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

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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.


  • Bilal Omar
  • Birgitte Andersen
  • Jacob Hald
  • Kirsten Raun
  • Erica Nishimura
  • Bo Ahrén
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)101-110
Issue number1
Publication statusPublished - 2014
Publication categoryResearch

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