title: Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic β cells.
abstract: Insulin secretion from pancreatic β cells is stimulated by glucagon-like peptide-1 (GLP-1), a blood glucose-lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal. GLP-1 mimetics (e.g., Byetta) and GLP-1 analogs (e.g., Victoza) activate the β cell GLP-1 receptor (GLP-1R), and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus (T2DM). An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase-IV (DPP-IV) inhibitors (e.g., Januvia, Galvus). These compounds slow metabolic degradation of intestinally released GLP-1, thereby raising post-prandial levels of circulating GLP-1 substantially. Investigational compounds that stimulate GLP-1 secretion also exist, and in this regard a noteworthy advance is the demonstration that small molecule GPR119 agonists (e.g., AR231453) stimulate L cell GLP-1 secretion while also directly stimulating β cell insulin release. In this review, we summarize what is currently known concerning the signal transduction properties of the β cell GLP-1R as they relate to insulin secretion. Emphasized are the cyclic AMP, protein kinase A, and Epac2-mediated actions of GLP-1 to regulate ATP-sensitive K⁺ channels, voltage-dependent K⁺ channels, TRPM2 cation channels, intracellular Ca⁺ release channels, and Ca⁺-dependent exocytosis. We also discuss new evidence that provides a conceptual framework with which to understand why GLP-1R agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM.
authors.affiliation: Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA. leechc@upstate.edu
authors.forename: Colin A
authors.initials: CA
authors.lastname: Leech
authors.forename: Igor
authors.initials: I
authors.lastname: Dzhura
authors.forename: Oleg G
authors.initials: OG
authors.lastname: Chepurny
authors.forename: Guoxin
authors.initials: G
authors.lastname: Kang
authors.forename: Frank
authors.initials: F
authors.lastname: Schwede
authors.forename: Hans-G
authors.initials: HG
authors.lastname: Genieser
authors.forename: George G
authors.initials: GG
authors.lastname: Holz
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000628:therapy; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D006801:Humans; D054795:Incretins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D054795:Incretins; D007328:Insulin; D052216:Glucagon-Like Peptide 1