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


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
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.
Bajaj
M
M
Diabetes Division, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA. mandeepbajaj@hotmail.com
Suraamornkul
S
S
Hardies
L J
LJ
Glass
L
L
Musi
N
N
DeFronzo
R A
RA
D055372:AMP-Activated Protein Kinases; D052242:Adiponectin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D052242:Adiponectin; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D009097:Multienzyme Complexes; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D011345:Fenofibrate; D000077205:Pioglitazone