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