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. 

• 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

• 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

• Brains and other tissues are dependent on it for energy,

• And because of high concentrations irreversibly damages cellular proteins

• 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

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

• 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

• 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

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

• 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!)

• 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)

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 (HbA_1C) >= 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 

• 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 

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

• PPP–Polyuria, Polydipsia, Polyphagia

• Unexplained Weight Loss/Fatigue/Lethargy

• Recurrent/Persistent Infections, Delayed Healing & Immunosuppression

+ Presentations:

• Hyperglycaemia

• Ketonuria(Ketoacidosis)→ Hyperventilation

• Nausea

• Vomiting

• Abdominal Pain

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

• 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
    

Fasting blood glucose

Random plasma glucose

Associated with metabolic syndromes

- Vascular:

• Macrovascular:

  • Heart Disease/Coronary Artery Disease/Atherosclerosis

  • Stroke

  • Peripheral Vascular Disease

• Microvascular:

  • Retinopathy

  • Neuropathy

  • Nephropathy

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