- 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:
- Glucose (Primary): Enters β-cells via GLUT transporters (mainly GLUT2 in rodents, GLUT1/3 in humans). Metabolism of glucose ↑ATP/ADP ratio → closure of ATP-sensitive K+ (KATP) channels → membrane depolarization → opening of voltage-gated Ca2+ channels (VGCC) → Ca2+ influx → insulin granule exocytosis. Glucokinase acts as the glucose sensor and is the rate-limiting step.
- Incretin Hormones (GLP-1, GIP): Released from GI tract post-prandially; potentiate glucose-stimulated insulin secretion (GSIS) via Gs-coupled receptors → ↑cAMP → PKA activation.
- Amino Acids: (e.g., leucine, arginine) Can stimulate insulin secretion, partly via incretin-dependent mechanisms or direct β-cell effects.
- Fatty Acids: Can augment GSIS; chronic excess can be detrimental (lipotoxicity).
- Parasympathetic Nervous System (Vagus nerve, Acetylcholine): Stimulates insulin release via Gq-coupled muscarinic receptors → ↑IP3 & DAG → Ca2+ release from ER & PKC activation.
- Sulfonylureas & Meglitinides: Drugs that close KATP channels, mimicking glucose effect.
- Glucagon: Can stimulate insulin secretion (paracrine effect within islet).
- Key Inhibitors of Insulin Release:
- Somatostatin: Released from pancreatic δ-cells; acts via Gi-coupled receptors → ↓cAMP, activates K+ channels (hyperpolarization), ↓Ca2+ influx.
- Sympathetic Nervous System (Norepinephrine, Epinephrine): Act via α2-adrenergic receptors (Gi-coupled) → ↓cAMP, inhibit adenylyl cyclase, open KATP channels, inhibit Ca2+ influx, and inhibit exocytosis.
- Diazoxide: Drug that opens KATP channels, inhibiting insulin secretion.
- Prostaglandins: Can inhibit insulin release.
- 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.
- 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).