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Journal of Lipid Research, Vol. 43, 1855-1863, November 2002
Copyright © 2002 by Lipid Research, Inc.
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agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats
AstraZeneca R&D, Research Area CV/GI, Mölndal S 431 83 Mölndal, Sweden
1 To whom correspondence should be addressed. e-mail: bengt.ljung{at}astrazeneca.com
Abnormalities in fatty acid (FA) metabolism underlie the development of insulin resistance and alterations in glucose metabolism, features characteristic of the metabolic syndrome and type 2 diabetes that can result in an increased risk of cardiovascular disease. We present pharmacodynamic effects of AZ 242, a novel peroxisome proliferator activated receptor (PPAR)
/
agonist. AZ 242 dose-dependently reduced the hypertriglyceridemia, hyperinsulinemia, and hyperglycemia of ob/ob diabetic mice. Euglycemic hyperinsulinemic clamp studies showed that treatment with AZ 242 (1 µmol/kg/d) restored insulin sensitivity of obese Zucker rats and decreased insulin secretion. In vitro, in reporter gene assays, AZ 242 activated human PPAR and PPAR with EC50 in the µmolar range. It also induced differentiation in 3T3-L1 cells, an established PPAR effect, and caused up-regulation of liver fatty acid binding protein in HepG-2 cells, a PPAR-mediated effect. PPAR-mediated effects of AZ 242 in vivo were documented by induction of hepatic cytochrome P 450-4A in mice.
The results indicate that the dual PPAR/ agonism of AZ 242 reduces insulin resistance and has beneficial effects on FA and glucose metabolism. This effect profile could provide a suitable therapeutic approach to the treatment of type 2 diabetes, metabolic syndrome, and associated vascular risk factors.
Abbreviations: CYP4A, cytochrome P450 4A activity; FA, fatty acid; FCS, fetal calf serum; FFA, free fatty acid; GIR, glucose infusion rate; HI, human insulin; I, insulin infusion rate; IS, insulin secretion; L-FABP, liver fatty acid binding protein; PPAR, peroxisome proliferator activated receptor; RI, rat insulin; RIA, radio immunoassay; TG, triglyceride
Supplementary key words hypertriglyceridemia • peroxisome proliferator activated receptor • type 2 diabetes
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