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Group of disorders characterized by insulin resistance, impaired insulin secretion and increased hepatic glucose production

Associated with metabolic syndromes

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Primary: (Idiopathic)

Type I:

Usually has an immune pathogenesis;

Characterized by severe insulin deficiency

Type II:

Results from insulin resistance + (less severe) insulin deficiency

Secondary: (box 23.3) to

Genetic defects

Exocrine pancreatic disease

Endocrine disease

Drugs and chemicals

Infection

Uncommon forms of immune-mediated diabetes

Other genetic syndromes

Note: All forms of diabetes result from inadequate insulin secretion relative to the body’s needs, and progressive insulin secretory failure is characteristic to both types.

Thus, some people with type I might not need insulin at diagnosis, whereas type 2 diabetics eventually do.

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1 In 11 have diabetes, and estimated to increase

Caused approx 4 million deaths or 10.7% of all deaths in 2017.

Secondary heart disease is most common cause of death (2/3rds of all DM deaths >65yo)

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Diagnosis at age 55 reduces life expectancy by 5-6 years.

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Key hormone involved in regulation of cellular energy supply and macronutrient balance, derived from food

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51-AA peptide hormone: 2 polypeptide chains (A and B chains)

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In beta cells of the pancreatic islets of Langerhans

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At a Slow rate through the day → low plasma insulin between meals and overnight;

In response to eating → rapid rise → back to baseline in 2 hours (fig. 23.5)

Glucose enters the  β cell via GLUT-2 transporter protein

Metabolism of glucose in the cell → generates ATP

ATP closes K⁺ channels in cell membrane (a in fig.)

→ Cell membrane depolarization → allows Ca²⁺ ions to enter the cell via Calcium Channels in cell membrane

(b in fig.) Rise in intracellular Ca²⁺ triggers activation of calcium-dependent phospholipid protein kinase → leads to:

(1)  Fusion of insulin-containing granules with the cell membrane

(2) Exocytosis of insulin-rich granule contents

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After secretion, Insulin enters portal circulation → to liver (prime target organ)

50% of insulin is extracted and degraded in liver

Note: C-peptide is only partially extracted by the liver: THUS, provides a useful index of the rate of insulin secretion.

Other 50% is degraded in kidneys

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(fig. 23.6)

Binding to an Insulin Receptor (on cell membranes)

Structure R.: a dimer with

2 α-subunits → binding site for insulin +

2 β-subunits → attach the cell membrane.

When insulin binds α-subunits → induces conformational change in β-subunits → activation of tyrosine kinase → cascade ‘insulin signal pathway’:

Translocation of GLUT-4 transporter to cell membrane → transports glucose into the cell

Effects on protein and lipid metabolism, and growth

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Blood glucose levels: 3.5-8 mmol/L (63-144 mg/dL) in healthy ppl

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Blood glucose levels: 3.5-8 mmol/L (63-144 mg/dL) in healthy ppl

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Tightly regulated because:

Brains and other tissues are dependent on it for energy,

And because of high concentrations irreversibly damages cellular proteins

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90% (of approx 200g used daily) is from liver glycogen and hepatic gluconeogenesis

Liver absorbs and stores glucose (as glycogen) in post-absorptive state

Releases it into circulation between meals to match rate of glucose utilization by peripheral tissues

Remainder: from renal gluconeogenesis

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Brain: needs 1 mg/kg weight per minute (~100g daily for 70kg person)

Not dependent on insulin

Used → oxidized to CO₂ and H₂O

Tissues: muscle and fat

Contain Insulin-response glucose transporters

Absorbed glucose in response to postprandial peaks in glucose and insulin

Other times: energy usd from fatty acid oxidation

Muscle: stores glucose as glycogen or metabolizes it to lactate or CO2  and H₂O.

Fat: uses it as a substrate for triglyceride synthesis

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GLUT proteins carry glucose across membrane → into cell

Function GLUT1-3: insulin-dependent; GLUT4: stimulates glucose uptake into muscle and adipose tissue (by binding of insulin to cell).

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Function of insulin:

Fasting state: regulates glucose release by liver

Postprandial state: additionally also promotes glucose uptake by fat and muscle

Regulation of insulin:

Low insulin: Glucagon → secreted from pancreatic alpha cells + noradrenaline, cortisol and GH are released:

Increase hepatic glucose production and reduce its utilization in fat and muscle for any given insulin concentration

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Genetic + environmental + immunologic factors → immune-mediated destruction of pancreatic beta cells → insulin deficiency

Disease of insulin deficiency

Rapid onset (typically)

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5-10% of all diabetes cases

Usually presents in childhood and young adults (peak incidence: puberty)

In 2017 more than a million children and adolescence have T1DM

High rates in northern Europe (scandanavian countries) and Middle East --> higher rate of HLA

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Type 1A: immune mediated***

Slow burning variant: Latent Autoimmune Diabetes in Adults (LADA)

Type 1B: non-immune mediated

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Autoimmune: Thyroid disease, celiac disease, Addison's disease, and PA

Genetic susceptibility and inheritance

It's genetic but not that much

90% carries genes: HLA-DR3DQ2,  HLA-DR4-DQ8 or both

Protective factor: DQB1*0602.

Environmental factors

80-90% do not have fam hx of diabetes

Hypothesis:

Maternal factors: GIT infections and older age

Viral infections: incl. Enteroviruses (Coxsackie B4)

Exposures to dietary constituents: early introduction to cow’s milk and deficiency of vit.D

Environmental toxins: eg. alloxan, Vacor

Childhood obesity

Psychological stress

Explanation to hypothesis:

Environmental factors damages beta cells leading to presentation of self-antigens to the T-helper cells → trigger autoimmune response against healthy beta cells

Self antigens may be modified and become antigenic

An immune response against environmental factor may cross-react with self-antigen : molecular mimicry

“Hygiene hypothesis

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Mechanism: triggering of a selective autoimmune destruction of insulin producing cells of a genetically predisposed individual

Usually starts with autoantibodies directed at the cells

Include: insulin, GAD, IA-2, ZnT8 and tetraspanin 7

Then asymptomatic loss of beta cell secretory capacity

Histologically: a chronic inflammatory mononuclear cell infiltrate of T lymphocytes and macrophages in the isolated: known as insulitis (fig. 23.9)

Then remaining b cells are not able to produce enough insulin to meet the body’s needs → diabetic symptoms

*some recovery endogenous insulin secretion may occur after diagnosis: ‘honeymoon period’→ reduce insulin dose

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90% of all cases

One of the most prevalent non-communicable diseases

Prevalence is rising rapidly because of population growth, aging, longer survival with type 2 diabetes . and earlier age of onset and better diagnosis

Increased as increase in obesity: “disease of nutrient excess”

High rates in Middle East, Pacific Islands, lowest in Africa and Europe

Mostly in countries with low-middle rapidly growing economic (india and china)

⅔ rds live in urban areas

>40 yo, ⅓ > 65 yo

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Genetic susceptibility and inheritance

Identical twins: more than 50% chance , non-identical 25% risk

Polygenic disorder (like T1DM)

Gene mutations relating to Beta cell function and development (No overlap in susceptible genes for type I):

TCF7-L2 most common variant for European

KCNQ1 in Asians

Some patients are not obese or overweight which shows very strong genetic impact

Aging

Pancreatic b cell function declines with age → incidence increase w age

Fetal origins of diabetes

Poor nutrition early in life impairs beta cell development and function → predisposing to diabetes

Low birth weight

Obesity

Increases risk by 80-100 fold, accounts for 80-85% of overall risk

Europe and america: 80-90% of adults with T2DM are overweight

Visceral fat (central distribution) → increases risk

Diet

Dietary fat, saturated fat, red and processed meat, fried foods, white rice and sodas

Decrease: wholegrains, fruit and vegetable intake, fermented dairy products, oily fish, and Mediterranean diet

Physical inactivity

Other factors

Urbanization

Poverty

Abnormal sleep patterns

Environmental toxins

Mental illness

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Defects of insulin secretion and action (differs in people)

Abnormalities of insulin action (resulting from nutrient excess)

Diminished because of insulin resistance: the inability of insulin to produce its usual biological effects at physiological concentrations. Insulin cannot:

Inhibit hepatic glucose output

Stimulate glucose uptake into skeletal muscle

Suppress lipolysis in adipose tissue

Intracellular triglyceride accumulates in the liver and skeletal muscles → impedes phosphorylation of post-receptor insulin receptor substrate IRS-1 → reduces insulin action of glucose and lipid metabolism; BUT, still able to activate MAP kinase pathway → involved in inflammation, cell proliferation and atherosclerosis :(

Abnormalities of insulin secretion

Impaired action → increase in insulin secretion: hypersecretion of insulin (early diabetes)

Still not able to restore glucose homeostasis, by time of diagnosis: 50% of beta cell mass and function has been lost

Insulin lack leads to

Increased glucose production from liver (bc of inadequate suppression of gluconeogenesis) & decreased insulin-mediated glucose uptake by peripheral tissues.

Hyperglycemia and lipid excess → toxic to beta cells → glucotoxicity

Further b cell loss and destroy glucose homeostasis

With time, insulin secretion of pancreas declines: “starling curve’ (time course varies per person)

* Thus, insulin deficiency compared to increased demand → Hypersecretion by depleted beta cell →Progression toward absolute insulin deficiency → Need for insulin therapy

Other hormonal abnormalities

Glucagon secretion is increased (probs because diminished intra-islet insulin) → increased hepatic glucose output

Incretin effect (impaired in DM2): response to oral glucose is greater than IV glucose

Mediated by two hormones: GLP-1 and GIP (released by GIT after eating)

(a) Increase glucose-induced beta-cell insulin secretion

(b) Suppress glucagon secretion

(c) Slow gastric emptying and induce satiety

Glucose reabsorption in kidneys

SGLT2: In proximal renal tubules, reabsorbs glucose from renal filtrate and restores it into circulation ← impaired in DM2

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Acute presentation

Children and young adults usually present with 2-6 weeks of these 3 symp.

Polyuria: due to osmotic diuresis that results when blood glucose levels exceed the renal threshold

+ ketonuria in young ppl → maybe ketoacidosis !!

Thirst and polydipsia: due to loss of fluid and electrolytes

Weight loss: due to fluid depletion and accelerated breakdown of fat and muscle secondary to insulin deficiency

Subacute presentation

Months or years, esp. In older patients

Acute symptoms +

Lack of energy,

Visual blurring (bc glucose-induced changes in refraction)

Pruritus vulvae or balanitis (bc candida infection)

Complications (as the presenting feature)

Staphylococcal skin infections

Retinopathy noted by optician

A polyneuropathy causing tingling and numbness in feet

Erectile dysfunction

Arterial disease, resulting in MI or Peripheral gangrene

Asymptomatic diabetes

50%, 1/3rd of diagnosis by incidental findings (SCRENNING!)

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Signs:

Weight loss and dehydration, breath smells like ketones

Older: complications

Physical signs of illness (causing secondary diabetes)

Severe insulin resistance: acanthosis nigricans

Blackish pigmentation at the nape of the neck and the axillae

HTN (50%) (more in African and Caribbean ethnicity)

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Diagnose Diabetes

1. Fasting plasma glucose (FPG) >= 7.0 mmol/l (126 mg/dL)

2. Random glucose / 2-hour plasma glucose after a 75g oral glucose tolerance test (OGTT) >= 11.1 mmol/L (200 mg/dL)

3. Alternative:

Glycated hemoglobin (HbA1C) >= 48 mmol/mol (6.5%):

integrated measure of person\s prevailing blood glucose concentrations overall several weeks, used to guide tx.

*Overt symptoms: 1 test needed

*Absence of clear symptoms: 2 abnormal tests needed

Determine type of diabetes

C-peptide in blood or urine (type I, at first)

Islet auto-antibodies

Other Tests:

Urine for protein, full blood count, urea and electrolytes, liver biochemistry and random lipids

Latter test: exclude hyperlipidemia

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Oral Glucose Tolerance Test (WHO Criteria)

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Oral Glucose Tolerance Test (WHO Criteria)

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Lifestyle:

Reduce body weight,

Reduce deity fat, esp. Saturated

Increasing fiber intake

Exercise 30 min a day

Drugs: (less effective than lifestyle)

Metformin and orlistat

Bariatric surgery

Can treat obesity and normalize elevated blood glucose

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Develop skills to manage their condition; Incl:

Prevention (& effective management if they occur) of life-threatening diabetic emergencies, such as:

Diabetic ketoacidosis

Hypoglycemia

Treatment of hyperglycemia symptoms

Minimization of long-term complications through screening and effective control of hyperglycemia and other cardiovascular risk factors

Avoidance of iatrogenic side-effects, like hypoglycemia

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source: https://pubmed.ncbi.nlm.nih.gov/12668546/

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Representation of basal and prandial insulin dosing.

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Representation of basal and prandial insulin dosing.

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Group of metabolic disorders that all have hyperglycemia

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Maturity onset diabetes of the young (MODY)

Transient neonatal diabetes

Diseases of the ecocrine pancreas

Genetic defects of insulin action

Endocrinopathies

Drug/chemical induced

Infections

Uncommon forms of immune mediated diabetes

Other genetic syndromes

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Prevalence has risen over the last 2 decades

Prevalence of both types are increasing but type 2 is increasing at a more rapid rate

Estimated 50% of cases are undiagnosed

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Initial Presentation:

PPP–Polyuria, Polydipsia, Polyphagia

Unexplained Weight Loss/Fatigue/Lethargy

Recurrent/Persistent Infections, Delayed Healing & Immunosuppression

+ Presentations:

Hyperglycaemia

Ketonuria(Ketoacidosis)→ Hyperventilation

Nausea

Vomiting

Abdominal Pain

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We thought only insulin independent receptors but now seeing that also dependent

Independent = receptor is not needed for insulin to enter the cell

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Polyuria: high urine output

Polydipsia: excessive thirst

Polyphagia: excessive hunger

Weight loss

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General info:

Peak onset @ ≈ 50yrs

Gradual Onset → Therefore ≈ 1/4 have Complications @ Diagnosis (Eg:Vascular)

Note: Many people spend years in a ‘Pre-Diabetic State’ – where blood glucose level is higher than normal but not high enough for a diagnosis of Type 2 Diabetes

Presentation:

Same as Type 1, except...

No Ketonuria

Usually Overweight (Central Obesity)

Metabolic Syndrome (Due to Insulin Resistance):

↑Circulating FFA’s

↑Insulin

↑Glucose

↓HDL’s

↑BP

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C-peptide measurement -- will be low

Fasting blood glucose

Random plasma glucose

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→ Caused by chronic exposure to Hyperglycaemia & Dyslipidaemia in the Insulin Insensitive Tissues

- Vascular:

Macrovascular:

Heart Disease/Coronary Artery Disease/Atherosclerosis

Stroke

Peripheral Vascular Disease

Microvascular:

Retinopathy

Neuropathy

Nephropathy

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Marisela question: which complications do you expect in a diabetic patient?

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Marisela question: which complications do you expect in a diabetic patient?

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Check the eyes, kidneys, heart, skin, immune system, etc.

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Marisela question: explain the hyperosmolar state

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Marisela question: explain the hyperosmolar state

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Hyperosmolar Hyperglycemic Syndrome → Flow diagram

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Hyperosmolar Hyperglycemic Syndrome → Flow diagram

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Treatment for HHS -- IV fluids, insulin + potassium, electrolyte replacement

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Aetiology – (**Diabetes + Insulin Overdose/Alcohol/Sepsis)

Mild (BGL 3.5-6.0mmol/L):

↓Insulin Secretion

↑CounterRegulatoryHormones(Glucagon/Catecholamines/Cortisol/GH)

Severe (BGL<3.5mmol/L):

Neurogenic Symptoms:

Adrenergic:

Palpitations

Anxiety

Tremor

Cholinergic:

Hunger

Sweating

Paraesthesia

Neuroglycopaenic Symptoms:

Behaviour Change

Cognitive Seizures

Coma

Symptoms (Summary):

Autonomic – (Sweating, Anxiety, Hunger, Tremor, Palpitations, Dizziness)

CNS – (Confusion, Drowsiness, Visual Disturbances, Seizures, Coma)

Treatment:

#1 – Oral/IV Glucose (Jellybeans/Juice/Biscuits/etc.)

OR – IM/IV Glucagon

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(Just remember what Andre was talking about)