Fibroblast growth factor 21 (FGF21) and glucagon-like peptide 1 contribute to diabetes resistance in glucagon receptor-deficient mice.
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.
Department of Clinical Sciences, Lund University, Lund, Sweden.
Bilal A
BA
Omar
Birgitte
B
Andersen
Jacob
J
Hald
Kirsten
K
Raun
Erica
E
Nishimura
Bo
B
Ahrén
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D050416:Glucagon-Secreting Cells / Q000378:metabolism; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C414620:fibroblast growth factor 21; C083773:exendin (9-39); D005346:Fibroblast Growth Factors; D052216:Glucagon-Like Peptide 1