Peroxisome Proliferator–Activated Receptor-α Agonist Treatment in a Transgenic Model of Type 2 Diabetes Reverses the Lipotoxic State and Improves Glucose Homeostasis
Peroxisome Proliferator–Activated Receptor-α Agonist Treatment in a Transgenic Model of Type 2 Diabetes Reverses the Lipotoxic State and Improves Glucose Homeostasis Hyunsook Kim 1 , Martin Haluzik 1 , Zeenat Asghar 2 , Daphne Yau 2 , Jamie W. Joseph 2 , Ana M. Fernandez 1 , Marc L. Reitman 1 , Shos...
Saved in:
Published in | Diabetes (New York, N.Y.) Vol. 52; no. 7; pp. 1770 - 1778 |
---|---|
Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Alexandria, VA
American Diabetes Association
01.07.2003
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Peroxisome Proliferator–Activated Receptor-α Agonist Treatment in a Transgenic Model of Type 2 Diabetes Reverses the Lipotoxic
State and Improves Glucose Homeostasis
Hyunsook Kim 1 ,
Martin Haluzik 1 ,
Zeenat Asghar 2 ,
Daphne Yau 2 ,
Jamie W. Joseph 2 ,
Ana M. Fernandez 1 ,
Marc L. Reitman 1 ,
Shoshana Yakar 1 ,
Bethel Stannard 1 ,
Lisa Heron-Milhavet 1 ,
Michael B. Wheeler 2 and
Derek LeRoith 1
1 Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda,
Maryland
2 Department of Physiology, University of Toronto, Toronto, Ontario, Canada
Address correspondence and reprint requests to Derek LeRoith, Molecular and Cellular Physiology Section, Diabetes Branch,
NIDDK, National Institutes of Health, 9000 Rockville Pike, Bldg. 10, Rm. 8D12, Bethesda, MD 20892-1758. E-mail: derek{at}helix.nih.gov
Abstract
Abnormalities in insulin action are the characteristics of type 2 diabetes. Dominant-negative muscle-specific IGF-I receptor
(MKR) mice exhibit elevated lipid levels at an early age and eventually develop type 2 diabetes. To evaluate the role of elevated
lipids in the progression of the diabetic state, MKR mice were treated with WY14,643, a peroxisome proliferator–activated
receptor (PPAR)-α agonist. WY14,643 treatment markedly reduced serum fatty acid and triglyceride levels within a few days,
as well as muscle triglyceride levels, and subsequently normalized glucose and insulin levels in MKR mice. Hyperinsulinemic-euglycemic
clamp analysis showed that WY14,643 treatment enhanced muscle and adipose tissue glucose uptake by improving whole-body insulin
sensitivity. Insulin suppression of endogenous glucose production by the liver of MKR mice was also improved. The expression
of genes involved in fatty acid oxidation was increased in liver and skeletal muscle, whereas gene expression levels of hepatic
gluconeogenic enzymes were decreased in WY14,643-treated MKR mice. WY14,643 treatment also improved the pattern of glucose-stimulated
insulin secretion from the perfused pancreata of MKR mice and reduced the β-cell mass. Taken together, these findings suggest
that the reduction in circulating or intracellular lipids by activation of PPAR-α improved insulin sensitivity and the diabetic
condition of MKR mice.
ACO, acyl-CoA oxidase
BrdU, 5-bromo-2′deoxyuridine
CPT-1, carnitine palmitoyl transferase 1
FA, fatty acid
IGF-IR, IGF-I receptor
PPAR, peroxisome proliferator–activated receptor
Footnotes
M.L.R. is an employee of Merck.
Accepted April 4, 2003.
Received December 10, 2002.
DIABETES |
---|---|
ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/diabetes.52.7.1770 |