Pancreatic beta cell dysfunction is pivotal to the development of diabetes, and restoration of insulin action is of primary importance. Here, we present a review of the mechanism of insulin secretion by pancreatic beta cells and discuss the mutual interaction of signaling pathways in stimulus - secretion coupling to better understand the scientific basis of pharmacological treatment for insulin secretion deficiency. Glucose stimulates insulin secretion
via membrane depolarization by closure of ATP-sensitive K
+ channels (K
ATP channels) and opening of L-type voltage-dependent Ca
2+ channels. The resultant elevation of cytosolic free Ca
2+ triggers insulin exocytosis. This is termed the “K
ATP-dependent pathway” and is shared by sulfonylurea, which closes K
ATP channels. Glucose also stimulates insulin release independent of its action on K
ATP channels. This is referred to as the “K
ATP-independent pathway,” the molecular basis of which remains elusive. In the pancreatic beta cell, incretin hormones increase cAMP level, which enhances glucose-stimulated insulin release by protein kinase A-dependent and -independent mechanisms. Importantly, cAMP does not directly augment Ca
2+-stimulated insulin release
per se. The stimulatory level of ambient glucose is an absolute requirement for incretin to enhance insulin release. Therefore, incretin/cAMP enhances K
ATP-independent insulinotropic action of glucose. The robust glucose-lowering effect of DPP4 inhibitor add-on in diabetic patients with sulfonylurea secondary failure is intriguing. With the clinical availability of DPP4 inhibitor and GLP-1 mimetics, the importance of the interactions between cAMP signaling and K
ATP channel-independent actions of glucose is reappraised.
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