Figure 3

Glucose control of insulin secretion. Glucose-stimulates insulin secretion via two mechanisms: the triggering pathway and the amplifying pathway. (1) Glucose enters beta cells through GLUT-2 and undergoes glycolysis. This metabolism increases the ratio of ATP to ADP, which inhibits the ATP-sensitive K_ATP-channels, leading to membrane depolarization and opening of voltage-dependent calcium channels (VDCC), with a resultant major increase in cytosolic calcium, which, in turn, triggers exocytosis. SNARE proteins play a critical role in insulin granule secretion. The linking of the plasma membrane proteins syntaxin and SNAP-25 to vesicle protein VAMP-2/synaptobrevin-2 cause the docking of the vesicle, bringing insulin granules in close contact with the plasma membrane and calcium channels, after opening of calcium channels, the readily releasable pool (RRP) insulin granules located nearby are exposed to high level of Ca2+, resulting in RRP granule exocytosis. CDK5 can inhibit VDCC activity by phosphorylating its subunit, thus inhibiting insulin secretion; however, high glucose concentrations inhibit the Cdk5 kinase activity which in turn increases Ca²⁺ influx, leading to enhanced insulin secretion. (2) Insulin granules in reserve pool must undergo acidification to gain secretion competence. This mobilization or priming process is dependent on the simultaneous operation of a V-type H⁺-ATPase and ClC-3 Cl^- channels. Cl^- uptake determines the extent of granular acidification by providing a counter-ion required to allow continuous H⁺ pumping. ADP can inhibit Cl- channel activity, however, glucose metabolism reduces the ADP level, leading to the loss of inhibition to Cl- channels, so insulin secretory granules undergo acidification and the secretion process is augmented.