Insulin

• Patho/Etiology: Insulin, produced by pancreatic β-cells, is the primary anabolic hormone crucial for glucose homeostasis. Its secretion is a tightly regulated process primarily triggered by blood glucose levels.
• Key Stimulators of Insulin Release:
  • Stimulators:
    • Glucose (Primary).
      1. Glucose enters $\beta$-cell via GLUT2 (insulin-independent).
      2. Metabolism → ↑ ATP.
      3. ATP binds/closes $K_{ATP}$ channels → Membrane Depolarization.
      4. Voltage-gated $C{a}^{2+}$ channels open → $C{a}^{2+}$ influx.
      5. Exocytosis of Insulin + C-peptide.
    • Incretins (GLP-1, GIP): Cause Oral glucose > IV glucose insulin response.
    • ${\beta }_2$-agonists.
    • Amino Acids: Specifically Leucine and Arginine.
    • Vagal Stimulation: Acetylcholine (M3 receptors) stimulates release.
    • Free Fatty Acids
  • Inhibitors:
    • ${\alpha }_2$-agonists (Sympathetic ${\alpha }_2$ effect > ${\beta }_2$ effect).
      • Epinephrine/Norepinephrine inhibits insulin release to keep glucose available for the brain/muscles during stress.
    • Somatostatin.
• Mechanism Highlights:
  • Synthesis: Preproinsulin → proinsulin (ER) → insulin + C-peptide (Golgi, stored in granules).
  • Secretion: Biphasic: 1st phase (rapid, release of readily releasable pool of granules); 2nd phase (sustained, mobilization and synthesis of new granules).
  • Amplifying Pathway: Mechanisms beyond KATP channel closure and Ca²⁺ influx that augment insulin secretion, often involving cAMP and byproducts of glucose metabolism.
• Function & Mechanism
  • Carbohydrates:
    • ↑ Glucose uptake in skeletal muscle & adipose via GLUT4 (insulin-dependent transporter).
    • Note: Brain, RBCs, Intestine, Cornea, Kidney, Liver use insulin-independent transporters (GLUT 1, 2, 3, 5).
    • ↑ Glycogen synthesis (↑ Glucokinase, ↑ Glycogen synthase).
    • ↓ Gluconeogenesis & Glycogenolysis.
  • Lipids:
    • ↑ Triglyceride synthesis in adipose.
    • ↓ Lipolysis (Inhibits Hormone-sensitive lipase).
    • ↓ Serum Ketones (Inhibits ketogenesis).
  • Proteins:
    • ↑ Amino acid uptake; ↑ Protein synthesis.
  • Electrolytes:
    • ↑ Cellular K+ uptake: Increases Na+/K+-ATPase activity.
    • Clinical Pearl: Insulin + Glucose is used to treat Hyperkalemia (shifts K+ intracellularly).
    • Promotes K+ entry into cells
      • The influx of potassium from the meal could cause a transient, but potentially fatal, hyperkalemia. Even a small rise in serum K+ can lead to cardiac arrhythmias. Thus need to be managed.
• Clinical Significance:
  • Diabetes Mellitus (Type 1 & 2): Deficiency or resistance to insulin.
  • Hyperinsulinemia/Insulinoma: Excessive insulin secretion (e.g., due to tumors, genetic defects like PHHI).
  • Drug Targets: KATP channels (sulfonylureas, meglitinides, diazoxide), GLP-1 receptor agonists, DPP-4 inhibitors (prevent incretin degradation).