TY - JOUR
T1 - Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus
AU - Bajaj, M.
AU - Suraamornkul, S.
AU - Hardies, L. J.
AU - Glass, L.
AU - Musi, N.
AU - DeFronzo, R. A.
N1 - Funding Information:
Acknowledgements This work was supported in part by National Institutes of Health Grant DK-24092, a Veterans Administration Merit Award and General Clinical Research Center Grant MO1-RR01346. The study medications PIO and FENO were provided by Takeda Pharmaceuticals and Abbott Laboratories Inc., respectively. The authors wish to thank the nurses on the GCRC for their diligent care of our patients and especially P. Wolff, N. Diaz, J. King and J. Kincade for carrying out the insulin clamp studies. We gratefully acknowledge the technical assistance of R. Castillo, K. Camp, C. Munoz and S. Taylor. L. Albarado and E. Chapa provided skilled secretarial support in the preparation of this manuscript.
Funding Information:
Duality of interest R. A. DeFronzo has received research grant support from and is a consultant to Takeda Pharmaceuticals. He is a member of the speakers’ bureau of Takeda Pharmaceuticals. M. Bajaj has received research grant support from and is a member of the speakers’ bureau of Takeda Pharmaceuticals. L. Glass is currently an employee of Eli-Lilly. N. Musi has received research grant support from Takeda Pharmaceuticals.
PY - 2007/8
Y1 - 2007/8
N2 - 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), 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.
AB - 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), 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.
KW - Adiponectin
KW - Insulin sensitivity
KW - PPAR-α
KW - PPAR-γ
KW - Type 2 diabetes
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U2 - 10.1007/s00125-007-0698-9
DO - 10.1007/s00125-007-0698-9
M3 - Article
C2 - 17520238
AN - SCOPUS:34447114640
SN - 0012-186X
VL - 50
SP - 1723
EP - 1731
JO - Diabetologia
JF - Diabetologia
IS - 8
ER -