| First Author | Leiss V | Year | 2014 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 307 |
| Issue | 9 | Pages | E800-12 |
| PubMed ID | 25205820 | Mgi Jnum | J:215545 |
| Mgi Id | MGI:5605609 | Doi | 10.1152/ajpendo.00337.2014 |
| Citation | Leiss V, et al. (2014) Insulin secretion stimulated by l-arginine and its metabolite l-ornithine depends on Galphai2. Am J Physiol Endocrinol Metab 307(9):E800-12 |
| abstractText | Bordetella pertussis toxin (PTx), also known as islet-activating protein, induces insulin secretion by ADP-ribosylation of inhibitory G proteins. PTx-induced insulin secretion may result either from inactivation of Galphao proteins or from combined inactivation of Galphao, Galphai1, Galphai2, and Galphai3 isoforms. However, the specific role of Galphai2 in pancreatic beta-cells still remains unknown. In global (Galphai2 (-/-)) and beta-cell-specific (Galphai2 (betacko)) gene-targeted Galphai2 mouse models, we studied glucose homeostasis and islet functions. Insulin secretion experiments and intracellular Ca(2+) measurements were used to characterize Galphai2 function in vitro. Galphai2 (-/-) and Galphai2 (betacko) mice showed an unexpected metabolic phenotype, i.e., significantly lower plasma insulin levels upon intraperitoneal glucose challenge in Galphai2 (-/-) and Galphai2 (betacko) mice, whereas plasma glucose concentrations were unchanged in Galphai2 (-/-) but significantly increased in Galphai2 (betacko) mice. These findings indicate a novel albeit unexpected role for Galphai2 in the expression, turnover, and/or release of insulin from islets. Detection of insulin secretion in isolated islets did not show differences in response to high (16 mM) glucose concentrations between control and beta-cell-specific Galphai2-deficient mice. In contrast, the two- to threefold increase in insulin secretion evoked by l-arginine or l-ornithine (in the presence of 16 mM glucose) was significantly reduced in islets lacking Galphai2. In accord with a reduced level of insulin secretion, intracellular calcium concentrations induced by the agonistic amino acid l-arginine did not reach control levels in beta-cells. The presented analysis of gene-targeted mice provides novel insights in the role of beta-cell Galphai2 showing that amino acid-induced insulin-release depends on Galphai2. |
