title: Glucose-incretin interaction revisited.
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 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.
authors.affiliation: Department of Diabetes, Endocrinology and Metabolism, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ishii
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Sato
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takei
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishio
authors.forename: Mitsuhisa
authors.initials: M
authors.lastname: Komatsu
mesh_terms: D020746:Calcium Channels, L-Type / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D054795:Incretins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D054086:KATP Channels / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020746:Calcium Channels, L-Type; D054795:Incretins; D007328:Insulin; D054086:KATP Channels; D005947:Glucose