Glucagon-like peptide-1 (GLP-1) potentiates glucose-stimulated insulin secretion via which intracellular mechanism in pancreatic beta cells?

• A GLP-1 directly blocks KATP channels, independently causing membrane depolarisation irrespective of glucose levels
• B GLP-1 activates Gq-PLC-IP3 pathway, releasing Ca2+ from the ER to stimulate insulin vesicle exocytosis
• C GLP-1 receptor (GPCR) activates Gs-adenylyl cyclase-cAMP-PKA pathway, potentiating KATP channel closure and Ca2+ influx triggered by glucose ✓
• D GLP-1 increases glucose uptake via GLUT-2 upregulation, amplifying the primary glucose signal

Explanation

GLP-1 binds its GPCR on pancreatic beta cells, coupling to Gs to activate adenylyl cyclase, increasing intracellular cAMP. cAMP activates PKA and EPAC2 (exchange protein activated by cAMP), which sensitise voltage-gated Ca2+ channels, enhance exocytosis of insulin granules, and synergise with the primary KATP-channel/Ca2+ influx signal from glucose metabolism. Crucially, GLP-1 only potentiates insulin secretion when glucose is present (glucose-dependent action), explaining why GLP-1 agonists rarely cause hypoglycaemia as monotherapy. It does not directly close KATP channels and does not use Gq as its primary signal.

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

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