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Standards

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HS.L1U1.20 Ask questions and/or make predictions based on observations and evidence to demonstrate how cellular organization, structure, and function allow organisms to maintain homeostasis.

HS+B.L1U1.6 Develop and use models to show how transport mechanisms function in cells.

Objective

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SWBAT explain how different body systems work together to maintain homeostasis.

SWBAT describe how diabetes affects multiple systems, not just the endocrine system

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CDC article that explains Type I diabetes really well. Very easy to read.

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With type 1 diabetes, your pancreas doesn't make insulin or makes very little insulin.

People with type 1 diabetes need to take insulin every day.

Currently, type 1 diabetes can't be prevented, but it can be treated effectively.

Overview

If you have type 1 diabetes, your pancreas doesn't make insulin or makes very little insulin. Insulin helps blood sugar enter the cells in your body for use as energy.

Without insulin, blood sugar can't get into cells and builds up in the bloodstream. High blood sugar is damaging to the body and causes many of the symptoms and complications of diabetes.

Type 1 diabetes was once called insulin-dependent or juvenile diabetes. It often develops in children, teens, and young adults, but it can happen at any age.

Type 1 diabetes is less common than type 2 -about 5-10% of people with diabetes have type 1. Currently, no one knows how to prevent type 1 diabetes, but it can be managed successfully by:

Signs and symptoms

It can take months or years before symptoms of type 1 diabetes are noticed. Type 1 diabetes symptoms can develop in just a few weeks or months. Once symptoms appear, they can be severe.

Some type 1 diabetes symptoms are similar to symptoms of other health conditions. Don't guess! If you think you could have type 1 diabetes, see your doctor to get your blood sugar tested. Untreated diabetes can lead to very serious-even fatal-health problems.

Risk factors

Risk factors for type 1 diabetes are not as clear as for prediabetes and type 2 diabetes. Known risk factors include:

Family history: Having a parent, brother, or sister with type 1 diabetes.

Age: You can get type 1 diabetes at any age, but it usually develops in children, teens, or young adults.

In the United States, White people are more likely to develop type 1 diabetes than African American and Hispanic or Latino people.

Causes

Type 1 diabetes is thought to be caused by an autoimmune reaction (the body attacks itself by mistake). This reaction destroys the cells in the pancreas that make insulin, called beta cells. This process can go on for months or years before any symptoms appear.

Some people have certain genes (traits passed on from parent to child) that increase their chance of developing type 1 diabetes. However, many of them won't go on to have type 1 diabetes even if they have the genes. A trigger in the environment, such as a virus, may also play a part in developing type 1 diabetes. Diet and lifestyle habits don't cause type 1 diabetes.

Testing and screening

A simple blood test is used to screen for diabetes. If you were tested at a health fair or pharmacy, follow up at a clinic or doctor's office. That way you'll be sure the results are accurate.

If your doctor thinks you have type 1 diabetes, your blood may also be tested for autoantibodies. These substances indicate your body is attacking itself and are often found with type 1 diabetes but not with type 2. You may have your urine tested for ketones. Ketones are produced when your body burns fat for energy. Having ketones in your urine indicates you have type 1 diabetes instead of type 2.

For parents‎

Treatment

Unlike many health conditions, diabetes is managed mostly by you, with support from your health care team:

Primary care doctor

Foot doctor

Dentist

Eye doctor

Registered dietitian nutritionist

Diabetes educator

Pharmacist

Also ask your family, teachers, and other important people in your life for help and support. Managing diabetes can be challenging, but everything you do to improve your health is worth it!

You'll need to take insulin shots (or wear an insulin pump) every day. Insulin is needed to manage your blood sugar levels and give your body energy. You can't take insulin as a pill. That's because the acid in your stomach would destroy it before it could get into your bloodstream. Your doctor will work with you to figure out the most effective type and dosage of insulin for you.

You'll also need to do regular blood sugar checks. Ask your doctor how often you should check it and what your target blood sugar levels should be. Keeping your blood sugar levels as close to target as possible will help you prevent or delay diabetes-related complications.

Hypoglycemia and diabetic ketoacidosis are common complications of diabetes, and you'll need to know how to handle them. Meet with your doctor for step-by-step instructions.

Stress is a part of life, but it can make managing diabetes harder. Regular physical activity, getting enough sleep, and exercises to relax can help. Talk to your doctor and diabetes educator about these and other ways you can manage stress.

Healthy lifestyle habits are really important too:

Regular appointments with your health care team can help you stay on track with your treatment plan and offer new ideas and strategies if needed.

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Learn about type 1 diabetes symptoms, testing, treatment and management.

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Published by the International Journal of Molecular Sciences

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1. Introduction

Type 2 Diabetes Mellitus (T2DM) is one of the most common metabolic disorders worldwide and its development is primarily caused by a combination of two main factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond to insulin [ 1]. Insulin release and action have to precisely meet the metabolic demand; hence, the molecular mechanisms involved in the synthesis and release of insulin, as well as the insulin response in tissues must be tightly regulated. Therefore, defects in any of the mechanisms involved can lead to a metabolic imbalance that leads to the pathogenesis of T2DM.

This review analyses the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism and associations between T2DM and cardiovascular pathophysiology. In this review, we describe the global trends of T2DM, the roles of major risk factors, in particular, obesity, lifestyle factors, genetic predispositions, gut dysbiosis, epigenetics and mitochondrial deregulation. We highlight physiological and molecular mechanisms leading to T2DM and its complications.

2. Type 2 Diabetes Mellitus: Background and Epidemiology

According to the World Health Organization (WHO) diabetes mellitus is a chronic, metabolic disease characterized by elevated levels of blood glucose, which leads over time to damage to the heart, vasculature, eyes, kidneys and nerves. Over 90% of diabetes mellitus cases are T2DM, a condition marked by deficient insulin secretion by pancreatic islet β-cells, tissue insulin resistance (IR) and an inadequate compensatory insulin secretory response [ 2, 3]. Progression of the disease makes insulin secretion unable to maintain glucose homeostasis, producing hyperglycaemia. Patients with T2DM are mostly characterized by being obese or having a higher body fat percentage, distributed predominantly in the abdominal region. In this condition, adipose tissue promotes IR through various inflammatory mechanisms, including increased free fatty acid (FFA) release and adipokine deregulation. The main drivers of the T2DM epidemic are the global rise in obesity, sedentary lifestyles, high caloric diets and population aging, which have quadrupled the incidence and prevalence of T2DM [ 4, 5].

The organs involved in T2DM development include the pancreas (β-cells and α-cells), liver, skeletal muscle, kidneys, brain, small intestine, and adipose tissue [ 6]. Evolving data suggest a role for adipokine dysregulation, inflammation, and abnormalities in gut microbiota, immune dysregulation, and inflammation have emerged as important pathophysiological factors [ 7].

Epidemiological data show alarming values that predict a worrisome projected future for T2DM. According to the International Diabetes Federation (IDF), in 2019, diabetes caused 4.2 million deaths; and 463 million adults aged between 20 and 79 years old were living with diabetes, a number that will likely rise up to 700 million by 2045. Diabetes was the underlying cause of at least 720 billion USD in health expenditure in 2019. Additionally, the true disease burden of T2DM is likely an underrepresentation as 1 in 3 diabetic people were underdiagnosed, equivalent to 232 million people. The greatest number of people suffering from diabetes are aged between 40 and 59 years old. Incidence and prevalence of T2DM vary according to geographical region, with more than 80% of patients living in low-to-middle-income countries, which poses additional challenges in effective treatment. Patients with T2DM have a 15% increased risk of all-cause mortality compared with people without diabetes with cardiovascular disease (CVD) as the greatest cause of morbidity and mortality associated with T2DM [ 8]. The association of diabetes with increased risk of coronary heart disease (hazard ratio [HR] 2.00; 95% CI 1.83-2.19), ischaemic stroke (HR 2.27; 1.95-2.65), and other vascular disease-related deaths (HR 1.73; 1.51-1.98) has been shown in a meta-analysis [ 9].

Epidemiology of T2DM is affected both by genetics and the environment. Genetic factors exert their effect following exposure to an environment characterized by sedentary behavior and high-calorie intake. Common glycaemic genetic variants for T2DM have been identified by genome-wide association studies, but these only account for 10% of total trait variance, suggesting that rare variants are important [ 10]. People of different ethnic origins may have different specific phenotypes that increase predisposition to clusters of CVD risk factors, including hypertension, insulin resistance, and dyslipidemia [ 11].

3. Risk Factors and Pathophysiology

T2DM risk factors include a complex combination of genetic, metabolic and environmental factors that interact with one another contributing to its prevalence. Although individual predisposition to T2DM due to non-modifiable risk factors (ethnicity and family history/genetic predisposition) has a strong genetic basis, evidence from epidemiological studies suggests that many cases of T2DM can be prevented by improving the main modifiable risk factors (obesity, low physical activity and an unhealthy diet) [ 12, 13].

3.1. Ethnicity and Family History/Genetic Predisposition

Globally, the incidence and prevalence of T2DM are found to vary widely depending on ethnicity and geographical region with Japanese, Hispanics and Native Americans having the highest risks [ 14, 15, 16]. It has been shown higher incidence rates in Asians compared with a White American population [ 17, 18], and white population in the UK, [ 19], where the highest risk is among the black population [ 20]. Whilst no clear reasons have been found, contributing factors such as modern lifestyle factors (which promote obesity), socioeconomic and direct genetic propensity or gene environmental interactions have been postulated.

3.2. Obesity, Low Physical Activity and Unhealthy Diet

Obesity (body-mass index [BMI]≥30 kg/m ²) is the strongest risk factor for T2DM [ 26, 27] and is associated with metabolic abnormalities resulting in IR [ 28]. There exist an inverse linear relationship between BMI and the age at diagnosis of T2DM [ 29]. The exact mechanisms by which obesity induces T2DM and IR remain to be elucidated; however, numerous factors have shown a significant role in the development of this pathological process, which involves both cell-autonomous mechanisms and inter-organ communications.

A sedentary lifestyle is another risk factor for T2DM as shown by the Women's Health Study and in the Kuipio Ischemic Heart Disease Risk Factor Study, which showed a reduction of 34% and 56% reduction of developing T2DM in participants walking 2-3 h a week or at least 40 min a week, respectively [ 30, 31]. There are three primary benefits of physical activity on the delay of T2DM onset. First, the contraction of skeletal muscle cells induces an increase in blood flow into the muscle, enhancing glucose uptake from plasma [ 32]. Second, physical activity reduces the notorious intra-abdominal fat, which is a known risk factor that promotes IR [ 33]. Finally, moderate-intensity exercise has been shown to improve glucose uptake by 40% [ 34]. Physical activity improves glucose uptake and insulin sensitivity but it can also improve or even reverse inflammation and oxidative stress, which are T2DM predisposing factors [ 32].

3.3. Pathophysiology

Regarding the pathophysiology of the disease, a malfunctioning of the feedback loops between insulin action and insulin secretion results in abnormally high glucose levels in blood [ 2]. In the case of β-cell dysfunction, insulin secretion is reduced, limiting the body's capacity to maintain physiological glucose levels. On the other hand, IR contributes to increased glucose production in the liver and decreased glucose uptake both in the muscle, liver and adipose tissue. Even if both processes take place early in the pathogenesis and contribute to the development of the disease, β-cell dysfunction is usually more severe than IR. However, when both β-cell dysfunction and IR are present, hyperglycaemia is amplified leading to the progression of T2DM [ 35, 36].

4. Mechanisms Leading to T2DM and Pathophysiology

4.1. Insulin Secretion: Physiological and Dysfunctional Mechanisms Leading to T2DM

4.1.1. β-Cell Physiology

To safeguard proper β-cell function, cellular integrity must be ensured and the mechanisms and pathways implicated in the physiology of β-cell must be tightly regulated [ 35].

β-cells are responsible for insulin production, which is synthesized as pre-proinsulin. In the maturation process, pre-proinsulin undergoes a conformational modification carried out with the help of several proteins in the endoplasmic reticulum (ER) to yield proinsulin [ 37]. Afterwards, proinsulin is translocated from the ER to the Golgi apparatus (GA), entering into immature secretory vesicles and being cleaved into C-peptide and insulin [ 38, 39].

Once matured, insulin is stored in granules until insulin release is triggered. Insulin release is primarily triggered by a response to high glucose concentrations. It is worth noting that some other factors can also induce insulin release such as amino acids, fatty acids and hormones [ 40]. When circulating glucose levels increase, β-cells take in glucose mainly through the glucose transporter 2 (GLUT2), a solute carrier protein that also works as a glucose sensor for β-cells. Once glucose enters, glucose catabolism is activated, increasing the intracellular ATP/ADP ratio, which induces the closing of ATP-dependant potassium channels in the plasma membrane. This leads to membrane depolarization and opening of the voltage dependant Ca ²⁺ channels, enabling Ca ²⁺ to enter the cell. The rise in the intracellular Ca ²⁺ concentration triggers the priming and fusion of the secretory insulin-containing granules to the plasma membrane, resulting in insulin exocytosis [ 38, 40, 41, 42] ( Figure 1 A).

Additionally, Ca ²⁺ signals can be amplified by the RY receptors (RYR) and may play important roles in stimulus- insulin secretion coupling by virtue of their strategic locations within the cell and their ability to mediate Ca ²⁺ induced Ca ²⁺ release (CICR). RYR amplifies Ca ²⁺ signals when the channel is sensitized by messenger molecules generated from the nutrient metabolism or ligand-binding and are involved in the amplification of insulin secretion [ 43] ( Figure 1 A).

Nevertheless, other cell signals can also assist or enhance insulin release from β-cells. Among them, cAMP might be the most important messenger potentiating insulin release. Accumulated evidence suggests that cAMP induces insulin-containing secretory vesicle mobilization by depleting intracellular Ca ²⁺ reservoirs, thereby increasing intracellular Ca ²⁺ concentrations [ 44]. There is also compelling evidence that extracellular ATP is another important regulator of β-cell function. It is well-documented that β-cells release ATP through exocytosis of insulin granules upon glucose stimulation. Purinergic signaling via P2Y and P2X purinergic receptors stimulates Ca ²⁺ mobilization and regulates insulin exocytosis also independently of glucose. P2Y purinoreceptors have been reported to be coupled to G-proteins [ 45, 46] whereas P2X-type receptors are ATP-activated ligand-gated ion channels non-selective for cations [ 47]. In the case of P2Y receptors, it has been proposed that insulin release could be mediated by intracellular Ca ²⁺ mobilization in response to inositol-1,4,5-trisphosphate (IP3) formation that triggers the release of Ca ²⁺ from ER stores, which amplifies the exocytosis-triggering Ca ²⁺ signal [ 48, 49] ( Figure 1 A).

4.1.2. Mechanisms Leading to β-Cell Dysfunction

β-cell dysfunction has been traditionally associated with β-cell death [ 50]. However, recent evidence suggests that the dysfunction of β-cells in T2DM might be due to a more complex network of interactions between the environment and different molecular pathways implicated in cell biology [ 51]. In an excessive nutritional state, similar to that found in obesity, hyperglycemia and hyperlipidemia are often present, favoring IR and chronic inflammation. Under these circumstances, β-cells, due to differences in their genetic susceptibility, are subject to toxic pressures including inflammation, inflammatory stress, ER stress, metabolic/oxidative stress, amyloid stress, with the potential of ultimately leading to a loss of islet integrity [ 50].

An excess of FFAs and hyperglycemia lead to β-cell dysfunction by inducing ER stress through the activation of the apoptotic unfolded protein response (UPR) pathways [ 52]. In fact, lipotoxicity, glucotoxicity and glucolipotoxicity occurring in obesity, induce metabolic and oxidative stress that leads to β-cell damage [ 51]. Stress derived from high levels of saturated FFAs can activate the UPR pathway by several mechanisms including inhibition of the sarco/endoplasmic reticulum Ca ²⁺ ATPase (SERCA) responsible for ER Ca ²⁺ mobilization; activation of IP3 receptors or direct impairment of ER homeostasis. In addition, sustained high glucose levels increase proinsulin biosynthesis and islet amyloid polypeptides (IAAP) in β-cells, leading to the accumulation of misfolded insulin and IAAP and increasing the production of oxidative protein folding-mediated reactive oxygen species (ROS) [ 52]. These effects alter physiological ER Ca ²⁺ mobilization and favor proapoptotic signals, proinsulin mRNA degradation and induce interleukin (IL)-1 β release that recruits macrophages and enhances local islet inflammation [ 51] ( Figure 1 B).

As previously mentioned, insulin secretion has to be finely regulated to precisely meet metabolic demand. For that reason, proper islet integrity must be conserved in order to allow β-cells to respond to metabolic needs. Under pathogenic conditions, the mechanism described above can ultimately lead to disruption of islet integrity/organization, impairing optimal cell-to-cell communication within pancreatic islets, contributing to poor regulation of insulin and glucagon release and ultimately exacerbating the hyperglycemia. Defects in the synthesis of any insulin precursors, or insulin itself, as well as disruption of the secretion mechanism, can lead to insulin secretory dysfunction, the primary driver of β-cell failure, and a foundation of T2DM. For instance, reduced expression in the GLUT2 glucose transporter would affect the downstream signaling pathway [ 53], while failure in the folding of proinsulin is another finding commonly linked to deficient insulin production and diabetes [ 54].

4.1.3. Pathological Conditions Perpetuating T2DM

Nutritional Factors

Physical Activity

Gut Dysbiosis

Mitochondrial Dysfunction

5. Insulin Resistance

IR refers to a decrease in the metabolic response of insulin-responsive cells to insulin or, at a systemic level, an impaired/lower response to circulating insulin by blood glucose levels [ 153]. There are three broad categories of IR or insulin-deficient conditions: (1) diminished insulin secretion by β-cells; (2) insulin antagonists in the plasma, due either to counter-regulatory hormones or non-hormonal bodies that impair insulin receptors or signaling; and (3) impaired insulin response in target tissues [ 154]. The action of insulin is influenced by the interplay of additional molecules including growth hormone and IGF-1 in the fed state. While fasting, the insulin response is mitigated by glucagon, glucocorticoids and catecholamines in order to prevent insulin-induced hypoglycemia. The ratio of insulin/glucagon plays a major role in this regulation, since it determines the relative degree of phosphorylation of downstream enzymes in the regulatory signaling pathways. While catecholamines promote lipolysis and glycogenolysis, glucocorticoids promote muscle catabolism, gluconeogenesis and lipolysis. Hence, excessive secretion of these hormones may be responsible for inducing IR [ 155, 156]. Regarding the last category, there are three main extra-pancreatic insulin-sensitive organs that play major roles in the aforementioned processes: skeletal muscle, adipose tissue and liver. A defective action of insulin in these tissues often precedes the development of systemic IR, thus progressively leading T2DM.

5.1. Skeletal Muscle

Skeletal muscle IR is considered to be the most important extra-pancreatic factor in the development of T2DM [ 157]. Under physiological conditions, insulin stimulates muscle glycogen synthesis by enhancing glucose uptake from plasma. There are three primary rate-limiting factors implicated in glucose uptake and glycogen synthesis: glycogen synthase, hexokinase and the glucose transporter GLUT4 [ 158]. Upon insulin binding to insulin receptor (INSR) in muscle cells, GLUT4 translocates from intracellular compartments (early endosomes (EE), endosomal recycling compartment (ERC) and trans-Golgi network (TGN)) to the plasma membrane. This process allows glucose uptake and reduces circulating glucose levels [ 159].

5.2. Adipose Tissue

Adipose tissue is a metabolically dynamic tissue capable of synthesizing a wide range of biologically active compounds that regulate metabolic homeostasis at a systemic level [ 163]. Indeed, adipose tissue participates in a broad range of biological processes involving, among others, immunity, coagulation, angiogenesis, fibrinolysis, reproduction, vascular tone control, appetite regulation, body weight homeostasis and glucose and lipid metabolism [ 164].

Insulin acts on adipose tissue in two different ways: (1) stimulating glucose uptake and triglyceride synthesis; and (2) suppressing triglyceride hydrolysis and inducing the uptake of FFA and glycerol from circulation [ 165]. In the fed state, GLUT4 allows uptake of glucose from the bloodstream into adipocytes, activating glycolysis in which glycerol-3-phospate (glycerol-3-P) is produced and incorporated into lipogenic pathways. Glycerol-3-P, along with the fatty acids coming from VLDLs, are esterified, forming triacylglycerol (TGA) that is stored in lipid droplets. During metabolic stress, TGA droplets the adipocyte are depleted, in order to provide FFA to be used as an energy source in other tissues.

An impaired response to insulin stimulation by adipose tissue is known as adipose IR (Adipose-IR). Adipose-IR can lead to impaired suppression of lipolysis, impaired glucose uptake, and enhanced FFA release into plasma even in the presence of high insulin levels [ 166]. Among the signaling elements affected by adipose-IR, we found that defective AKT activation impairs GLUT4 translocation to the membrane and promotes the activation of lipolytic enzymes that aggravate hyperglycemia [ 153]. Adipose-IR, as mentioned before, is associated with glucose intolerance and elevated release of FFA into a plasma that accumulates in other tissues such as muscle or liver. In the case of the liver, FFA accumulation results in impaired insulin signaling that promotes hepatic gluconeogenesis and impairs the glucose-stimulated insulin response, inducing T2DM development.

5.3. Liver

In the liver, insulin does not only regulate glucose production/utilization but also affects lipid metabolism more broadly. When circulating glucose levels increase and insulin is secreted by pancreatic β-cells, insulin binding to liver INSR induces autophosphorylation of the receptor. Consequently, insulin receptor substrates (IRSs) are recruited and phosphorylated. In turn, IRSs activate PI3K, which phosphorylates phosphatidylinositol (4,5)-bisphosphate (PIP2), generating phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 then activates PDK1, which phosphorylates AKT. In addition, AKT is phosphorylated by mTORC2. Once AKT is fully activated, it participates in several downstream pathways that regulate multiple metabolic processes including glycogen synthesis, gluconeogenesis, glycolysis and lipid synthesis [ 169].

In physiological states, the combined action of glucagon and insulin allows the precise regulation of hepatic glucose output. While glucagon induces hepatic glucose production, insulin acts as a potent inhibitor of glucose production when its concentration in the blood is elevated [ 170]. The effect of insulin on hepatic glucose production is due to both direct and indirect mechanisms. However, the relative importance of each of these mechanisms remains unclear [ 171].

Similar to the case in insulin-sensitive tissues, in states of IR, physiologic levels of circulating insulin are insufficient to elicit the appropriate insulin response in hepatic cells [ 176]. In the liver, IR impairs glycogen synthesis, fails to suppress glucose production, enhances lipogenesis, and increases the synthesis of proteins such as the proinflammatory CRP. In fact, the abnormal production of proinflammatory proteins such as adipocytokines and cytokines, combined with conditions such as oxidative stress, can lead to an inflammatory state responsible for altered insulin response by the liver [ 175].

6. T2DM Outcomes/Complications: Cardiovascular Risk

As described in the previous sections, T2DM is a multisystem disease with a strong correlation with CVD development [ 177]. T2DM leads to a two- to four-fold increase in the mortality rate of adults from heart disease and stroke and is associated with both micro- and macro-vascular complications, the latter consisting of accelerated atherosclerosis leading to severe peripheral vascular disease, premature coronary artery disease (CAD) and increased risk of cerebrovascular diseases [ 178, 179, 180]. These factors lead to T2DM being considered a significant risk factor for CVD [ 181], likely through the involvement of several molecular mechanisms and pathological pathways. These include the role of IR in atherosclerosis, vascular function, oxidative stress, hypertension, macrophage accumulation and inflammation [ 182, 183, 184, 185]. The following sections describe in detail the main factors implicated in cardiovascular risk outcomes from T2DM and the interactions between them ( Figure 6).

6.1. Diabetic Dyslipidaemia and Atherosclerosis Development

Dyslipidaemia is a common feature of T2DM, and increases the incidence of atherosclerosis and mortality of diabetic patients [ 186]. The hallmark of diabetic dyslipidemia is a characteristic dyslipidaemic profile consisting of elevated TG, TG-rich lipoproteins (TRLs), small dense LDLs (sdLDL), and reduced HDL levels [ 187, 188, 189]. Although the pathophysiology of dyslipidemia in T2DM is not completely characterized, several factors such as hyperglycemia, insulin resistance, hyperinsulinemia, abnormalities in adipokines and adipocytokines have been implicated [ 190]. Epidemiological studies indicate that TG-rich lipoproteins and their remnants contribute to atherogenesis and CVD risk [ 191, 192, 193, 194, 195] and experimental studies indicated a connection between cholesterol deposition and inflammation as a result of TRLs entry into the artery wall [ 196, 197]. TRLs consist of a great variety of nascent and metabolically modified lipoprotein particles including intestine-derived apoB48 (chylomicrons and chylomicron remnants) and liver-derived apoB100 (VLDL and its remnants). TRLs are highly heterogeneous in size, density, and apolipoprotein composition [ 198].

Mechanisms Leading to T2DM Dyslipidemia and Atherosclerosis

Increased hepatic TG content present in T2DM patients leads to elevated hepatic production of VLDL and normal or slightly elevated LDL-C levels, most commonly sdLDLs enriched in TG [ 189, 201]. One of the primary abnormalities in IR is impaired adipose tissue fat storage, resulting from insulin's inability to inhibit hormone-sensitive lipase (HSL). This results in constitutive FFA release from the intracellular TG stores of adipocytes. The released FFAs are taken up by hepatocytes, where they can be directed to the mitochondria and undergo β-oxidation; be re-assimilated into TG to assemble new VLDL particles; shifted to gluconeogenesis resulting in a worsening of hyperglycemia; or stored as TG leading to hepatic steatosis.

The dominant feature of diabetic dyslipidemia is the increased production rate of VLDL-apoB100 by the liver, mainly VLDL1, which is related to insulin sensitivity indices [ 202]. This highlights the role of insulin on VLDL assembly and secretion by hepatocytes [ 203]. Insulin plays a role in almost all the steps of VLDL assembly and secretion. It is known that insulin inhibits the transcription of Mttp, the gene coding for the microsomal transfer protein (MTP), the protein responsible for assembling TG with apoB100 [ 204]. MTP facilitates concerted lipid transfer and apoB100 folding as it enters the ER lumen and lipidation determines the amount of the active pool of apoB100 [ 205]. Lipidation of apoB100 is a co-translational event and a rate-limiting step of apoB100 mRNA stability thus low availability of TG leads to apoB100 degradation. The addition of TG to apoB100 generates nascent VLDL particles that are transported to the GA by Sar2/COPII-containing vesicles. Within the GA, VLDL maturation occurs in a process promoted by the phospholipase D1 (PLD1) [ 203]. Therefore, in insulin-resistant condition, MTP expression and activity is increased thus contributing to raising apoB100 lipidation and to its rescue from degradation. Indeed, IR leads to a loss of the acute insulin-mediated inhibition of apoB100 secretion [ 205].

Availability of TGs within hepatocytes is important for VLDL synthesis [ 206] and the liver uses both de novo synthesized FAs and extra-hepatic FFAs as a substrate for TG synthesis [ 207]. De novo lipogenesis occurs primarily in the fed state in which the expression of lipogenic genes is regulated by the sterol regulatory element-binding protein (SREBP). The SREBP-1c isoform up-regulates almost all the enzymes involved in FA synthesis as well as enzymes that supply acetyl-CoA units and reducing equivalents to the pathway [ 208]. Insulin regulates SREBP-1c, which explains the lipogenic effect of chronic hyperinsulinemia [ 208]. FFAs derived from adipose tissue is also a major source of liver TGs and VLDL production. As mentioned above, T2DM is characterized by increased production of FFAs by adipose tissue [ 207]. Therefore, in IR, an increase in TG lipolysis in adipose tissue and FFA influx serves as another source of lipid to the liver [ 207].

The lower HDL concentration and modified composition of HDL have an important impact in diminishing the particle capacity of inducing cholesterol efflux from the cells, which is the first step in reverse cholesterol transport (RCT) [ 218]. The impaired RCT activity has been associated with increased risk of CAD [ 219] and with flow-mediated vasodilation in T2DM patients [ 220].

Atherosclerosis is accelerated by the increased permeability of sdLDL into the subendothelial space ( Figure 7) [ 221, 222]. SdLDL particles are characterized by a lower affinity for LDLR due to conformational rearrangements occurring in apoB100 as the particle decreases in volume and size [ 223]. Furthermore, sdLDL particles are more susceptible to oxidation and thus avidly scavenged by activated macrophages in the subendothelial space, giving rise to foam cells [ 224]. In addition, sdLDL particles show increased proteoglycan binding and facilitated entry into the arterial wall, increased arterial retention, and a longer half-life [ 225]. sdLDL particles are also more likely to be glycated, more resistant to breakdown, and more susceptible to oxidation by free radicals [ 226].

There is an insulin response element in the gene for apoA-I, the primary apolipoprotein constituent of HDL particles [ 227, 228]. As the liver becomes more insulin resistant, less apoA-I is produced and there is less HDL biogenesis. Adipocytes express the ATP-binding membrane cassette transport protein A1 (ABCA1). IR downregulates the expression of ABCA1 on the surface of adipocytes and reduces HDL formation by these cells [ 229, 230, 231]. Chylomicrons are enriched with apoA-I. IR reduces the release of this apoA-I into the serum by inhibiting LPL. In addition, within the milieu of IR of diabetes, HDL particle concentrations are not only quantitatively reduced, but also tend to be dysfunctional and unable to perform their primary functions, including reversal of cholesterol transport and inhibition of oxidative and inflammatory phenomena [ 232].

Diabetic dyslipidemia acts in concert with other metabolic and vascular abnormalities to further compound vascular risk. Chronic hyperglycemia induces endothelial dysfunction through a variety of mechanisms such as by reducing vasodilation, increasing vasoconstriction, increasing exposure to free radicals and impairing endothelial cell function, with a net effect of facilitating pro-atherogenic conditions [ 238]. Increased activity of the renin-angiotensin axis has also been found to further increase oxidative stress [ 239].

6.2. Impaired Endothelial Function and Atherosclerosis Development

Endothelium plays an important role in the regulation of vascular tone and structure through a balanced release of endothelial-derived relaxing and contracting factors. This balance is altered in T2DM leading to alteration of the physicochemical properties of the vascular wall via endothelial dysfunction, oxidative stress, platelet hyperreactivity, and inflammation [ 240, 241]. These abnormalities lead to enhanced vasoconstriction, development of atherosclerosis, and favored thrombus formation [ 179, 180].

6.2.1. Mechanisms Leading to Endothelial Dysfunction in T2DM

Vascular endothelial cells are particularly susceptible to developing intracellular hyperglycemia because glucose diffuses passively through their plasma membrane. In T2DM, the excess of glucose can be metabolized in the sorbitol pathway to sorbitol and fructose by aldose reductase, which activates the aldose reductase secondary metabolic pathway, with concomitant oxidation of NADPH to NADP⁺ and reduction of NAD⁺ to NADH. NADPH depletion and an increased NADH/NAD⁺ cytosolic ratio leads to a change in redox potential that accelerates glycolysis and increases de novo synthesis of DAG [ 242]. As a result, protein kinase C (PKC) is activated, nitric oxide (NO) is reduced. These effects cause vascular permeability and increase contractility. Simultaneously, the increased NADH/NAD⁺ ratio also results in higher production of O ₂−, LDL oxidation, cytotoxic effects on endothelial cells and reduced NO availability, leading to endothelial dysfunction [ 241, 242].

The overproduction of aldoses by the sorbitol pathway promotes protein glycosylation that yields the formation of the stable Amadori products (such as glycosylated hemoglobin) and AGEs. AGEs are associated with several molecules that augment oxidant activity and consequently the production of ROS, which increases oxidative stress and prevents the release of NO, resulting in vascular lesions. AGEs may also reduce endothelium-derived NO bioavailability and activity, further compromising vascular activity [ 243]. In addition, AGEs can trigger an inflammatory and pro-coagulant state and can cause endothelial activation through the induction of receptor-mediated gene transcription. AGE binding to the RAGE-receptor, nuclear transcription factor NF-κB [ 242, 243] is activated leading to transcription of endothelin-1, VCAM-1, ICAM-1, E-selectin, thrombomodulin, TF, vascular endothelial growth factor (VEGF), IL-1, IL-6, and TNF-α [ 242, 244]. Increased expression of inflammatory and adhesion molecules amplifies the inflammatory response and aggravates diabetic vascular complications. These pro-inflammatory cytokines stimulate the expression and release of pro-coagulant molecules and inhibit the expression of anti-coagulant molecules by endothelial cells [ 245]. This leads to a pro-coagulant state in the surface of the endothelium and increases growth factor production resulting in a thickening of the basement membrane, thus favoring protein and lipid deposition and impairing vasodilation [ 242, 246].

6.2.2. Endothelial Dysfunction in T2DM and Atherosclerosis Development

6.3. Diabetes-Associated Chronic Inflammation and Atherosclerosis Progression

A critical component of T2DM is a chronic low-grade inflammatory state, referred to as "metaflammation" [ 250]. This chronic condition involves the same cellular and molecular players of acute inflammatory responses and has been suggested as an underlying cause of the progression of atherosclerosis in T2DM. Hyperglycaemia can increase circulating cytokines that can lead to chronic inflammation in T2DM [ 250]. Among them, patients with T2DM have higher levels of IL-1b, IL-6, IL-8, MCP-1, and other major cytokines in both monocytes and macrophages [ 130]. The underlying mechanisms involved in this process are ROS-mediated activation of p38 and other proinflammatory kinases, upregulation of NF-kB induction, oxidative stress, and activation of the AGE-RAGE pathway [ 129, 130]. In addition, exposure to high glucose levels impairs the phagocytic activity of macrophages, which partially explains the increased incidence of chronic infection among T2DM patients [ 251]. Indeed, T2DM is associated with increased activity of the inflammasome, upregulation of the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3), increased levels of IL-1β and IL-18 [ 252, 253, 254]. These events trigger neutrophil extracellular trap activation, or NETosis, a characteristic cell death of macrophages causing chronic inflammation [ 255]. High levels of these markers have been found in T2DM patients [ 256], which are enhanced in hyperglycaemic conditions [ 257].

6.4. Adipokine Balance and CVD Risk

Adipose tissue dysfunction as a result of T2DM can result in an imbalance between pro-inflammatory and anti-inflammatory adipokines, and is one of the mechanisms of T2DM complications. Several studies indicate that adipokines are related to IR, and can result in endothelial dysfunction, and pro-inflammatory and pro-atherogenic states [ 258, 259].

Adiponectin is a well-described insulin-sensitizing hormone and its expression and circulating levels are inversely proportional to the extent of adiposity. Adiponectin has insulin-sensitizing properties [ 260, 261]. Adiponectin acts through ADIPOR1 and ADIPOR2 receptors [ 262] and the peroxisome proliferator-activated receptor α (PPARα) pathway, leading to decreased hepatic gluconeogenesis, increased liver and skeletal muscle fatty acid oxidation, increased glucose uptake in skeletal muscle and white adipose tissue, and decreased white adipose tissue inflammation [ 263]. In addition, adiponectin ameliorates β-cell death by neutralizing inflammatory and lipotoxic ceramides and DAGs [ 264] and shows strong anti-inflammatory effects on other cell types such as macrophages and fibrogenic cells [ 263, 265, 266]. Low concentrations of adiponectin have been found in T2DM patients and are correlated with increased risk of developing premature arteriosclerosis, and are thus considered an additional CVD risk factor [ 267]. Notably, adiponectin deficiency is associated with coronary artery disease, hypertension, endothelial dysfunction and greater carotid intima-media thickness [ 268, 269, 270, 271]. Low concentrations of adiponectin lead to an increased expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, promotes differentiation of macrophages into foam cells and enhances the proliferation and migration of smooth muscle cells [ 272].

Omentin is an adipokine secreted from white adipose tissue and is involved in glucose homeostasis [ 273, 274]. Omentin circulates in the blood [ 275, 276], and is associated with reduced levels in T2DM patients [ 277, 278]. In vitro studies have shown that omentin enhances insulin-stimulated glucose uptake in human adipocytes by AKT signaling pathway activation [ 273]. In humans, an inverse correlation between omentin levels and IR is seen, both at the protein and mRNA levels [ 277, 279, 280]. Additional studies show that omentin has anti-inflammatory properties, diminishes cytokine expression [ 281, 282], and is negatively associated with systemic inflammatory markers such as TNF and IL-6 [ 283].

Vaspin (visceral adipose tissue-derived serine protease inhibitor) is an adipokine that inhibits proteases responsible for IR and protects against atherosclerosis and plaque development [ 284, 285]. It has been shown that T2DM patients have higher serum vaspin levels than healthy controls. Higher vaspin levels are associated with a 1.7-fold increased risk of CVD [ 70]. High vaspin is also associated with increased severity of coronary artery disease [ 286].

7. Conclusions

The importance of research in the fields of glucose homeostasis, insulin and diabetes has not faded. In fact, due to rapid globalization and the normalization of a sedentary lifestyle, along with increased obesity, diabetes and their consequent co-morbidities, research in this topic must continue to grow. Understanding the mechanisms implicated in every step in the development and complications of T2DM is crucial in order to prevent, control, treat or revert the pathophysiology of T2DM its complications. Although quality outcomes for patients are optimized by early detection of T2DM through screening and intensive patient-centered management, research efforts are needed to define causative factors accounting for correlations among different demographic subsets and the corresponding variable risks for T2DM as well as the drivers of increased risk in individuals of low socioeconomic status. Being the pathophysiology and underlying mechanisms of T2DM increasingly understood, precision medicine should be implemented and treatments individualized and targeted appropriately with the help of molecular genetic tools by identifying specific variants contributing to disease development as well as by searching biomarkers to assess progression and response to therapeutic interventions. Additional research is needed to determine a direct causal role of the intestinal microbiota in pathogenesis of T2DM and response to therapies needs to be determined.

Taking everything in this review into consideration, it is clear that there is still a long way until we fully understand each of the many stakeholders in glucose homeostasis.

Author Contributions

U.G.-C., A.B.-V., S.J., A.L.-S., H.S., K.B.U., H.O. and C.M. have contributed to the writing of the manuscript. U.G.-G. and C.M. conceptualized the review. A.B.-V. and C.M. drawn the images. H.S. edited language. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Basque Government (Grupos Consolidados IT-1264-19). U.G-G. was supported by Fundación Biofísica Bizkaia. A.B.-V. was supported by Programa de especializaci.n de Personal Investigador Doctor en la UPV/EHU (2019) 2019-2020. S.J. and A.L-S. were supported by a grant PIF (2017-2018) and (2019-2020), Gobierno Vasco, respectively. A.L.-S. was partially supported by Fundación Biofísica Bizkaia.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Li, G.D.; Milani, D.; Dunne, M.J.; Pralong, W.F.; Theler, J.M.; Petersen, O.H.; Wollheim, C.B. Extracellular ATP causes Ca2(+)− dependent and -independent insulin secretion in RINm5F cells. Phospholipase C mediates Ca²⁺ mobilization but not Ca²⁺ influx and membrane depolarization. J. Biol. Chem. 1991, 266, 3449-3457. [Google Scholar]

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Figure 1. Signaling pathways involved in insulin secretion in β-cells in physiological conditions ( A) and mechanisms leading to dysfunction ( B). ( A) Insulin release is primarily triggered by a response to high glucose concentrations and glucose in mainly internalized mainly through GLUT2 transporter. Glucose catabolism increases ATP/ADP ratio, ATP-dependant potassium channels are closed leading to membrane depolarization and opening of the voltage dependant Ca ²⁺ channels. The latter enables Ca ²⁺ influx triggering insulin exocytosis. Additional Ca ²⁺ channels as P2X, P2Y, SERCA and RYR contribute to Ca ²⁺ mobilization and insulin secretion. ( B) hyperglycemia and hyperlipidemia promote oxidative stress leading to ROS generation that inhibits Ca ²⁺ mobilization and activates proapoptotic signals. Additionally, an excess of FFAs and hyperglycemia lead to the activation of the apoptotic unfolded protein response (UPR) pathways and generation of ER stress. Sustained high glucose levels increase proinsulin and IAAP biosynthesis, which generate ROS. GLUT2: glucose transporter 2, P2X: purinergic receptor X; P2Y: purinergic receptor Y; IP2: inositol 1,3-bisphosphate; IP3: inositol 1,4,5-trisphosphate; RYR: ryanodine receptor channel; SERCA: sarco-endoplasmic reticulum Ca ²⁺-ATPase; FFA: free fatty acid, ROS: reactive oxygen species; UPR: unfolded protein response.

Figure 3. Mitochondrial dysfunction and contribution to T2DM development. Oxidative stress, defective mitochondrial biogenesis and impaired mitophagy promote mitochondrial dysfunction. Generation of ROS links mitochondrial dysfunction and IR. As a consequence of nutrient overload, electron supply to the mitochondrial ETC increases and the electron excess is transferred to oxygen generating O ₂− and H ₂O ₂. ROS oxidize proteins, damage DNA and membrane lipids. Mitofusin-2 and PGC 1α are downregulated leading to reduced mitochondrial biogenesis. Cellular stress and ROS production contribute to higher mitochondrial fission and impaired mitophagy. PCG 1α: Peroxisome proliferator-activated receptor-gamma coactivator-1.

Figure 7. Diabetic dyslipidemia: mechanisms leading to T2DM dyslipidemia and lipoprotein clearance in physiological an IR conditions. ( A) IR leads to an impaired adipose tissue fat storage, resulting in constitutive FFA release from the intracellular TG stores of adipocytes. The released FFAs are taken up by hepatocytes, where they can be directed to the mitochondria and undergo β-oxidation; be re-assimilated into TG to assemble new VLDL particles; shifted to gluconeogenesis resulting in a worsening of hyperglycemia; or stored as TG leading to hepatic steatosis. ( B) Under physiological conditions, VLDL particles incorporate apo-CII and apoE from HDL allowing VLDL to be progressively lipolyzed leading to the generation of smaller VLDL particles (upper panel). T2DM and IR impair metabolism and clearance of chylomicrons and VLDLs. Activation of CETP promotes an exchange of TG out of RLPs and incorporates CE from HDL and LDL particles leading to reduced levels of circulating HDL-C and an increase in the more atherogenic sdLDL particles (lower panel). TG: triglyceride; FFA: free fatty acid, LPL: lipoprotein Lipase; CR: chylomicron remnants; HL: hepatic lipase; CETP: Cholesteryl Ester Transfer Protein; ApoE: apolopoprotein E; ApoC-II: apolipoprotein CII; apoC-III: apolipoprotein CIII; VLDL: very low-density lipoprotein; sdLDL: small dense lipoprotein.

Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, Ostolaza H, Martín C. Pathophysiology of Type 2 Diabetes Mellitus. International Journal of Molecular Sciences. 2020; 21(17):6275. https://doi.org/10.3390/ijms21176275

Chicago/Turabian Style

Galicia-Garcia, Unai, Asier Benito-Vicente, Shifa Jebari, Asier Larrea-Sebal, Haziq Siddiqi, Kepa B. Uribe, Helena Ostolaza, and César Martín. 2020. "Pathophysiology of Type 2 Diabetes Mellitus" International Journal of Molecular Sciences 21, no. 17: 6275. https://doi.org/10.3390/ijms21176275

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Pathophysiology of Type 2 Diabetes Mellitus

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Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin.

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The Effects of Diabetes on Kidneys Article

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The Effects of Diabetes on Kidneys Article

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The Effects of Diabetes on Kidneys – Kidney Clinic of North Florida PLLC

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Diabetes, a chronic condition characterized by high blood sugar levels, can lead to a host of complications if not managed properly. One of the most serious complications is its effect on the kidneys, which can result in a condition known as diabetic nephropathy. This blog will explore how diabetes affects the kidneys, the symptoms and stages of diabetic nephropathy, and the importance of early detection and management.

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Diabetes and nerve damage Information Article

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Diabetes and nerve damage Information Article

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Learn about Diabetes and nerve damage, find a doctor, complications, outcomes, recovery and follow-up care for Diabetes and nerve damage.

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Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research

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The incidence of diabetes mellitus (DM) continues to rise and has quickly become one of the most prevalent and costly chronic diseases worldwide. A close link exists between DM and cardiovascular disease (CVD), which is the most prevalent cause of…

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Find out about type 2 diabetes, risk factors, and how to manage it.

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Global and Societal Implications of Diabetes

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Global and Societal Implications of Diabetes

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Global and societal implications of the diabetes epidemic - PubMed

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Changes in human behaviour and lifestyle over the last century have resulted in a dramatic increase in the incidence of diabetes worldwide. The epidemic is chiefly of type 2 diabetes and also the associated conditions known as ‘diabesity’ and ‘metabolic syndrome’. In conjunction with genetic suscept …

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Microvascular and Macrovascular Complications of Diabetes

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Diabetes is a group of chronic diseases characterized by hyperglycemia. Modern medical care uses a vast array of lifestyle and pharmaceutical interventions aime

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National Institute of Diabetes and Digestive and Kidney Diseases

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Having diabetes means that you are more likely to develop heart disease and have a greater chance of a heart attack or a stroke. People with diabetes are also more likely to have certain conditions, or risk factors, that increase the chances of having heart disease or stroke, such as high blood pressure or high cholesterol. If you have diabetes, you can protect your heart and health by managing your blood glucose, also called blood sugar, as well as your blood pressure and cholesterol. If you smoke, get help to stop.

Over time, high blood glucose from diabetes can damage your blood vessels and the nerves that control your heart and blood vessels. The longer you have diabetes, the higher the chances that you will develop heart disease. ¹

People with diabetes tend to develop heart disease at a younger age than people without diabetes. In adults with diabetes, the most common causes of death are heart disease and stroke. Adults with diabetes are nearly twice as likely to die from heart disease or stroke as people without diabetes. ²

The good news is that the steps you take to manage your diabetes also help to lower your chances of having heart disease or stroke.

What else increases my chances of heart disease or stroke if I have diabetes?

If you have diabetes, other factors add to your chances of developing heart disease or having a stroke.

Smoking

Smoking raises your risk of developing heart disease. If you have diabetes, it is important to stop smoking because both smoking and diabetes narrow blood vessels. Smoking also increases your chances of developing other long-term problems such as lung disease. Smoking also can damage the blood vessels in your legs and increase the risk of lower leg infections, ulcers, and amputation.

High blood pressure

If you have high blood pressure, your heart must work harder to pump blood. High blood pressure can strain your heart, damage blood vessels, and increase your risk of heart attack, stroke, eye problems, and kidney problems.

Abnormal cholesterol levels

Cholesterol is a type of fat produced by your liver and found in your blood. You have two kinds of cholesterol in your blood: LDL and HDL.

LDL, often called "bad" cholesterol, can build up and clog your blood vessels. High levels of LDL cholesterol raise your risk of developing heart disease.

Another type of blood fat, triglycerides, also can raise your risk of heart disease when the levels are higher than recommended by your health care team.

Obesity and belly fat

Being overweight or obese can affect your ability to manage your diabetes and increase your risk for many health problems, including heart disease and high blood pressure. If you are overweight, a healthy eating plan with reduced calories often will lower your glucose levels and reduce your need for medications.

Excess belly fat around your waist, even if you are not overweight, can raise your chances of developing heart disease.

Even if you are a normal weight, excess belly fat can raise your risk for heart disease.

You have excess belly fat if your waist measures

more than 40 inches and you are a man

more than 35 inches and you are a woman

Learn how to correctly measure your waist.
Family history of heart disease

A family history of heart disease may also add to your chances of developing heart disease. If one or more of your family members had a heart attack before age 50, you may have an even higher chance of developing heart disease. ³

You can't change whether heart disease runs in your family, but if you have diabetes, it's even more important to take steps to protect yourself from heart disease and decrease your chances of having a stroke.

How can I lower my chances of a heart attack or stroke if I have diabetes?

Taking care of your diabetes is important to help you take care of your heart. You can lower your chances of having a heart attack or stroke by taking the following steps to manage your diabetes to keep your heart and blood vessels healthy.

Manage your diabetes ABCs

Knowing your diabetes ABCs will help you manage your blood glucose, blood pressure, and cholesterol. Stopping smoking if you have diabetes is also important to lower your chances for heart disease.

A is for the A1C test. The A1C test shows your average blood glucose level over the past 3 months. This is different from the blood glucose checks that you do every day. The higher your A1C number, the higher your blood glucose levels have been during the past 3 months. High levels of blood glucose can harm your heart, blood vessels, kidneys, feet, and eyes.

The A1C goal for many people with diabetes is below 7 percent. Some people may do better with a slightly higher A1C goal. Ask your health care team what your goal should be.

B is for blood pressure. Blood pressure is the force of your blood against the wall of your blood vessels. If your blood pressure gets too high, it makes your heart work too hard. High blood pressure can cause a heart attack or stroke and damage your kidneys and eyes.

The blood pressure goal for most people with diabetes is below 140/90 mm Hg. Ask what your goal should be.

C is for cholesterol. You have two kinds of cholesterol in your blood: LDL and HDL. LDL or "bad" cholesterol can build up and clog your blood vessels. Too much bad cholesterol can cause a heart attack or stroke. HDL or "good" cholesterol helps remove the "bad" cholesterol from your blood vessels.

Ask your health care team what your cholesterol numbers should be. If you are over 40 years of age, you may need to take medicine such as a statin to lower your cholesterol and protect your heart. Some people with very high LDL ("bad") cholesterol may need to take medicine at a younger age.

S is for stop smoking. Not smoking is especially important for people with diabetes because both smoking and diabetes narrow blood vessels, so your heart has to work harder.

If you quit smoking

you will lower your risk for heart attack, stroke, nerve disease, kidney disease, eye disease, and amputation

your blood glucose, blood pressure, and cholesterol levels may improve

your blood circulation will improve

you may have an easier time being physically active

If you smoke or use other tobacco products, stop. Ask for help so you don't have to do it alone. You can start by calling the national quitline at 1-800-QUITNOW or 1-800-784-8669. For tips on quitting, go to Smokefree.gov.

Ask your health care team about your goals for A1C, blood pressure, and cholesterol, and what you can do to reach these goals.

Develop or maintain healthy lifestyle habits

Developing or maintaining healthy lifestyle habits can help you manage your diabetes and prevent heart disease.

Follow your healthy eating plan.

Make physical activity part of your routine.

Stay at or get to a healthy weight

Get enough sleep.

Learn more about these tips to manage diabetes.

Develop or maintain healthy lifestyle habits. Physical activity can help you manage your diabetes and may help you cope with stress.

Watch a video about what you can do to keep your heart healthy.
Learn to manage stress

Managing diabetes is not always easy. Feeling stressed, sad, or angry is common when you are living with diabetes. You may know what to do to stay healthy but may have trouble sticking with your plan over time. Long-term stress can raise your blood glucose and blood pressure, but you can learn ways to lower your stress. Try deep breathing, gardening, taking a walk, doing yoga, meditating, doing a hobby, or listening to your favorite music. Learn more about healthy ways to cope with stress.

Take medicine to protect your heart

Medicines may be an important part of your treatment plan. Your doctor will prescribe medicine based on your specific needs. Medicine may help you

meet your A1C (blood glucose), blood pressure, and cholesterol goals.

reduce your risk of blood clots, heart attack, or stroke.

treat angina, or chest pain that is often a symptom of heart disease. (Angina can also be an early symptom of a heart attack.)

Ask your doctor whether you should take aspirin. Aspirin is not safe for everyone. Your doctor can tell you whether taking aspirin is right for you and exactly how much to take.

Statins can reduce the risk of having a heart attack or stroke in some people with diabetes. Statins are a type of medicine often used to help people meet their cholesterol goals. Talk with your doctor to find out whether taking a statin is right for you.

Talk with your doctor if you have questions about your medicines. Before you start a new medicine, ask your doctor about possible side effects and how you can avoid them. If the side effects of your medicine bother you, tell your doctor. Don't stop taking your medicines without checking with your doctor first.

Take medicines as prescribed.

How do doctors diagnose heart disease in diabetes?

Doctors diagnose heart disease in diabetes based on

your symptoms

your medical and family history

how likely you are to have heart disease

a physical exam

results from tests and procedures

Tests used to monitor your diabetes-A1C, blood pressure, and cholesterol-help your doctor decide whether it is important to do other tests to check your heart health.

Your health care provider will do a physical exam.

What are the warning signs of heart attack and stroke?

Call 9-1-1 right away if you have warning signs of a heart attack:

pain or pressure in your chest that lasts longer than a few minutes or goes away and comes back

pain or discomfort in one or both of your arms or shoulders; or your back, neck, or jaw

shortness of breath

sweating or light-headedness

indigestion or nausea (feeling sick to your stomach)

feeling very tired

Treatment works best when it is given right away. Warning signs can be different in different people. You may not have all of these symptoms.

If you have angina, it's important to know how and when to seek medical treatment.

Women sometimes have nausea and vomiting, feel very tired (sometimes for days), and have pain in the back, shoulders, or jaw without any chest pain.

People with diabetes-related nerve damage may not notice any chest pain.

Call 9-1-1 right away if you have warning signs of a stroke, including sudden

weakness or numbness of your face, arm, or leg on one side of your body

confusion, or trouble talking or understanding

dizziness, loss of balance, or trouble walking

trouble seeing out of one or both eyes

sudden severe headache

If you have any one of these warning signs, call 9-1-1. You can help prevent permanent damage by getting to a hospital within an hour of a stroke.

Call 9-1-1 if you have the warning signs of a heart attack or stroke. Treatment works best when given right away.

References

[1] Huo X, Gao L, Guo L, et al. Risk of non-fatal cardiovascular diseases in early-onset versus late-onset type 2 diabetes in China: a cross-sectional study. The Lancet Diabetes & Endocrinology. 2016;4(2):115-124.

[2] National Centers for Disease Control and Prevention. National diabetes statistics report, 2014. https://www.cdc.gov/diabetes/data/statistics/statistics-report.html. Accessed December 22, 2016.

[3] Kolber MR, Scrimshaw C. Family history of cardiovascular disease. Canadian Family Physician. 2014;60(11):1016.

Clinical Trials

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and other components of the National Institutes of Health (NIH) conduct and support research into many diseases and conditions.

What are clinical trials, and are they right for you?

Clinical trials are part of clinical research and at the heart of all medical advances. Clinical trials look at new ways to prevent, detect, or treat disease. Researchers also use clinical trials to look at other aspects of care, such as improving the quality of life for people with chronic illnesses. Find out if clinical trials are right for you.

What clinical trials are open?

Clinical trials that are currently open and are recruiting can be viewed at www.ClinicalTrials.gov.

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Diabetes, Heart Disease, and Stroke | NIDDK

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Having diabetes means that you are more likely to develop heart disease and have a greater chance of a heart attack or a stroke. People with diabetes are also more likely to have certain conditions, or risk factors, that increase the chances of having heart disease or stroke, such as high blood pressure or high cholesterol.

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Understanding the Social Factors That Contribute to Diabetes: A Means to Informing Health Care and Social Policies for the Chronically Ill

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Social determinants of health are increasingly being recognized for their relationship to the soaring incidence of Type 2 diabetes in the US. Interventions focus on biologic and behavioral factors, such as symptoms, diet, and physical activity. It…

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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.

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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.

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National Institute of Diabetes and Digestive and Kidney Diseases

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Diabetes is a disease that occurs when your blood glucose, also called blood sugar, is too high. Over time, having too much glucose in your blood can cause other health problems such as heart disease, nerve damage, eye problems, and kidney disease. You can take steps to prevent or manage diabetes.

According to the Centers for Disease Control and Prevention's National Diabetes Statistics Report, an estimated 38.4 million people in the United States, or 11.6% of the population, have diabetes. About 1 in 5 adults with diabetes don't know they have the disease. An estimated 97.6 million American adults have prediabetes, which means their blood glucose levels are higher than normal but not high enough to be diagnosed as diabetes.

Many areas of the body can be affected by diabetes. Learn about diabetes health problems.

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Diabetes affects over 38 million people in the United States. Learn how you can take steps to prevent or manage this disease with information from NIDDK.

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Seminar published by the National Library of Medicine, very heavy scientific terminology but a great read for those that like a challenge.

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Over the past decade, knowledge of the pathogenesis and natural history of type 1 diabetes has grown substantially, particularly with regard to disease prediction and heterogeneity, pancreatic pathology, and epidemiology. Technological improvements…

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DKD by the National Institute of Diabetes and Digestive and Kidney Disease

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DKD by the National Institute of Diabetes and Digestive and Kidney Disease

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National Institute of Diabetes and Digestive and Kidney Diseases

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What is diabetic kidney disease?

Diabetic kidney disease is a type of kidney disease caused by diabetes.

Diabetes is the leading cause of kidney disease. About 1 out of 3 adults with diabetes has kidney disease. ¹

The main job of the kidneys is to filter wastes and extra water out of your blood to make urine. Your kidneys also help control blood pressure and make hormones that your body needs to stay healthy.

Your kidneys are located in the middle of your back, just below your rib cage.

When your kidneys are damaged, they can't filter blood like they should, which can cause wastes to build up in your body. Kidney damage can also cause other health problems.

Kidney damage caused by diabetes usually occurs slowly, over many years. You can take steps to protect your kidneys and to prevent or delay kidney damage.

Watch a video about diabetes and kidney disease.

What are other names for diabetic kidney disease?

Diabetic kidney disease is also called DKD, chronic kidney disease, CKD, kidney disease of diabetes, or diabetic nephropathy.

How does diabetes cause kidney disease?

High blood glucose, also called blood sugar, can damage the blood vessels in your kidneys. When the blood vessels are damaged, they don't work as well. Many people with diabetes also develop high blood pressure, which can also damage your kidneys. Learn more about high blood pressure and kidney disease.

What increases my chances of developing diabetic kidney disease?

Having diabetes for a longer time increases the chances that you will have kidney damage. If you have diabetes, you are more likely to develop kidney disease if your

blood glucose is too high

blood pressure is too high

African Americans, American Indians, and Hispanics/Latinos develop diabetes, kidney disease, and kidney failure at a higher rate than Caucasians.

You are also more likely to develop kidney disease if you have diabetes and

smoke

don't follow your diabetes eating plan

eat foods high in salt

are not active

are overweight

have heart disease

have a family history of kidney failure

If you have diabetes, you are more likely to develop kidney disease if you have high blood pressure.

How can I tell if I have diabetic kidney disease?

Most people with diabetic kidney disease do not have symptoms. The only way to know if you have diabetic kidney disease is to get your kidneys checked.

Health care professionals use blood and urine tests to check for diabetic kidney disease. Your health care professional will check your urine for albumin and will also do a blood test to see how well your kidneys are filtering your blood.

You should get tested every year for kidney disease if you

Health care professionals use blood and urine tests to check for kidney disease.

How can I keep my kidneys healthy if I have diabetes?

The best way to slow or prevent diabetes-related kidney disease is to try to reach your blood glucose and blood pressure goals. Healthy lifestyle habits and taking your medicines as prescribed can help you achieve these goals and improve your health overall.

Reach your blood glucose goals

Your health care professional will test your A1C. The A1C is a blood test that shows your average blood glucose level over the past 3 months. This is different from the blood glucose checks that you may do yourself. The higher your A1C number, the higher your blood glucose levels have been during the past 3 months.

The A1C goal for many people with diabetes is below 7 percent. Ask your health care team what your goal should be. Reaching your goal numbers will help you protect your kidneys.

To reach your A1C goal, your health care professional may ask you to check your blood glucose levels. Work with your health care team to use the results to guide decisions about food, physical activity, and medicines. Ask your health care team how often you should check your blood glucose level.

Protect your kidneys by keeping your blood glucose under control.

Control your blood pressure

Blood pressure is the force of your blood against the wall of your blood vessels. High blood pressure makes your heart work too hard. It can cause heart attack, stroke, and kidney disease.

Your health care team will also work with you to help you set and reach your blood pressure goal. The blood pressure goal for most people with diabetes is below 140/90 mm Hg. Ask your health care team what your goal should be.

Protect your kidneys by keeping your blood pressure under control.

Medicines that lower blood pressure can also help slow kidney damage. Two types of blood pressure medicines, ACE inhibitors and ARBs, play a special role in protecting your kidneys. Each has been found to slow kidney damage in people with diabetes who have high blood pressure and DKD. The names of these medicines end in -pril or -sartan. ACE inhibitors and ARBs are not safe for women who are pregnant.

Develop or maintain healthy lifestyle habits

Healthy lifestyle habits can help you reach your blood glucose and blood pressure goals. Following the steps below will also help you keep your kidneys healthy

Stop smoking.

Work with a dietitian to develop a diabetes meal plan and limit salt and sodium.

Make physical activity part of your routine.

Stay at or get to a healthy weight.

Get enough sleep. Aim for 7 to 8 hours of sleep each night.

Learn more about these tips to manage diabetes.

Take medicines as prescribed

Medicines may be an important part of your treatment plan. Your health care professional will prescribe medicine based on your specific needs. Medicine can help you meet your blood glucose and blood pressure goals. You may need to take more than one kind of medicine to control your blood pressure.

Talk to your health care professional or pharmacist about all of the medicines you take, including over-the-counter medicines.

How can I cope with the stress of managing my diabetes?

Managing diabetes isn't always easy. Feeling stressed, sad, or angry is common when you are living with diabetes. You may know what to do to stay healthy but may have trouble sticking with your plan over time. Long-term stress can raise your blood glucose and blood pressure, but you can learn ways to lower your stress. Try deep breathing, gardening, taking a walk, doing yoga, meditating, doing a hobby, or listening to your favorite music. Learn more about healthy ways to cope with stress.

Does diabetic kidney disease get worse over time?

Kidney damage from diabetes can get worse over time. However, you can take steps to keep your kidneys healthy and help slow kidney damage to prevent or delay kidney failure. Kidney failure means that your kidneys have lost most of their ability to function-less than 15 percent of normal kidney function. However, most people with diabetes and kidney disease don't end up with kidney failure.

If your kidneys become damaged as a result of diabetes, learn how to manage kidney disease.

References

[1] Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2019. Atlanta, GA: US Department of Health and Human Services. Centers for Disease Control and Prevention; 2019.

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Diabetic kidney disease is a type of kidney disease caused by diabetes. Diabetes is the leading cause of kidney disease. About 1 out of 3 adults with diabetes has kidney disease. 1 The main job of the kidneys is to filter wastes and extra water out of your blood to make urine.

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National Institute of Diabetes and Digestive and Kidney Diseases

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What are diabetic neuropathies?

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.

What causes diabetic neuropathies?

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

What are the symptoms of diabetic neuropathies?

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.

What are the 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.

Neuropathy Affects Nerves Throughout the Body

Peripheral neuropathy affects

Autonomic neuropathy affects

Proximal neuropathy affects

Focal neuropathy affects

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 affects the nerves in your toes, feet, legs, hands, and arms.

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.

Autonomic neuropathy affects the nerves in your heart, stomach, intestines, bladder, sex organs, sweat glands, eyes, and lungs.

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.

Can diabetic neuropathies be prevented?

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.

How are diabetic neuropathies diagnosed?

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.

How are diabetic neuropathies treated?

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.

Clinical Trials

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and other components of the National Institutes of Health (NIH) conduct and support research into many diseases and conditions.

What are clinical trials, and are they right for you?
Clinical trials are part of clinical research and at the heart of all medical advances. Clinical trials look at new ways to prevent, detect, or treat disease. Researchers also use clinical trials to look at other aspects of care, such as improving the quality of life for people with chronic illnesses. Find out if clinical trials are right for you.

What clinical trials are open?
Clinical trials that are currently open and are recruiting can be viewed at www.ClinicalTrials.gov.

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Nerve Damage (Diabetic Neuropathies) | NIDDK

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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.

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Type 2 diabetes | Sarah Hallberg | TEDxPurdueU

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Diabetic neuropathy is a type of nerve damage that can occur if you have diabetes. High blood sugar (glucose) can injure nerves throughout the body. Diabetic neuropathy most often damages nerves in the legs and feet.

Depending on the affected nerves, diabetic neuropathy symptoms include pain and numbness in the legs, feet and hands. It can also cause problems with the 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.

There are four main types of diabetic neuropathy. You can have one type or more than one type of neuropathy.

Your symptoms 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 feeling

Sharp pains or cramps

Muscle weakness

Extreme 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 damage

Autonomic neuropathy

The autonomic nervous system controls blood pressure, heart rate, sweating, eyes, bladder, digestive system and sex organs. Diabetes can affect nerves in any of these areas, possibly causing signs and symptoms including:

A lack of awareness that blood sugar levels are low (hypoglycemia unawareness)

Drops in blood pressure when rising from sitting or lying down that may cause dizziness or fainting (orthostatic hypotension)

Bladder or bowel problems

Slow stomach emptying (gastroparesis), causing nausea, vomiting, sensation of fullness and loss of appetite

Difficulty swallowing

Changes in the way the eyes adjust from light to dark or far to near

Increased or decreased sweating

Problems with sexual response, such as vaginal dryness in women and erectile dysfunction in men

Proximal neuropathy (diabetic polyradiculopathy)

This type of neuropathy 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. Proximal neuropathy may include:

Severe pain in the buttock, hip or thigh

Weak and shrinking thigh muscles

Difficulty rising from a sitting position

Chest or abdominal wall pain

Mononeuropathy (focal neuropathy)

Mononeuropathy refers to damage to a single, specific nerve. The nerve may be in the face, torso, arm or leg. Mononeuropathy may lead to:

Difficulty focusing or double vision

Paralysis on one side of the face

Numbness or tingling in the hand or fingers

Weakness in the hand that may result in dropping things

Pain in the shin or foot

Weakness causing difficulty lifting the front part of the foot (foot drop)

Pain in the front of the thigh

Call your health care provider 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 (ADA) recommends that screening for diabetic neuropathy begin immediately after someone is diagnosed with type 2 diabetes or five years after diagnosis with type 1 diabetes. After that, screening is recommended once a year.

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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.

Anyone who has diabetes can develop neuropathy. But these risk factors make nerve damage more likely:

Poor blood sugar control. Uncontrolled blood sugar increases the risk of every diabetes complication, including nerve damage.

Diabetes history. The risk of diabetic neuropathy increases the longer a person has diabetes, especially if 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 the risk of diabetic neuropathy.

Smoking. Smoking narrows and hardens the arteries, reducing blood flow to the legs and feet. This makes it more difficult for wounds to heal and damages the peripheral nerves.

Diabetic neuropathy can cause a number of serious complications, including:

Hypoglycemia unawareness. Blood sugar levels below 70 milligrams per deciliter (mg/dL) - 3.9 millimoles per liter (mmol/L) - usually cause shakiness, sweating and a fast heartbeat. But people who have autonomic neuropathy may not experience these warning signs.

Loss of a toe, foot or leg. Nerve damage can cause a loss of feeling in the feet, so even minor cuts can turn into sores or ulcers without being noticed. In severe cases, an infection can spread to the bone or lead to tissue death. Removal (amputation) of a toe, foot or even part of the leg may be necessary.

Urinary tract infections and urinary incontinence. If the nerves that control the bladder are damaged, the bladder may not empty completely when urinating. Bacteria can build up in the bladder and kidneys, causing urinary tract infections. Nerve damage can also affect the ability to feel the 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 the body's ability to adjust blood pressure. This can cause a sharp drop in pressure when standing after sitting or lying down, which may lead to lightheadedness and fainting.

Digestive problems. If nerve damage occurs in the digestive tract, constipation or diarrhea, or both are possible. Diabetes-related nerve damage can lead to gastroparesis, a condition in which the stomach empties too slowly or not at all. This can cause 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 the sweat glands work and make it difficult for the body to control its temperature properly.

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 (ADA) recommends that people living with diabetes have a glycated hemoglobin (A1C) test at least twice a year. This test indicates your average blood sugar level for the past 2 to 3 months.

glycated hemoglobin (A1C) goals may need to be individualized, but for many adults, the ADA recommends an A1C of less than 7.0%. 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 or physical activity.

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. Also have your health care provider check your feet at each office visit and take good care of your feet at home.

Follow your health care provider'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. Don't soak your feet. Dry your feet and between your toes thoroughly.

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 so that you have smooth edges. If you can't do this yourself, a specialist in foot problems (podiatrist) can help.

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. Wear closed-toed shoes or slippers to protect your feet. Make sure your shoes fit properly and allow your toes to move. A foot specialist 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.

1. Ferri FF. Diabetic polyneuropathy. In: Ferri's Clinical Advisor 2022. Elsevier; 2020. https://www.clinicalkey.com. Accessed Dec. 17, 2021.

2. Diabetic neuropathy. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/nerve-damage-diabetic-neuropathies/all-content. Accessed Jan. 10, 2020.

3. American Diabetes Association. Standards of medical care in diabetes - 2021. Diabetes Care. 2021. https://care.diabetesjournals.org/content/44/Supplement_1. Accessed Nov. 11, 2021.

4. AskMayoExpert. Peripheral neuropathy (adult). Mayo Clinic; 2021.

5. Feldman EL, et al. Management of diabetic neuropathy. https://www.uptodate.com/contents/search. Accessed Dec. 17, 2021.

6. Diabetes and foot problems. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/foot-problems#healthyfeet. Accessed Jan. 10, 2020.

7. Jankovic J, et al., eds. Disorders of peripheral nerves. In: Bradley and Daroff's Neurology in Clinical Practice. 8th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed Jan. 11, 2020.

8. Baute V, et al. Complementary and alternative medicine for painful peripheral neuropathy. Current Treatment Options in Neurology. 2019; doi:10.1007/s11940-019-0584-z.

9. Feldman EL, et al. Diabetic neuropathy. Nature Reviews - Disease Primers. 2019; doi:10.1038/s41572-019-0092-1.

10. Cutsforth-Gregory (expert opinion). Mayo Clinic. Dec. 24, 2021.

11. Castro MR (expert opinion). Mayo Clinic. Jan. 21, 2022.

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