Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice.

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Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice. / Ahlkvist, Linda; Omar, Bilal; Valeur, Anders; Fosgerau, Keld; Ahrén, Bo.

In: Journal of Endocrinology, Vol. 228, 2016, p. 171-178.

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T1 - Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice.

AU - Ahlkvist, Linda

AU - Omar, Bilal

AU - Valeur, Anders

AU - Fosgerau, Keld

AU - Ahrén, Bo

PY - 2016

Y1 - 2016

N2 - Stimulation of insulin secretion by short-term glucagon receptor (GCGR) activation is well characterized, however, the effect of long-term GCGR activation on beta-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 (2wk) infused with the stable glucagon analogue ZP-GA-1 and challenged with oral glucose and intravenous glucose +/- GLP-1. Islets were isolated to evaluate the insulin secretory response to glucose +/- GLP-1 and pancreases were collected for immunohistochemical analysis. Two-week 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 GLP-1. Also, we observed increased beta-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 beta-cell function during development of type 2 diabetes.

AB - Stimulation of insulin secretion by short-term glucagon receptor (GCGR) activation is well characterized, however, the effect of long-term GCGR activation on beta-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 (2wk) infused with the stable glucagon analogue ZP-GA-1 and challenged with oral glucose and intravenous glucose +/- GLP-1. Islets were isolated to evaluate the insulin secretory response to glucose +/- GLP-1 and pancreases were collected for immunohistochemical analysis. Two-week 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 GLP-1. Also, we observed increased beta-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 beta-cell function during development of type 2 diabetes.

U2 - 10.1530/JOE-15-0371

DO - 10.1530/JOE-15-0371

M3 - Article

VL - 228

SP - 171

EP - 178

JO - Journal of Endocrinology

JF - Journal of Endocrinology

SN - 1479-6805

ER -