Diabetes mellitus pathology

DM Diagnosis - The Sweet Numbers

• Definition: A state of chronic hyperglycemia due to defects in insulin secretion, action, or both.

• Diagnostic Criteria: Any of the following. Confirmation often requires a repeat test.

  • HbA1c: ≥6.5%
  • Fasting Plasma Glucose (FPG): ≥126 mg/dL (no caloric intake for ≥8 hrs)
  • 2-hr Oral Glucose Tolerance Test (OGTT): ≥200 mg/dL (post 75g glucose load)
  • Random Plasma Glucose (RPG): ≥200 mg/dL (with classic symptoms like polyuria, polydipsia)

⭐ HbA1c is advantageous as it doesn't require fasting and reflects long-term glycemic control (2-3 months).

Type 1 DM Pathophysiology - Beta Cell Betrayal

• Autoimmune Attack: A chronic, T-cell mediated (Type IV hypersensitivity) assault on pancreatic β-cells.
• Genetic Susceptibility: Strongly linked to specific HLA genes, notably HLA-DR3 and HLA-DR4.
  • 📌 DR 3 & 4 are the doors to T1D.
• Key Markers: Autoantibodies are present in >85% of newly diagnosed patients.
  • Anti-glutamic acid decarboxylase (anti-GAD65)
  • Islet cell autoantibodies (ICA)
• Histopathology: Characterized by "insulitis"-a lymphocytic infiltrate within pancreatic islets.
• End Result: Absolute deficiency of insulin.

⭐ Exam Favorite: Autoantibodies (e.g., GAD65) are often detectable years before hyperglycemia manifests, marking a preclinical phase of active, ongoing β-cell destruction.

Type 2 DM Pathophysiology - Resistance is Futile

• Insulin Resistance: The cornerstone defect where peripheral tissues (muscle, liver, adipose) show a diminished response to normal insulin levels.

  • Key Drivers: Central obesity, metabolic syndrome, and strong genetic predisposition are major risk factors.
  • Adipokine Role: Dysregulated secretion from visceral fat; ↓ adiponectin (sensitizer) and ↑ resistin (antagonist) worsen resistance.

• Relative Insulin Deficiency: Occurs as pancreatic β-cells fail to meet the demand.

  • β-cell Exhaustion: Initially, hyperinsulinemia compensates for resistance. Over time, β-cells become exhausted, leading to dysfunction and ↓ insulin secretion.
  • Amyloid Deposition: Islet Amyloid Polypeptide (IAPP) co-secreted with insulin deposits in islets, further impairing β-cell function.

⭐ Glucagon levels are often paradoxically elevated in T2DM, exacerbating hyperglycemia by driving unopposed hepatic glucose production.

Chronic Complications - The Sugar Fallout

• Microvascular Damage

  • Retinopathy: Non-proliferative (hemorrhages, exudates) & proliferative (neovascularization).
  • Nephropathy: Nodular glomerulosclerosis (Kimmelstiel-Wilson lesions).
  • Neuropathy: Peripheral "stocking-glove" sensory loss; autonomic dysfunction (gastroparesis).

• Macrovascular Damage

  • Accelerated atherosclerosis leading to:
    • Coronary Artery Disease (CAD) → Myocardial Infarction
    • Peripheral Vascular Disease (PVD) → Limb ischemia
    • Cerebrovascular Accident (CVA) → Stroke

⭐ HbA1c reflects average blood glucose over the prior ~3 months because the glycation of hemoglobin is irreversible, mirroring the red blood cell lifespan.

High‑Yield Points - ⚡ Biggest Takeaways

• Type 1 DM is an autoimmune process destroying pancreatic β-cells, strongly associated with HLA-DR3/DR4.
• Type 2 DM is defined by insulin resistance and later, relative insulin deficiency, with characteristic islet amyloid deposition.
• Chronic complications are driven by non-enzymatic glycosylation (AGEs) and the polyol pathway.
• Kimmelstiel-Wilson lesions (nodular glomerulosclerosis) are pathognomonic for diabetic nephropathy.
• Accelerated atherosclerosis is the major cause of morbidity/mortality.