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

Abstract

Aims/hypothesis The aim of the study was to examine the effects of pioglitazone (PIO), a peroxisome proliferatoractivated 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 openlabel study. Subjects received a 4 h hyperinsulinaemiceuglycaemic 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.

Undernutrition during suckling in rats elevates plasma adiponectin and its receptor in skeletal muscle regardless of diet composition: a protective effect?

“…39,40 Rats undernourished during postnatal development had elevated expression of PPARa as well as the oxidative enzyme COX4 in skeletal muscle. Taken together, these results suggest that rats undernourished during suckling may have a greater ability to oxidize fatty acids, utilize glucose and increase insulin sensitivity.…”

Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

“…Furthermore, no biopsy, which is the ''gold standard'' for NAFLD diagnosis and staging, was performed [99] . Another small study included 15 patients with T2DM randomized to fenofibrate or pioglitazone [100] . Pioglitazone significantly improved glucose homeostasis and reduced fasting TG and free fatty acid (FFA) concentrations.…”

Non-alcoholic Steatohepatitis—An Endocrine Disorder

“…40 In contrast, no such effect of fenofibrate on liver enzymes or hepatic/muscle insulin sensitivity (assessed by the gold-standard insulin clamp technique) was observed in studies performed in obese subjects with type 2 diabetes. 41 In a similar way, while rosiglitazone has been reported to improve elevated liver function tests (LFTs) and steatosis in humans, 42 in mice rosiglitazone increases hepatic transaminases and worsens necroinflammation and steatosis. 43 …”