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Glucose-incretin interaction revisited Ishii H; Sato Y; Takei M; Nishio S; Komatsu MEndocr J 2011[]; 58 (7): 519-25Pancreatic 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.|Calcium Channels, L-Type/metabolism[MESH]|Diabetes Mellitus, Type 2/*metabolism[MESH]|Glucose/*metabolism[MESH]|Humans[MESH]|Incretins/*metabolism[MESH]|Insulin-Secreting Cells/*metabolism[MESH]|Insulin/*metabolism[MESH]|KATP Channels/metabolism[MESH]|Signal Transduction[MESH] |
