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

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 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.

Absence of Glucagon and Insulin Action Reveals a Role for the GLP-1 Receptor in Endogenous Glucose Production

“…Lack of the Glp-1r did not affect oral glucose tolerance in nondiabetic DKO animals, likely due to the compensatory upregulation of other incretin pathways upon Glp-1r ablation (30). In an OGTT 1 week after STZ administration, Gcgr These results are similar to those showing acute blockade of the GLP-1R using exendin-4 worsens glucose tolerance in STZ-treated Gcgr-null mice (19). An assessment of gastric emptying between the two STZ-treated genotypes failed to show any difference (plasma acetaminophen AUC (0-2 h) : Gcgr 2/2 23.0 6 1.7, and DKO 25.4 6 1.8 mg $ h/mL).…”

“…This report also indicated circulating levels of fibroblast growth factor 21 (FGF21) are increased in Gcgr 2/2 mice, a finding paradoxical to other studies showing activation of the GCGR increases hepatic and circulating FGF21 levels (20,21). The combination of exendin-4 and FGF21 antisera worsened the glucose excursion for animals undergoing an oral glucose tolerance test (OGTT) (19 mice and in insulinopenic wild-type and Glp-1r 2/2 animals treated with a high-affinity GCGR antagonist antibody.…”

“…The goal of our studies using the Gcgr knockout model was to determine whether the GLP-1R plays a significant role in maintaining normal glycemia when these animals are made insulin deficient. Use of the Gcgr 2/2 , Glp-1r 2/2 , and Gcgr 2/2 :Glp-1r 2/2 genetic models here builds on previous work in Gcgr 2/2 mice showing that administration of the GLP-1R peptide antagonist, exendin-4 , worsens glucose tolerance in these animals (19). Further, use of the high-affinity monoclonal GCGR antagonist antibody enabled complimentary studies that pharmacologically recapitulated the genetically driven loss of Gcgr in insulinopenic wild-type and Glp-1r 2/2 animals.…”

Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes

“…To compare the cell specificity of DPP-4 expression in mouse islets, we used glucagon receptor-deficient mice, a mouse model of alpha cell hyperplasia. Glucagon receptor-deficient (Gcgr −/− ) mice displayed large islets with hyperplastic alpha cells as previously described [15,23]. Similar to ND-and HFD-fed C57BL6 mice, Gcgr −/− mouse islets displayed abundant staining for DPP-4, with the predominance of immunostaining in the beta cells (Fig.…”

Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes

“…The contribution of increased GLP-1 concentrations to the altered glucose tolerance in Gcgr -/-has been investigated in STZ-treated Gcgr -/-mice, and inhibition of GLP-1 action had no effect on glucose tolerance but eliminated the improvement found in the STZ-treated Gcgr -/-mice [19]. The double knockout mouse, Gcgr -/-Glp1r -/- [20] has normal random fed blood glucose levels and a normal i.p.…”