Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells involves a specific sequence of intracellular events. Which step is MOST DIRECTLY responsible for triggering insulin exocytosis?
- A Glucose binds glucokinase (GKRP), directly activating PKC which phosphorylates synaptotagmin on secretory vesicles
- B Incretin hormones (GIP) are released and directly trigger cAMP-mediated Ca²⁺ release from ER, bypassing membrane depolarization
- C Glucose activates hexosamine pathway, producing O-GlcNAc modifications that directly open voltage-gated Ca²⁺ channels
- D Glucose uptake via GLUT2, glycolysis raising ATP/ADP ratio, KATP channel closure, membrane depolarization, L-type Ca²⁺ channel opening, and Ca²⁺ influx triggering vesicle fusion ✓
Correct answer: D. Glucose uptake via GLUT2, glycolysis raising ATP/ADP ratio, KATP channel closure, membrane depolarization, L-type Ca²⁺ channel opening, and Ca²⁺ influx triggering vesicle fusion
Explanation
The canonical GSIS pathway: glucose enters β-cells via GLUT2 (low-affinity, high-capacity), is phosphorylated by glucokinase (the β-cell's glucose sensor), and metabolized to raise the ATP/ADP ratio. Elevated ATP closes KATP channels (Kir6.2/SUR1 complex), causing membrane depolarization which opens voltage-gated L-type Ca²⁺ channels; Ca²⁺ influx is the direct trigger for SNARE-mediated insulin granule exocytosis. Incretins amplify—but do not initiate—this pathway via cAMP/PKA.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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