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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 antidiabetic actions of FGF21 in insulin-deficient Gcgr(-/-) mice, an FGF21-neutralizing antibody was administered prior to oral glucose tolerance tests (OGTTs). 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 1 (GLP-1) also has insulin-independent glucose-lowering properties, and an elevated circulating level of GLP-1 is a known characteristic of Gcgr(-/-) mice. Neutralization of FGF21, while concurrently blocking the GLP-1 receptor with the antagonist Exendin 9-39 (Ex9-39), resulted in significant hyperglycemia in insulin-deficient Gcgr(-/-) mice, while blocking with Ex9-39 alone did not. In conclusion, FGF21 acts additively with GLP-1 to prevent insulinopenic diabetes in mice lacking glucagon action.

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