Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice. Issue 3 (23rd December 2015)

• Record Type: Journal Article
• Authors: Ahlkvist, Linda; Omar, Bilal; Valeur, Anders; Fosgerau, Keld; Ahrén, Bo
• Is Part Of: Journal of endocrinology. Volume 228:Issue 3(2016)
• Page Start: 171
• Page End: 178
• Publication Date: 2015-12-23
• Subjects: insulin -- β-cell function -- glucose intolerance -- chronic glucagon receptor activation; Endocrinology -- Periodicals; 616.4005
• DOI: 10.1530/JOE-15-0371
• Languages: English
• ISSNs: 0022-0795

Abstract

Abstract : Stimulation of insulin secretion by short-term glucagon receptor (GCGR) activation is well characterized; however, the effect of long-term GCGR activation on β-cell function is not known, but of interest, since hyperglucagonemia occurs early during development of type 2 diabetes. Therefore, we examined whether chronic GCGR activation affects insulin secretion in glucose intolerant mice. To induce chronic GCGR activation, high-fat diet fed mice were continuously (2 weeks) infused with the stable glucagon analog ZP-GA-1 and challenged with oral glucose and intravenous glucose±glucagon-like peptide 1 (GLP1). Islets were isolated to evaluate the insulin secretory response to glucose±GLP1 and their pancreas were collected for immunohistochemical analysis. Two weeks of ZP-GA-1 infusion reduced insulin secretion both after oral and intravenous glucose challenges in vivo and in isolated islets. These inhibitory effects were corrected for by GLP1. Also, we observed increased β-cell area and islet size. We conclude that induction of chronic ZP-GA-1 levels in glucose intolerant mice markedly reduces insulin secretion, and thus, we suggest that chronic activation of the GCGR may contribute to the failure of β-cell function during development of type 2 diabetes.