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.
- Received May 3, 2013.
- Accepted September 18, 2013.
- © 2013 by the American Diabetes Association.
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