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

Diabetologia. 2007 Aug;50(8):1723-31. doi: 10.1007/s00125-007-0698-9. Epub 2007 May 23.

Abstract

Aims/hypothesis: The aim of the study was to examine the effects of pioglitazone (PIO), 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 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 microg/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 micromol 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 micromol/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 micromol kg(-1) min(-1), p < 0.005) and AD (4.1 +/- 0.8 to 13.1 +/- 2.5 microg/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-alpha therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-alpha agonist to a PPAR-gamma agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AMP-Activated Protein Kinases
  • Adiponectin / blood
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Drug Therapy, Combination
  • Female
  • Fenofibrate / pharmacology
  • Fenofibrate / therapeutic use
  • Glucose / metabolism*
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / blood
  • Insulin Resistance
  • Lipid Metabolism / drug effects*
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Middle Aged
  • Multienzyme Complexes / metabolism
  • PPAR alpha / agonists*
  • PPAR gamma / agonists*
  • Phosphorylation / drug effects
  • Pioglitazone
  • Protein-Serine-Threonine Kinases / metabolism
  • Thiazolidinediones / pharmacology
  • Thiazolidinediones / therapeutic use
  • Treatment Outcome

Substances

  • Adiponectin
  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Multienzyme Complexes
  • PPAR alpha
  • PPAR gamma
  • Thiazolidinediones
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Glucose
  • Fenofibrate
  • Pioglitazone