In type 1 diabetes, loss of first-phase insulin secretion is an early marker. Which cellular mechanism governs first-phase insulin exocytosis?
- A Glucose entry via GLUT-2 → glycolysis → ATP rise → KATP channel closure → beta-cell depolarization → voltage-gated Ca²⁺ influx → exocytosis of readily releasable pool (RRP) granules ✓
- B Glucose binding to surface glucose receptors activating cAMP → PKA → phosphorylation of insulin granule SNARE proteins
- C Amino acid-induced activation of mTORC1 triggering insulin granule synthesis in the RER over 5 minutes
- D Incretins (GLP-1) binding GLP-1R on beta cells causing immediate first-phase release via Gs/cAMP
Explanation
First-phase insulin secretion (occurring within 0–10 min of glucose stimulus) is triggered by the KATP channel-mediated pathway: glucose enters via GLUT-2 (low-affinity, high-capacity transporter), undergoes glycolysis → pyruvate → TCA cycle → ATP generation raises ATP:ADP ratio → closes KATP (Kir6.2/SUR1) channels → membrane depolarizes → L-type Ca2+ channels open → Ca2+ influx → rapid exocytosis of the readily releasable pool of pre-docked insulin granules. GLP-1 amplifies rather than initiates first-phase release (it raises cAMP/PKA to sensitize granule exocytosis). Amino acid/mTOR pathways affect second-phase secretion and insulin synthesis. Glucose does not have surface receptors.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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