title: Improved insulin sensitivity and islet function after PPARdelta activation in diabetic db/db mice.
abstract: 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.
authors.affiliation: Department of Clinical Sciences, Medicine, BMC, B11, SE-221 84 Lund, Sweden. Maria.Sorhede_Winzell@med.lu.se
authors.forename: Maria Sörhede
authors.initials: MS
authors.lastname: Winzell
authors.forename: Erik Max
authors.initials: EM
authors.lastname: Wulff
authors.forename: Grith Skytte
authors.initials: GS
authors.lastname: Olsen
authors.forename: Per
authors.initials: P
authors.lastname: Sauerberg
authors.forename: Carsten F
authors.initials: CF
authors.lastname: Gotfredsen
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism; D013997:Time Factors
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D047494:PPAR delta; D010168:Palmitates; D005947:Glucose