Glucagon-like peptide-1 (GLP-1) potentiates glucose-stimulated insulin secretion (GSIS) through which intracellular pathway in the beta cell?

• A GLP-1R → Gq → phospholipase C → IP3/DAG → PKC → insulin granule translocation independent of KATP channel
• B GLP-1R → Gi → inhibition of adenylyl cyclase → reduced cAMP → prolonged KATP channel closure → tonic insulin release
• C GLP-1R → β-arrestin → PI3K pathway → Akt activation → mTOR → increased insulin gene transcription within minutes
• D GLP-1R → Gs → adenylyl cyclase → cAMP → PKA + EPAC2 → closure of KATP and L-type Ca²⁺ channel activation → amplified insulin exocytosis ✓

Explanation

GLP-1 acts on the GLP-1 receptor (Gs-coupled GPCR) to activate adenylyl cyclase, raising cAMP in the beta cell. Elevated cAMP activates two downstream effectors: protein kinase A (PKA), which phosphorylates components of the exocytotic machinery and closes KATP channels via direct phosphorylation of Kir6.2, and EPAC2 (exchange protein directly activated by cAMP), which directly interacts with Rap1 and facilitates granule priming and docking. Crucially, GLP-1 only amplifies insulin secretion when glucose is elevated (i.e., glucose-dependent insulinotropic effect), explaining why GLP-1 agonists have very low risk of hypoglycemia. The incretin effect accounts for about 50–70% of postprandial insulin response.

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

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