attributes.attachment_link.title
Diabetic neuropathy - Symptoms and causes

# data[].attributes.attachment_link.description
Diabetic neuropathy is a type of nerve damage that can occur if you have diabetes. High blood sugar (glucose) can injure nerves throughout your body. Diabetic neuropathy most often damages nerves in your legs and feet.

# data[].attributes.attachment_link.readable_text
Overview

Type 2 diabetes is a condition that happens because of a problem in the way the body regulates and uses sugar as a fuel. That sugar also is called glucose. This long-term condition results in too much sugar circulating in the blood. Eventually, high blood sugar levels can lead to disorders of the circulatory, nervous and immune systems.

In type 2 diabetes, there are primarily two problems. The pancreas does not produce enough insulin - a hormone that regulates the movement of sugar into the cells. And cells respond poorly to insulin and take in less sugar.

Type 2 diabetes used to be known as adult-onset diabetes, but both type 1 and type 2 diabetes can begin during childhood and adulthood. Type 2 is more common in older adults. But the increase in the number of children with obesity has led to more cases of type 2 diabetes in younger people.

There's no cure for type 2 diabetes. Losing weight, eating well and exercising can help manage the disease. If diet and exercise aren't enough to control blood sugar, diabetes medications or insulin therapy may be recommended.

Symptoms

Symptoms of type 2 diabetes often develop slowly. In fact, you can be living with type 2 diabetes for years and not know it. When symptoms are present, they may include:

Increased thirst.

Frequent urination.

Increased hunger.

Unintended weight loss.

Fatigue.

Blurred vision.

Slow-healing sores.

Frequent infections.

Numbness or tingling in the hands or feet.

Areas of darkened skin, usually in the armpits and neck.

When to see a doctor

See your health care provider if you notice any symptoms of type 2 diabetes.

Causes

Type 2 diabetes is mainly the result of two problems:

Cells in muscle, fat and the liver become resistant to insulin As a result, the cells don't take in enough sugar.

The pancreas can't make enough insulin to keep blood sugar levels within a healthy range.

Exactly why this happens is not known. Being overweight and inactive are key contributing factors.

How insulin works

Insulin is a hormone that comes from the pancreas - a gland located behind and below the stomach. Insulin controls how the body uses sugar in the following ways:

Sugar in the bloodstream triggers the pancreas to release insulin.

Insulin circulates in the bloodstream, enabling sugar to enter the cells.

The amount of sugar in the bloodstream drops.

In response to this drop, the pancreas releases less insulin.

The role of glucose

Glucose - a sugar - is a main source of energy for the cells that make up muscles and other tissues. The use and regulation of glucose includes the following:

Glucose comes from two major sources: food and the liver.

Glucose is absorbed into the bloodstream, where it enters cells with the help of insulin.

The liver stores and makes glucose.

When glucose levels are low, the liver breaks down stored glycogen into glucose to keep the body's glucose level within a healthy range.

In type 2 diabetes, this process doesn't work well. Instead of moving into the cells, sugar builds up in the blood. As blood sugar levels rise, the pancreas releases more insulin. Eventually the cells in the pancreas that make insulin become damaged and can't make enough insulin to meet the body's needs.

Risk factors

Factors that may increase the risk of type 2 diabetes include:

Weight. Being overweight or obese is a main risk.

Fat distribution. Storing fat mainly in the abdomen - rather than the hips and thighs - indicates a greater risk. The risk of type 2 diabetes is higher in men with a waist circumference above 40 inches (101.6 centimeters) and in women with a waist measurement above 35 inches (88.9 centimeters).

Inactivity. The less active a person is, the greater the risk. Physical activity helps control weight, uses up glucose as energy and makes cells more sensitive to insulin.

Family history. An individual's risk of type 2 diabetes increases if a parent or sibling has type 2 diabetes.

Race and ethnicity. Although it's unclear why, people of certain races and ethnicities - including Black, Hispanic, Native American and Asian people, and Pacific Islanders - are more likely to develop type 2 diabetes than white people are.

Blood lipid levels. An increased risk is associated with low levels of high-density lipoprotein (HDL) cholesterol - the "good" cholesterol - and high levels of triglycerides.

Age. The risk of type 2 diabetes increases with age, especially after age 35.

Prediabetes. Prediabetes is a condition in which the blood sugar level is higher than normal, but not high enough to be classified as diabetes. Left untreated, prediabetes often progresses to type 2 diabetes.

Pregnancy-related risks. The risk of developing type 2 diabetes is higher in people who had gestational diabetes when they were pregnant and in those who gave birth to a baby weighing more than 9 pounds (4 kilograms).

Polycystic ovary syndrome. Having polycystic ovary syndrome - a condition characterized by irregular menstrual periods, excess hair growth and obesity - increases the risk of diabetes.

Complications

Type 2 diabetes affects many major organs, including the heart, blood vessels, nerves, eyes and kidneys. Also, factors that increase the risk of diabetes are risk factors for other serious diseases. Managing diabetes and controlling blood sugar can lower the risk for these complications and other medical conditions, including:

Heart and blood vessel disease. Diabetes is associated with an increased risk of heart disease, stroke, high blood pressure and narrowing of blood vessels, a condition called atherosclerosis.

Nerve damage in limbs. This condition is called neuropathy. High blood sugar over time can damage or destroy nerves. That may result in tingling, numbness, burning, pain or eventual loss of feeling that usually begins at the tips of the toes or fingers and gradually spreads upward.

Other nerve damage. Damage to nerves of the heart can contribute to irregular heart rhythms. Nerve damage in the digestive system can cause problems with nausea, vomiting, diarrhea or constipation. Nerve damage also may cause erectile dysfunction.

Kidney disease. Diabetes may lead to chronic kidney disease or end-stage kidney disease that can't be reversed. That may require dialysis or a kidney transplant.

Eye damage. Diabetes increases the risk of serious eye diseases, such as cataracts and glaucoma, and may damage the blood vessels of the retina, potentially leading to blindness.

Skin conditions. Diabetes may raise the risk of some skin problems, including bacterial and fungal infections.

Slow healing. Left untreated, cuts and blisters can become serious infections, which may heal poorly. Severe damage might require toe, foot or leg amputation.

Hearing impairment. Hearing problems are more common in people with diabetes.

Sleep apnea. Obstructive sleep apnea is common in people living with type 2 diabetes. Obesity may be the main contributing factor to both conditions.

Dementia. Type 2 diabetes seems to increase the risk of Alzheimer's disease and other disorders that cause dementia. Poor control of blood sugar is linked to a more rapid decline in memory and other thinking skills.

Prevention

Healthy lifestyle choices can help prevent type 2 diabetes. If you've received a diagnosis of prediabetes, lifestyle changes may slow or stop the progression to diabetes.

A healthy lifestyle includes:

Eating healthy foods. Choose foods lower in fat and calories and higher in fiber. Focus on fruits, vegetables and whole grains.

Getting active. Aim for 150 or more minutes a week of moderate to vigorous aerobic activity, such as a brisk walk, bicycling, running or swimming.

Losing weight. If you are overweight, losing a modest amount of weight and keeping it off may delay the progression from prediabetes to type 2 diabetes. If you have prediabetes, losing 7% to 10% of your body weight may reduce the risk of diabetes.

Avoiding long stretches of inactivity. Sitting still for long periods of time can increase the risk of type 2 diabetes. Try to get up every 30 minutes and move around for at least a few minutes.

For people with prediabetes, metformin (Fortamet, Glumetza, others), a diabetes medication, may be prescribed to reduce the risk of type 2 diabetes. This is usually prescribed for older adults who are obese and unable to lower blood sugar levels with lifestyle changes.

# data[].attributes.attachment_link.description
High blood sugar levels are the main problem in diabetes. Learn about lifestyle changes to lower the risk and treatments to manage type 2 diabetes.

# data[].attributes.attachment_link.provider_name
American Association of Nurse Practitioners

# data[].attributes.attachment_link.readable_text
NP Pulse: The Voice of the Nurse Practitioner®

The American Association of Nurse Practitioners ® (AANP) NP Pulse: The Voice of the Nurse Practitioner ® podcast brings you discussions on the most important topics and issues related to nurse practitioner (NP) practice, education, advocacy, research and leadership. Tune in each month for stories and in-depth conversations with NPs and health care leaders that you can't hear anywhere else.

Latest Episode

All Episodes

Listen to Every Episode of NP Pulse on Your Favorite Podcast Platform

Use the links below to enjoy this podcast on any of the platforms listed. Be sure to subscribe, share with your colleagues and check back each month for new conversations with NPs and health care leaders from across the nation.

Are You Not Yet a Member? Join AANP

Being a part of AANP is more than just a membership - it's a real opportunity to make a measurable difference in the strength of your profession and the health of this country. When you join AANP, you are joining a movement - a vibrant, professional community of NPs more than 118,000 strong. That's 118,000 members who have chosen to put their passion for improving the health of our nation into practice by supporting the advancement of the NP role.
Learn More About AANP Membership

# data[].attributes.attachment_link.description
NP Pulse: The Voice of the Nurse Practitioner® The American Association of Nurse Practitioners ® (AANP) NP Pulse: The Voice of the Nurse Practitioner ® podcast brings you discussions on the most important topics and issues related to nurse practitioner (NP) practice, education, advocacy, research...

# data[].attributes.body
FIgure 22.14 McCance Book

# data[].attributes.attachment_link.readable_text
Microvascular Complications of Diabetes

Diabetic retinopathy

Diabetic retinopathy may be the most common microvascular complication of diabetes. It is responsible for ∼ 10,000 new cases of blindness every year in the United States alone. The risk of developing diabetic retinopathy or other microvascular complications of diabetes depends on both the duration and the severity of hyperglycemia. Development of diabetic retinopathy in patients with type 2 diabetes was found to be related to both severity of hyperglycemia and presence of hypertension in the U.K. Prospective Diabetes Study (UKPDS), and most patients with type 1 diabetes develop evidence of retinopathy within 20 years of diagnosis. Retinopathy may begin to develop as early as 7 years before the diagnosis of diabetes in patients with type 2 diabetes. There are several proposed pathological mechanisms by which diabetes may lead to development of retinopathy.

Aldose reductase may participate in the development of diabetes complications. Aldose reductase is the initial enzyme in the intracellular polyol pathway. This pathway involves the conversion of glucose into glucose alcohol (sorbitol). High glucose levels increase the flux of sugar molecules through the polyol pathway, which causes sorbitol accumulation in cells. Osmotic stress from sorbitol accumulation has been postulated as an underlying mechanism in the development of diabetic microvascular complications, including diabetic retinopathy. In animal models, sugar alcohol accumulation has been linked to microaneurysm formation, thickening of basement membranes, and loss of pericytes. Treatment studies with aldose reductase inhibitors, however, have been disappointing.

Cells are also thought to be injured by glycoproteins. High glucose concentrations can promote the nonenzymatic formation of advanced glycosylated end products (AGEs). In animal models, these substances have also been associated with formation of microaneurysms and pericyte loss. Evaluations of AGE inhibitors are underway.

Oxidative stress may also play an important role in cellular injury from hyperglycemia. High glucose levels can stimulate free radical production and reactive oxygen species formation. Animal studies have suggested that treatment with antioxidants, such as vitamin E, may attenuate some vascular dysfunction associated with diabetes, but treatment with antioxidants has not yet been shown to alter the development or progression of retinopathy or other microvascular complications of diabetes.

Growth factors, including vascular endothelial growth factor (VEGF), growth hormone, and transforming growth factor β, have also been postulated to play important roles in the development of diabetic retinopathy. VEGF production is increased in diabetic retinopathy, possibly in response to hypoxia. In animal models, suppressing VEGF production is associated with less progression of retinopathy.

Diabetic retinopathy is generally classified as either background or proliferative. It is important to have a general understanding of the features of each to interpret eye examination reports and advise patients of disease progression and prognosis.

Background retinopathy includes such features as small hemorrhages in the middle layers of the retina. They clinically appear as "dots" and therefore are frequently referred to as "dot hemorrhages." Hard exudates are caused by lipid deposition that typically occurs at the margins of hemorrhages. Microaneurysms are small vascular dilatations that occur in the retina, often as the first sign of retinopathy. They clinically appear as red dots during retinal examination. Retinal edema may result from microvascular leakage and is indicative of compromise of the blood-retinal barrier. The appearance is one of grayish retinal areas. Retinal edema may require intervention because it is sometimes associated with visual deterioration.

Proliferative retinopathy is characterized by the formation of new blood vessels on the surface of the retina and can lead to vitreous hemorrhage. White areas on the retina ("cotton wool spots") can be a sign of impending proliferative retinopathy. If proliferation continues, blindness can occur through vitreous hemorrhage and traction retinal detachment. With no intervention, visual loss may occur. Laser photocoagulation can often prevent proliferative retinopathy from progressing to blindness; therefore, close surveillance for the existence or progression of retinopathy in patients with diabetes is crucial.

Diabetic nephropathy

Diabetic nephropathy is the leading cause of renal failure in the United States. It is defined by proteinuria > 500 mg in 24 hours in the setting of diabetes, but this is preceded by lower degrees of proteinuria, or "microalbuminuria." Microalbuminuria is defined as albumin excretion of 30-299 mg/24 hours. Without intervention, diabetic patients with microalbuminuria typically progress to proteinuria and overt diabetic nephropathy. This progression occurs in both type 1 and type 2 diabetes.

As many as 7% of patients with type 2 diabetes may already have microalbuminuria at the time they are diagnosed with diabetes. In the European Diabetes Prospective Complications Study, the cumulative incidence of microalbuminuria in patients with type 1 diabetes was ∼ 12% during a period of 7 years. In the UKPDS, the incidence of microalbuminuria was 2% per year in patients with type 2 diabetes, and the 10-year prevalence after diagnosis was 25%.

The pathological changes to the kidney include increased glomerular basement membrane thickness, microaneurysm formation, mesangial nodule formation (Kimmelsteil-Wilson bodies), and other changes. The underlying mechanism of injury may also involve some or all of the same mechanisms as diabetic retinopathy.

Screening for diabetic nephropathy or microalbuminuria may be accomplished by either a 24-hour urine collection or a spot urine measurement of microalbumin. Measurement of the microalbumin-to-creatinine ratio may help account for concentration or dilution of urine, and spot measurements are more convenient for patients than 24-hour urine collections. It is important to note that falsely elevated urine protein levels may be produced by conditions such as urinary tract infections, exercise, and hematuria.

Initial treatment of diabetic nephropathy, as of other complications of diabetes, is prevention. Like other microvascular complications of diabetes, there are strong associations between glucose control (as measured by hemoglobin A 1c [A1C]) and the risk of developing diabetic nephropathy. Patients should be treated to the lowest safe glucose level that can be obtained to prevent or control diabetic nephropathy. Treatment with angiotensin-converting enzyme (ACE) inhibitors has not been shown to prevent the development of microalbuminuria in patients with type 1 diabetes but has been shown to decrease the risk of developing nephropathy and cardiovascular events in patients with type 2 diabetes.

In addition to aggressive treatment of elevated blood glucose, patients with diabetic nephropathy benefit from treatment with antihypertensive drugs. Renin-angiotensin system blockade has additional benefits beyond the simple blood pressure-lowering effect in patients with diabetic nephropathy. Several studies have demonstrated renoprotective effects of treatment with ACE inhibitors and antiotensin receptor blockers (ARBs), which appear to be present independent of their blood pressure-lowering effects, possibly because of decreasing intraglomerular pressure. Both ACE inhibitors and ARBs have been shown to decrease the risk of progression to macroalbuminuria in patients with microalbuminuria by as much as 60-70%. These drugs are recommended as the first-line pharmacological treatment of microalbuminuria, even in patients without hypertension.

Similarly, patients with macroalbuminuria benefit from control of hypertension. Hypertension control in patients with macroalbuminuria from diabetic kidney disease slows decline in glomerular filtration rate (GFR). Treatment with ACE inhibitors or ARBs has been shown to further decrease the risk of progression of kidney disease, also independent of the blood pressure-lowering effect.

Combination treatment with an ACE inhibitor and an ARB has been shown to have additional renoprotective effects. It should be noted that patients treated with these drugs (especially in combination) may experience an initial increase in creatinine and must be monitored for hyperkalemia. Considerable increase in creatinine after initiation of these agents should prompt an evaluation for renal artery stenosis.

Diabetic neuropathy

Diabetic neuropathy is recognized by the American Diabetes Association (ADA) as "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes." As with other microvascular complications, risk of developing diabetic neuropathy is proportional to both the magnitude and duration of hyperglycemia, and some individuals may possess genetic attributes that affect their predisposition to developing such complications.

The precise nature of injury to the peripheral nerves from hyperglycemia is not known but likely is related to mechanisms such as polyol accumulation, injury from AGEs, and oxidative stress. Peripheral neuropathy in diabetes may manifest in several different forms, including sensory, focal/multifocal, and autonomic neuropathies. More than 80% of amputations occur after foot ulceration or injury, which can result from diabetic neuropathy. Because of the considerable morbidity and mortality that can result from diabetic neuropathy, it is important for clinicians to understand its manifestations, prevention, and treatment.

Pure sensory neuropathy is relatively rare and associated with periods of poor glycemic control or considerable fluctuation in diabetes control. It is characterized by isolated sensory findings without signs of motor neuropathy. Symptoms are typically most prominent at night.

Mononeuropathies typically have a more sudden onset and involve virtually any nerve, but most commonly the median, ulnar, and radial nerves are affected. Cranial neuropathies have been described but are rare. It should be noted that nerve entrapment occurs frequently in the setting of diabetes. Electrophysiological evaluation in diabetic neuropathy demonstrates decreases in both amplitude of nerve impulse and conduction but may be useful in identifying the location of nerve entrapment. Diabetic amyotrophy may be a manifestation of diabetic mononeuropathy and is characterized by severe pain and muscle weakness and atrophy, usually in large thigh muscles.

Several other forms of neuropathy may mimic the findings in diabetic sensory neuropathy and mononeuropathy. Chronic inflammatory polyneuropathy, vitamin B ₁₂ deficiency, hypothyroidism, and uremia should be ruled out in the process of evaluating diabetic peripheral neuropathy.

There is no specific treatment of diabetic neuropathy, although many drugs are available to treat its symptoms. The primary goal of therapy is to control symptoms and prevent worsening of neuropathy through improved glycemic control. Some studies have suggested that control of hyperglycemia and avoidance of glycemic excursions may improve symptoms of peripheral neuropathy. Amitriptyline, imiprimine, paroxetine, citalopram, gabapentin, pregablin, carbamazepine, topiramate, duloxetine, tramadol, and oxycodone have all been used to treat painful symptoms, but only duloxetine and pregablin possess official indications for the treatment of painful peripheral diabetic neuropathy. Treatment with some of these medications may be limited by side effects of the medication, and no single drug is universally effective. Treatment of autonomic neuropathy is targeted toward the organ system that is affected, but also includes optimization of glycemic control.

Macrovascular Complications of Diabetes

The central pathological mechanism in macrovascular disease is the process of atherosclerosis, which leads to narrowing of arterial walls throughout the body. Atherosclerosis is thought to result from chronic inflammation and injury to the arterial wall in the peripheral or coronary vascular system. In response to endothelial injury and inflammation, oxidized lipids from LDL particles accumulate in the endothelial wall of arteries. Angiotensin II may promote the oxidation of such particles. Monocytes then infiltrate the arterial wall and differentiate into macrophages, which accumulate oxidized lipids to form foam cells. Once formed, foam cells stimulate macrophage proliferation and attraction of T-lymphocytes. T-lymphocytes, in turn, induce smooth muscle proliferation in the arterial walls and collagen accumulation. The net result of the process is the formation of a lipid-rich atherosclerotic lesion with a fibrous cap. Rupture of this lesion leads to acute vascular infarction.

In addition to atheroma formation, there is strong evidence of increased platelet adhesion and hypercoagulability in type 2 diabetes. Impaired nitric oxide generation and increased free radical formation in platelets, as well as altered calcium regulation, may promote platelet aggregation. Elevated levels of plasminogen activator inhibitor type 1 may also impair fibrinolysis in patients with diabetes. The combination of increased coagulability and impaired fibrinolysis likely further increases the risk of vascular occlusion and cardiovascular events in type 2 diabetes.

Diabetes increases the risk that an individual will develop cardiovascular disease (CVD). Although the precise mechanisms through which diabetes increases the likelihood of atherosclerotic plaque formation are not completely defined, the association between the two is profound. CVD is the primary cause of death in people with either type 1 or type 2 diabetes. In fact, CVD accounts for the greatest component of health care expenditures in people with diabetes.

Among macrovascular diabetes complications, coronary heart disease has been associated with diabetes in numerous studies beginning with the Framingham study. More recent studies have shown that the risk of myocardial infarction (MI) in people with diabetes is equivalent to the risk in nondiabetic patients with a history of previous MI. These discoveries have lead to new recommendations by the ADA and American Heart Association that diabetes be considered a coronary artery disease risk equivalent rather than a risk factor.

There has not been a large, long-term, controlled study showing decreases in macrovascular disease event rates from improved glycemic control in type 2 diabetes. Modification of other elements of the metabolic syndrome, however, has been shown to very significantly decrease the risk of cardiovascular events in numerous studies. Blood pressure lowering in patients with type 2 diabetes has been associated with decreased cardiovascular events and mortality. The UKPDS was among the first and most prominent study demonstrating a reduction in macrovascular disease with treatment of hypertension in type 2 diabetes.

There is additional benefit to lowering blood pressure with ACE inhibitors or ARBs. Blockade of the renin-angiotensin system using either an ACE inhibitor or an ARB reduced cardiovascular endpoints more than other antihypertensive agents. It should be noted that use of ACE inhibitors and ARBs also may help slow progression of diabetic microvascular kidney disease. Multiple drug therapy, however, is generally required to control hypertension in patients with type 2 diabetes.

Another target of therapy is blood lipid concentration. Numerous studies have shown decreased risk in macrovascular disease in patients with diabetes who are treated with lipid-lowering agents, especially statins. These drugs are effective for both primary and secondary prevention of CVD, but patients with diabetes and preexisting CVD may receive the highest benefit from treatment. Although it is beyond the scope of this article to review all relevant studies, it should be noted these beneficial effects of lipid and blood pressure lowering are relatively well proven and likely also extend to patients with type 1 diabetes. In addition to statin therapy, fibric acid derivates have beneficial effects. They raise HDL levels and lower triglyceride concentrations and have been shown to decrease the risk of MI in patients with diabetes in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial.

Practice Recommendations

Patients with type 1 diabetes of > 5 years' duration should have annual screening for microalbuminuria, and all patients with type 2 diabetes should undergo such screening at the time of diagnosis and yearly thereafter. All patients with diabetes should have serum creatinine measurement performed annually. Patients with microalbuminuria or macroalbuminuria should be treated with an ACE inhibitor or ARB unless they are pregnant or cannot tolerate the medication. Patients who cannot tolerate one of these medications may be able to tolerate the other. Potassium should be monitored in patients on such therapy. Patients with a GFR < 60 ml/min or with uncontrolled hypertension or hyperkalemia may benefit from referral to a nephrologist.

Patients with type 1 diabetes should receive a comprehensive eye examination and dilation within 3-5 years after the onset of diabetes. Patients with type 2 diabetes should undergo such screening at the time of diagnosis. Patients should strive for optimal glucose and blood pressure control to decrease the likelihood of developing diabetic retinopathy or experiencing progression of retinopathy.

All patients with diabetes should undergo screening for distal symmetric polyneuropathy at the time of diagnosis and yearly thereafter. Atypical features may prompt electrophysiological testing or testing for other causes of peripheral neuropathy. Patients who experience peripheral neuropathy should begin appropriate foot self-care, including wearing special footwear to decrease their risk of ulceration. They may also require referral for podiatric care. Screening for autonomic neuropathy should take place at the time of diagnosis in type 2 diabetes and beginning 5 years after the diagnosis of type 1 diabetes. Medication to control the symptoms of painful peripheral neuropathy may be effective in improving quality of life in patients but do not appear to alter the natural course of the disease. For this reason, patients and physicians should continue to strive for the best possible glycemic control.

In light of the above strong evidence linking diabetes and CVD and to control and prevent the microvascular complications of diabetes, the ADA has issued practice recommendations regarding the prevention and management of diabetes complications.

Blood pressure should be measured routinely. Goal blood pressure is < 130/80 mmHg. Patients with a blood pressure ≥ 140/90 mmHg should be treated with drug therapy in addition to diet and lifestyle modification. Patients with a blood pressure of 130-139/80-89 mmHg may attempt a trial of lifestyle and behavioral therapy for 3 months and then receive pharmacological therapy if their goal blood pressure is not achieved. Initial drug therapy should be with a drug shown to decrease CVD risk, but all patients with diabetes and hypertension should receive an ACE inhibitor or ARB in their antihypertensive regimen.

Lipid testing should be performed in patients with diabetes at least annually. Lipid goals for adults with diabetes should be an LDL < 100 mg/dl (or < 70 mg/dl in patients with overt CVD), HDL > 50 mg/dl, and fasting triglycerides < 150 mg/dl. All patients with diabetes should be encouraged to limit consumption of saturated fat, trans fat, and cholesterol. Statin therapy to lower LDL by 30-40% regardless of baseline is recommended to decrease the risk of CVD in patients > 40 years of age. Patients < 40 years of age may also be considered for therapy. In individuals with overt CVD, special attention should be paid to treatment to lower triglycerides or raise HDL. Combination therapy with a statin plus other drugs, such as fibrates or niacin, may be necessary to achieve ideal lipid control, but patients should be monitored closely for possible adverse reactions of therapy.

Aspirin therapy (75-162 mg/day) is indicated in secondary prevention of CVD and should be used in patients with diabetes who are > 40 years of age and in those who are 30-40 years of age if other risk factors are present. Patients < 21 years of age should not receive aspirin therapy because of the risk of Reye's syndrome. Patients who cannot tolerate aspirin therapy because of allergy or adverse reaction may be considered for other antiplatelet agents.

In addition to the above pharmacological recommendations, patients with diabetes should be encouraged to not begin smoking or to stop smoking to decrease their risk of CVD and benefit their health in other ways. It should also be noted that statins, ACE inhibitors, and ARBs are strongly contraindicated in pregnancy.

# data[].attributes.attachment_link.title
Microvascular and Macrovascular Complications of Diabetes

# data[].attributes.attachment_link.description
Diabetes is a group of chronic diseases characterized by hyperglycemia. Modern medical care uses a vast array of lifestyle and pharmaceutical interventions aimed at preventing and controlling hyperglycemia. In addition to ensuring the adequate delivery of glucose to the tissues of the body, treatment of diabetes attempts to decrease the likelihood that the tissues of the body are harmed by hyperglycemia.

# data[].attributes.attachment_link.readable_text
Nerve damage from diabetes is called diabetic neuropathy (new-ROP-uh-thee). About half of all people with diabetes have some form of nerve damage. It is more common in those who have had the disease for a number of years and can lead to many kinds of problems.

If you keep your blood glucose levels on target, you may help prevent or delay nerve damage. If you already have nerve damage, this will help prevent or delay further damage. There are also other treatments that can help.

Peripheral neuropathy

Peripheral neuropathy can cause tingling, pain, numbness, or weakness in your feet and hands.

Autonomic neuropathy

Autonomic neuropathy affects the nerves in your body that control your body systems.

Additional types of neuropathy

Additional types of neuropathy people with diabetes may experience.

Steps to prevent or delay nerve damage

Take these steps to prevent or delay nerve damage.

# data[].attributes.attachment_link.description
Nerve damage from diabetes is called diabetic neuropathy (new-ROP-uh-thee). About half of all people with diabetes have some form of nerve damage. It is more common in those who have had the disease for a number of years and can lead to many kinds of problems. If you keep your blood glucose levels on target, you may help prevent or delay nerve damage.

# data[].attributes.body
McCance on Treatment of Type I DM