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 (PIO), a peroxisome proliferator-activated receptor (PPAR)-γ agonist, and fenofibrate (FENO), a PPAR-α agonist, as monotherapy and in combination on glucose and lipid metabolism. Subjects and methods: Fifteen type 2 diabetic patients received FENO (n=8) or PIO (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 PIO, 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 μg/ml [SEM], p<0.03) and the rate of insulin-stimulated total-body glucose disposal (R _d) (23.8±3.8 to 40.5±4.4 μmol kg^-1 min^-1, p<0.005) increased. After FENO, FPG, HbA_1c, AD and R _d did not change. PIO reduced fasting NEFA (784±53 to 546±43 μmol/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 PIO had no effect on R _d, 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 PIO to FENO increased R _d (24.9±4.4 to 36.1±2.2 μmol kg^-1 min^-1, p<0.005) and AD (4.1±0.8 to 13.1±2.5 μg/ml, p<0.005) and reduced FPG (p<0.05), HbA _1c (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′-monophosphate-activated protein kinase (AMPK) activity did not change following FENO; following the addition of PIO, 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-α therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-α agonist to a PPAR-γ agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.