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Fibroblast Growth Factor 21 (FGF21) and Glucagon Like-Peptide 1 Contribute to Diabetes Resistance in Glucagon Receptor Deficient Mice.

Omar, Bilal LU ; Andersen, Birgitte; Hald, Jacob; Raun, Kirsten; Nishimura, Erica and Ahrén, Bo LU (2014) In Diabetes 63(1). p.101-110
Abstract
Mice genetically deficient in the glucagon receptor (Gcgr(-/-)) show improved glucose tolerance, insulin sensitivity and α-cell hyperplasia. In addition, Gcgr(-/-) mice do not develop diabetes after chemical destruction of β-cells. Since fibroblast growth factor 21 (FGF21) has insulin independent glucose lowering properties we investigated whether FGF21 was contributing to diabetes resistance in insulin deficient Gcgr(-/-) mice. Plasma FGF21 was 25 fold higher in Gcgr(-/-) mice than in wild type mice. FGF21 was found to be expressed in pancreatic β- and α-cells, with high expression in the hyperplastic α-cells of Gcgr(-/-) mice. FGF21 expression was also significantly increased in liver and adipose tissue of Gcgr(-/-) mice. To investigate... (More)
Mice genetically deficient in the glucagon receptor (Gcgr(-/-)) show improved glucose tolerance, insulin sensitivity and α-cell hyperplasia. In addition, Gcgr(-/-) mice do not develop diabetes after chemical destruction of β-cells. Since fibroblast growth factor 21 (FGF21) has insulin independent glucose lowering properties we investigated whether FGF21 was contributing to diabetes resistance in insulin deficient Gcgr(-/-) mice. Plasma FGF21 was 25 fold higher in Gcgr(-/-) mice than in wild type mice. FGF21 was found to be expressed in pancreatic β- and α-cells, with high expression in the hyperplastic α-cells of Gcgr(-/-) mice. FGF21 expression was also significantly increased in liver and adipose tissue of Gcgr(-/-) mice. To investigate the potential anti-diabetic actions of FGF21 in insulin deficient Gcgr(-/-) mice, an FGF21 neutralizing antibody was administered prior to oral glucose tolerance tests (OGTT). FGF21 neutralization caused a decline in glucose tolerance in insulin deficient Gcgr(-/-) mice during the OGTT. Despite this decline, insulin deficient Gcgr(-/-) mice did not develop hyperglycemia. Glucagon-like peptide (GLP-1) also has insulin independent glucose lowering properties and elevated circulating GLP-1 is a known characteristic of Gcgr(-/-) mice. Neutralization of FGF21 while concurrently blocking the GLP-1 receptor with the antagonist Exendin9-39 resulted in significant hyperglycemia in insulin deficient Gcgr(-/-) mice, while Exendin9-39 alone did not. In conclusion, FGF21 acts additively with GLP-1 to prevent insulinopenic diabetes in mice lacking glucagon action. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
63
issue
1
pages
101 - 110
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000328680400018
  • pmid:24062250
  • scopus:84891803047
ISSN
1939-327X
DOI
10.2337/db13-0710
language
English
LU publication?
yes
id
ed475310-257a-41e4-9c63-0f1a322a8aa8 (old id 4065437)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24062250?dopt=Abstract
date added to LUP
2013-10-03 21:51:05
date last changed
2017-10-01 03:20:14
@article{ed475310-257a-41e4-9c63-0f1a322a8aa8,
  abstract     = {Mice genetically deficient in the glucagon receptor (Gcgr(-/-)) show improved glucose tolerance, insulin sensitivity and α-cell hyperplasia. In addition, Gcgr(-/-) mice do not develop diabetes after chemical destruction of β-cells. Since fibroblast growth factor 21 (FGF21) has insulin independent glucose lowering properties we investigated whether FGF21 was contributing to diabetes resistance in insulin deficient Gcgr(-/-) mice. Plasma FGF21 was 25 fold higher in Gcgr(-/-) mice than in wild type mice. FGF21 was found to be expressed in pancreatic β- and α-cells, with high expression in the hyperplastic α-cells of Gcgr(-/-) mice. FGF21 expression was also significantly increased in liver and adipose tissue of Gcgr(-/-) mice. To investigate the potential anti-diabetic actions of FGF21 in insulin deficient Gcgr(-/-) mice, an FGF21 neutralizing antibody was administered prior to oral glucose tolerance tests (OGTT). FGF21 neutralization caused a decline in glucose tolerance in insulin deficient Gcgr(-/-) mice during the OGTT. Despite this decline, insulin deficient Gcgr(-/-) mice did not develop hyperglycemia. Glucagon-like peptide (GLP-1) also has insulin independent glucose lowering properties and elevated circulating GLP-1 is a known characteristic of Gcgr(-/-) mice. Neutralization of FGF21 while concurrently blocking the GLP-1 receptor with the antagonist Exendin9-39 resulted in significant hyperglycemia in insulin deficient Gcgr(-/-) mice, while Exendin9-39 alone did not. In conclusion, FGF21 acts additively with GLP-1 to prevent insulinopenic diabetes in mice lacking glucagon action.},
  author       = {Omar, Bilal and Andersen, Birgitte and Hald, Jacob and Raun, Kirsten and Nishimura, Erica and Ahrén, Bo},
  issn         = {1939-327X},
  language     = {eng},
  number       = {1},
  pages        = {101--110},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Fibroblast Growth Factor 21 (FGF21) and Glucagon Like-Peptide 1 Contribute to Diabetes Resistance in Glucagon Receptor Deficient Mice.},
  url          = {http://dx.doi.org/10.2337/db13-0710},
  volume       = {63},
  year         = {2014},
}