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

Ahlkvist, Linda LU ; Omar, Bilal LU ; Valeur, Anders; Fosgerau, Keld and Ahrén, Bo LU (2016) In Journal of Endocrinology 228. p.171-178
Abstract
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.... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Endocrinology
volume
228
pages
171 - 178
publisher
Society for Endocrinology
external identifiers
  • pmid:26698567
  • scopus:84975764023
  • wos:000374956900009
ISSN
1479-6805
DOI
10.1530/JOE-15-0371
language
English
LU publication?
yes
id
1d4d9b95-18b4-41a3-90e5-22afee2b6ee8 (old id 8503825)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26698567?dopt=Abstract
date added to LUP
2016-01-06 13:11:50
date last changed
2017-01-01 07:37:42
@article{1d4d9b95-18b4-41a3-90e5-22afee2b6ee8,
  abstract     = {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.},
  author       = {Ahlkvist, Linda and Omar, Bilal and Valeur, Anders and Fosgerau, Keld and Ahrén, Bo},
  issn         = {1479-6805},
  language     = {eng},
  pages        = {171--178},
  publisher    = {Society for Endocrinology},
  series       = {Journal of Endocrinology},
  title        = {Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice.},
  url          = {http://dx.doi.org/10.1530/JOE-15-0371},
  volume       = {228},
  year         = {2016},
}