Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential.
Glucagon-like peptide-1 (GLP-1) is an intestinally derived insulinotropic hormone currently under investigation for use as a novel therapeutic agent in the treatment of type 2 diabetes. One of several important effects of GLP-1 is on nutrient-induced pancreatic hormone release and is mediated by binding to a specific G-protein coupled receptor resulting in the activation of adenylate cyclase and an increase in cAMP generation. In the beta-cell, cAMP binds and modulates activities of both protein kinase A and cAMP-regulated guanine nucleotide exchange factor II, thereby enhancing glucose-dependent insulin secretion. The stimulatory action of GLP-1 on insulin secretion involves interaction with a plethora of signal transduction processes including ion channel activity, intracellular Ca(2+) handling and exocytosis of the insulin-containing granules. In this review we focus principally on recent advances in our understanding on the cellular mechanisms proposed to underlie GLP-1's insulinotropic effect and attempt to incorporate this knowledge into a working model for the control of insulin secretion. Lastly, this review discusses the applicability of GLP-1 as a therapeutic agent for the treatment of type 2 diabetes.
Gromada
Jesper
J
Department of Pharmacology, University of Aarhus, Universitetsparken, DK-8000 Aarhus C, Denmark. gromada@lilly.com
Brock
Birgitte
B
Schmitz
Ole
O
Rorsman
Patrik
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use*; D011498:Protein Precursors / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000378:metabolism
C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D007473:Ion Channels; D010446:Peptide Fragments; D011498:Protein Precursors; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D000255:Adenosine Triphosphate; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D005947:Glucose; D002118:Calcium