Published in:
01-08-2007 | Article
Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus
Published in: Diabetologia | Issue 8/2007
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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 HbA1c (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, HbA1c, 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, HbA1c, 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), HbA1c (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.