The incretin effect accounts for approximately 50-70% of postprandial insulin secretion. Which receptor/signaling cascade mediates GLP-1's insulinotropic effect on β-cells?

• A GLP-1R → Gq → PLC → IP3 → Ca²⁺ release from ER → direct insulin exocytosis without PKA
• B GLP-1R → Gi → reduced cAMP → increased intracellular Ca²⁺ via T-type channels
• C GLP-1R → tyrosine kinase activity → IRS-1 phosphorylation → PI3K → Akt → GLUT4 translocation in β-cells
• D GLP-1R → Gs → adenylyl cyclase → cAMP → PKA activation AND Epac2 (exchange protein directly activated by cAMP) → augments Ca²⁺-dependent insulin exocytosis ✓

Explanation

GLP-1 (glucagon-like peptide-1) acts on β-cell GLP-1 receptors (Gs-coupled GPCRs). Gs activation raises cAMP via adenylyl cyclase. Elevated cAMP signals through two pathways: (1) PKA phosphorylates proteins of the insulin exocytosis machinery (SNAP25, synapsin), potentiating KATP channel-independent insulin secretion; (2) Epac2 (cAMP-regulated guanine nucleotide exchange factor) directly activates Rap1/Rim2, augmenting Ca²⁺ sensing at the secretory granule. Both pathways potentiate glucose-stimulated insulin secretion. This is why GLP-1 agonists (liraglutide, semaglutide) cause insulin secretion only when glucose is elevated — glucose must first close KATP channels to depolarize the cell.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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