Glucose-incretin interaction revisited [Review]

Endocrine Journal

Yoshihiko Sato¹  Mitsuhisa Komatsu¹  Hiroaki Ishii¹  Shinichi Nishio¹  Masahiro Takei¹ 

[1] Department of Diabetes, Endocrinology and Metabolism, Shinshu University School of Medicine, Matsumoto 390-8621, Japan

关键词: Glucose;    Insulin secretion;    ATP-sensitive K+ channel;    Incretin;    cAMP;   

DOI  :  10.1507/endocrj.EJ11-0064

学科分类：内分泌与代谢学

来源: Japan Endocrine Society

【 摘 要 】

References(41)Cited-By(4)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 (KATP channels) and opening of L-type voltage-dependent Ca2+ channels.The resultant elevation of cytosolic free Ca2+ triggers insulin exocytosis.This is termed the “KATP-dependent pathway” and is shared by sulfonylurea, which closes KATP channels.Glucose also stimulates insulin release independent of its action on KATP channels.This is referred to as the “KATP-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 KATP-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 KATP channel-independent actions of glucose is reappraised.

【 授权许可】

Unknown