Mechanism

Glucose-stimulated insulin release from beta-cells of the pancreatic islets of Langerhans depends on the coupling of metabolism to the modification of ion channel activity. Glucose uptake and entry into glycolysis is proportional to the circulating glucose concentration because of the high K_M values of the GLUT2 glucose transporter and the first enzyme in the glycolytic pathway, glucokinase (Fig. 3.29.1). The internalized glucose is then metabolized rapidly with the concomitant production of ATP. In the resting beta-cell, active ATP-sensitive K⁺ (K_ATP) channels contribute to the resting membrane potential (Ch. 17). These channels close in response to raised ATP concentration and falling ADP concentration (Fig. 3.29.1D). This results in a gradual membrane depolarization and activation of L-type voltage-gated Ca²⁺ channels. A burst of action potentials follows, the length of which is proportional to the glucose concentration. Entry of Ca²⁺ during these bursts raises [Ca²⁺] _i and triggers the exocytosis of insulin-containing secretory vesicles (Fig. 3.29.1E). In addition to the repolarizing influence of activated delayed rectifier K⁺ channels during each action potential, the raised [Ca²⁺]_i

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