Diabetes Mellitus: Biochemical Aspects

DM Diagnosis - Numbers Game

• Key Diagnostic Tests:
  • Fasting Plasma Glucose (FPG): No caloric intake for ≥ 8 hours.
  • 2-hour Post-OGTT: Plasma glucose 2 hours after 75g oral glucose load.
  • Glycated Hemoglobin (HbA1c): Reflects long-term glycemic control.
• Diagnostic Criteria (ADA/WHO):

⭐ HbA1c reflects average blood glucose over the past 2-3 months; less affected by acute fluctuations.

Insulin Action - Key Player

• Synthesis:
  • Preproinsulin (RER) → Proinsulin (Golgi) → Insulin + C-peptide (secretory granules).
  • C-peptide: Marker of endogenous insulin production.
• Secretion (β-cells):

-   Stimuli: Glucose (major), amino acids, incretins (GLP-1, GIP).

• Receptor & Signaling:
  • Receptor: Tyrosine kinase (RTK); 2α (binding) & 2β (kinase) subunits.
  • Signaling: Insulin binds → Autophosphorylation → IRS activation →
    • PI3K/Akt pathway: GLUT4 translocation, glycogen synthesis, lipogenesis, protein synthesis.
    • MAPK pathway: Mitogenic effects (cell growth).
• GLUT4:

  ⭐ GLUT4 is the insulin-dependent glucose transporter found in muscle (skeletal, cardiac) and adipose tissue.

  • Insulin mediates its membrane translocation.
• Metabolic Effects (Anabolic):
  • Carbs: ↑ Glucose uptake (GLUT4), ↑ Glycogenesis, ↓ Gluconeogenesis, ↓ Glycogenolysis.
  • Fats: ↑ Lipogenesis, ↓ Lipolysis.
  • Proteins: ↑ Protein synthesis.

Metabolic Mayhem - Sweet Chaos

• Hyperglycemia: ↓ Insulin action → ↓ glucose uptake, ↑ gluconeogenesis & glycogenolysis.
• Diabetic Ketoacidosis (DKA): Severe insulin deficiency (often T1DM).
  • Pathogenesis: ↑ Lipolysis → ↑ FFAs → ↑ hepatic ketogenesis ($Acetoacetate, \beta-Hydroxybutyrate$).
  • Features: Hyperglycemia (>250 mg/dL), metabolic acidosis (anion gap >12 mEq/L), ketonemia, ketonuria.
  • 📌 DKA: Dehydration, Ketones & Kussmaul, Acidosis, Abdominal pain.
• Hyperosmolar Hyperglycemic State (HHS): Relative insulin deficiency (often T2DM).
  • Features: Severe hyperglycemia (>600 mg/dL), hyperosmolality (>320 mOsm/kg), profound dehydration, minimal ketosis.
• Dyslipidemia: ↑ TGs, ↑ VLDL, ↓ HDL due to altered lipid metabolism.
• Biochemical Pathways: Disrupted glycolysis, gluconeogenesis, lipolysis, protein catabolism. Polyol pathway activation (sorbitol). Advanced Glycation End-products (AGEs) formation.

⭐ Kussmaul breathing in DKA is a compensatory hyperventilation to counteract metabolic acidosis by expelling carbon dioxide.

Chronic Damage - Sugar's Scars

Persistent hyperglycemia fuels chronic complications via key biochemical pathways:

• Advanced Glycation End products (AGEs): Non-enzymatic glycation alters protein/lipid structure & function.
• Polyol Pathway: Glucose → sorbitol (by aldose reductase); ↑sorbitol causes osmotic stress.

  ⭐ Sorbitol accumulation via aldose reductase contributes to osmotic damage in diabetic complications (e.g., cataracts, neuropathy).

• Protein Kinase C (PKC) Activation: Hyperglycemia → diacylglycerol (DAG) → PKC activation → vascular dysfunction.
• Oxidative Stress: ↑Reactive oxygen species (ROS) overwhelm antioxidant defenses.

These converge, causing:

• Microvascular damage: Retinopathy, nephropathy, neuropathy.
• Macrovascular damage: Atherosclerosis, CAD, PVD.

High‑Yield Points - ⚡ Biggest Takeaways

• Insulin deficiency or resistance is the core defect in Diabetes Mellitus.
• Persistent hyperglycemia results from impaired glucose uptake and ↑ hepatic glucose production.
• Diabetic Ketoacidosis (DKA), in Type 1 DM, is caused by ↑ lipolysis and ketogenesis.
• HbA1c is a key indicator of long-term glycemic control (non-enzymatic glycation).
• Advanced Glycation End products (AGEs) mediate many chronic diabetic complications.
• The polyol pathway (sorbitol accumulation) contributes to neuropathy and cataracts.
• Glucagon excess contributes to hyperglycemia in diabetes.