title: Mechanism of action of glucagon-like peptide-1(7-36NH2) in isolated rat pancreatic islets and abrogation of its effects in long-term incubations.
abstract: Glucagon-like peptide-1(7-37/36NH2) (GLP-1) potently stimulates acute glucose-dependent insulin secretionin vitro andin vivo. Islet cell lines have been used extensively to examine the effects of GLP-1(7-37/36NH2) on adenylyl cyclase as well as the phenomenon of homologous receptor desensitization. However, neither the effects of GLP-1(7-37/36NH2) on the protein kinase A pathway nor its chronic effects on insulin secretion have been examined in normal B cells. The isolated rat pancreatic islet was therefore employed to study these phenomena in a more physiologic model. GLP-1(7-36NH2) (10(-8)M) increased islet cAMP content to 391±196% of control after 30 min of incubation (P<0.05), and stimulated glucose-dependent insulin secretion by 2.0±0.1-fold in acutely perifused islets (P<0.001). In chronic 24 h incubations, insulin secretion was stimulated two to fourfold by 10 as compared to 5 mM glucose (P<0.001), and three to fourfold by 10 μM forskolin plus 10μM isobutylmethylxanthine (P<0.01-0.001). However, 10(-8) M GLP-1(7-36NH2) did not stimulate insulin secretion at either 5 or 10 mM glucose, or in the presence of forskolin and IBMX. This specific lack of GLP-1(7-36NH2) effectiveness was not due to peptide degradation or accumulation of somatostatin in the medium. The results of the present study establish for the first time that GLP-1(7-36NH2) induces insulin secretion in normal B cells through a protein kinase A-dependent mechanism. The loss of insulinotropic effect of GLP-1(7-36NH2) in long-term incubations, despite the ability of glucose and cAMP to increase insulin secretion, suggests that the GLP-1(7-37/36NH2) receptor in normal islets may undergo homologous desensitization during chronic exposure to GLP-1(7-36NH2).
authors.affiliation: Department of Physiology, University of Toronto, M5S 1A8, Toronto, Ontario, Canada.
authors.forename: K A
authors.initials: KA
authors.lastname: Gronau
authors.forename: P L
authors.initials: PL
authors.lastname: Brubaker