Improved insulin sensitivity and islet function after PPARδ activation in diabetic db/db mice

The peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Several reports have shown that PPARδ is involved in lipid metabolism, increasing fat oxidation and depleting lipid accumulation. Whether PPARδ is involved in the regulation of glucose metabolism is not completely understood. In this study, we examined effects of long-term PPARδ activation on glycemic control, islet function and insulin sensitivity in diabetic db/db mice. Male db/db mice were administered orally once daily with a selective and partial PPARδ agonist (NNC 61-5920, 30mg/kg) for eight weeks; control mice received vehicle. Fasting and non-fasting plasma glucose were reduced, reflected in reduced hemoglobinA1c (3.6±1.6% vs. 5.4±1.8 in db/db controls, P<0.05) and furthermore, the AUCglucose after oral glucose (3g/kg) was reduced by 67% (P<0.05) after long-term PPARδ activation. Following intravenous glucose (1g/kg), glucose tolerance was improved after PPARδ activation (KG 1.3±0.6 vs. −0.05±0.7 %/min, P=0.048). Insulin sensitivity, measured as the glucose clearance after intravenous injection of glucose (1g/kg) and insulin (0.75 or 1.0U/kg), during inhibition of endogenous insulin secretion by diazoxide (25mg/kg), was improved (KG 2.9±0.6 vs. 1.3±0.3 %/min in controls, P<0.05) despite lower insulin levels. Furthermore, islets isolated from PPARδ agonist treated mice demonstrated improved glucose responsiveness as well as improved cellular topography. In conclusion, PPARδ agonism alleviates insulin resistance and improves islet function and topography, resulting in improved glycemia in diabetic db/db mice. This suggests that activation of PPARδ improves glucose metabolism and may therefore potentially be target for treatment of type 2 diabetes.