Diabetes mellitus

1. Definition

• DM = heterogenous group of systemic metabolic diseases characterized by hyperglycemia.
• Underlying mechanism: defect in insulin secretion, insulin action, or both.

2. Complications (overview)

• Acute: hyper-/hypoglycemic shock, diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state.
• Late: chronic hyperglycemia damages kidneys, eyes, nerves, blood vessels.

3. Classification

Feature	Type 1 DM	Type 2 DM
Synonym	Juvenile, insulin-dependent	Non-insulin dependent
Mechanism	Absolute insulin deficiency — autoimmune β-cell destruction	Insulin resistance • inadequate β-cell secretion
Onset	Childhood / puberty	Adult, often obese
HLA	HLA-DR3/DR4 (chr 6p21)	No HLA link
Autoantibodies	Anti-insulin, anti-GAD, anti-islet	Absent
Ketosis	Common	Rare
Treatment	Exogenous insulin (mandatory)	Diet, oral agents ± insulin

4. Metabolic Effects of Insulin

• Anabolic — ↑ synthesis of glycogen, lipid, protein.
• Principal action: ↑ glucose transport (GLUT4) into muscle/adipose cells.

5. Pathogenesis of T1DM

• Autoimmune disease: islet destruction by T-cells reacting against β-cell antigens.
• Develops in childhood, manifests at puberty, progresses with age.
• Patients depend on exogenous insulin.
• Disease starts years before clinical onset (chronic immune attack).
• Classic Sx (hyperglycemia + ketosis) appear when >90 % of β-cells destroyed.
• Mechanisms of β-cell destruction:
  • CD8⁺ T cells react against β-cell antigens
  • Locally produced cytokines (IFN-γ, TNF) damage β-cells
  • Autoantibodies against insulin, GAD, etc.
• Principal susceptibility locus: MHC II (HLA-D) on chromosome 6p21.

6. Pathogenesis of T2DM

• Pathogenesis unclear; sedentary lifestyle + dietary habits play a role.
• Two metabolic defects:
  1. Insulin resistance — peripheral tissues fail to respond.
     • Genetic defects of insulin receptor / signaling
     • Obesity (adipokines, FFA → insulin resistance)
  2. β-cell dysfunction — β-cells fail to compensate with ↑ secretion.

7. Complications of DM

A) Macrovascular — atherosclerosis

• Accelerated atherosclerosis in large arteries → MI, stroke, peripheral vascular disease.

B) Microvascular — microangiopathy

• Hyperglycemia → non-enzymatic glycation → abnormal metabolite deposition → basement membrane thickening.

C) Diabetic retinopathy

• Microaneurysms → rupture → retinal hemorrhage → fibrotic replacement.
• Proliferative phase: neovascularization + CT accumulation → blindness.

D) Diabetic nephropathy

• Accelerated atherosclerosis of renal vessels.
• Pyelonephritis — most severe with papillary necrosis.
• Kimmelstiel-Wilson syndrome — nodular glomerulosclerosis → nephrotic syndrome (proteinuria, hypoalbuminemia, edema, hyperlipidemia, hypercholesterolemia).

E) Diabetic neuropathy & foot

• Distal symmetric polyneuropathy + autonomic.
• Diabetic foot — necrotic ulcers; painless (neuropathy + ischemia).

💡 High-yield: T1DM = autoimmune β-cell destruction (HLA-DR3/DR4), absolute insulin deficiency, ketosis, juvenile onset. T2DM = insulin resistance + β-cell failure, adult/obese, no HLA link. Symptoms appear when >90 % β-cells lost. Late complications: macro (MI, stroke, PVD) + micro (retinopathy with microaneurysms, neuropathy, nephropathy = Kimmelstiel-Wilson nodular glomerulosclerosis, diabetic foot ulcers).