Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

Aims/hypothesis The aim of the study was to examine the effects of pioglitazone (PTO), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, and fenofibrate (FENO), a PPAR-alpha agonist, as monotherapy and in combination on glucose and lipid metabolism. Subjects and methods Fifteen type 2 diabetic patients received FENO (n = 8) or PTO (n = 7) for 3 months, followed by the addition of the other agent for 3 months in an open-label study. Subjects received a 4 h hyperinsulinaemic-euglycaemic clamp and a hepatic fat content measurement at 0, 3 and 6 months. Results Following PTO, fasting plasma glucose (FPG) (p<0.05) and HbA(1c) (p<0.01) decreased, while plasma adiponectin (AD) (5.5 +/- 0.9 to 13.8 +/- 3.5 mu g/ml [SEM], p<0.03) and the rate of insulin-stimulated total-body glucose disposal (Rd) (23.8 +/- 3.8 to 40.5 +/- 4.4 mu mol kg(-1) min(-1), p<0.005) increased. After FENO, FPG, HbA(1c), AD and Rd did not change. PTO reduced fasting NEFA (784 +/- 53 to 546 +/- 43 mu mol/l, p<0.05), triacylglycerol (2.12 +/- 0.28 to 1.61 +/- 0.22 mmol/l, p<0.05) and hepatic fat content (20.4 +/- 4.8 to 10.2 +/- 2.5%, p<0.02). Following FENO, fasting NEFA and hepatic fat content did not change, while triacylglycerol decreased (2.20 +/- 0.14 to 1.59 +/- 0.13 mmol/l, p<0.01). Addition of FENO to PTO had no effect on Rd, FPG, HbA(1c), NEFA, hepatic fat content or AD, but triacylglycerol decreased (1.61 +/- 0.22 to 1.00 +/- 0.15 mmol/l, p<0.05). Addition of PTO to FENO increased Rd (24.9 +/- 4.4 to 36.1 +/- 2.2 mu mol kg(-1) min(-1) p<0.005) and AD (4.1 +/- 0.8 to 13.1 +/- 2.5 mu g/ml, p<0.005) and reduced FPG (p<0.05), MAI, (p<0.05), NEFA (p<0.01), hepatic fat content (18.3 +/- 3.1 to 13.5 +/- 2.1%, p<0.03) and triacylglycerol (1.59 0.13 to 0.96 +/- 0.9 mmol/l, p<0.01). Muscle adenosine 5'-monophospbate-activated protein kinase (AMPK) activity did not change following FENO; following the addition of PTO, muscle AMPK activity increased significantly (phosphorylated AMPK:total AMPK ratio 1.2 +/- 0.2 to 2.2 +/- 0.3,p<0.01). Conclusions/interpretation We conclude that PPAR-alpha therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-alpha agonist to a PPAR-alpha agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.