Glucose-incretin interaction revisited [Review]

Abstract

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 Ca²⁺ channels. The resultant elevation of cytosolic free Ca²⁺ 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 Ca²⁺-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.