Abstract
Glucagon-like peptide-17–37/36NH2 (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-17–37/36NH2 on adenylyl cyclase as well as the phenomenon of homologous receptor desensitization. However, neither the effects of GLP-17–37/36NH2 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-17–36NH2 (10−8M) 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-17–36NH2 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-17–36NH2 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-17–36NH2 induces insulin secretion in normal B cells through a protein kinase A-dependent mechanism. The loss of insulinotropic effect of GLP-17–36NH2 in long-term incubations, despite the ability of glucose and cAMP to increase insulin secretion, suggests that the GLP-17–37/36NH2 receptor in normal islets may undergo homologous desensitization during chronic exposure to GLP-17–36NH2
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Gronau, K.A., Brubaker, P.L. Mechanism of action of glucagon-like peptide-17–36NH2 in isolated rat pancreatic islets and abrogation of its effects in long-term incubations. Endocr 3, 795–799 (1995). https://doi.org/10.1007/BF02935683
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DOI: https://doi.org/10.1007/BF02935683