Fibroblast growth factor 21 prevents glycemic deterioration in insulin deficient mouse models of diabetes

Abstract

In type 1 diabetes, there is a rapid loss of glycemic control immediately after onset of the disease. We aimed to determine if the deterioration of glycemic control that occurs early after the onset of insulin-deficient diabetes could be blunted by treatment with recombinant fibroblast growth factor 21 (FGF21). Normal C57BL/6J mice made diabetic by a single high dose injection of streptozotocin (STZ) were randomized to receive twice daily subcutaneous injection of vehicle or recombinant human FGF21 at doses of 0.3 and 1.0mg/kg for 10 days. Body weight was recorded daily and 5h fasted glucose, insulin, glucagon, free fatty acids and ketones were determined at 6 and 10 days post-randomization.The increase in fasting plasma glucose induced by STZ in untreated mice was prevented with FGF21 at 0.3mg/kg BID. In contrast, at 1.0mg/kg BID, FGF21 did not prevent the rise in plasma glucose after STZ. At the end of the study, plasma glucagon was significantly higher in the diabetic group treated with FGF21 1.0mg/kg BID than in the untreated group. This was not seen for the group treated with FGF21 0.3mg/kg BID. There were significant dose dependent reductions in plasma free fatty acids with FGF21 treatment but no significant change in plasma ketones (β-hydroxybutyrate). FGF21 treatment did not have significant effects on body weight in lean insulin deficient mice.In conclusion, FGF21 prevents increases in glycaemia and has lipid lowering properties in mouse models of insulin deficient diabetes, although by increasing the dose increased glucagon levels are seen and hyperglycemia persists.