Abstract |
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)alpha/gamma 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 micromol/kg/d) restored insulin sensitivity of obese Zucker rats and decreased insulin secretion. In vitro, in reporter gene assays, AZ 242 activated human PPARalpha and PPARgamma with EC(50) in the micro molar range. It also induced differentiation in 3T3-L1 cells, an established PPARgamma effect, and caused up-regulation of liver fatty acid binding protein in HepG-2 cells, a PPARalpha-mediated effect. PPARalpha-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 PPARalpha/gamma 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.
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Authors | Bengt Ljung, Krister Bamberg, Björn Dahllöf, Ann Kjellstedt, Nicholas D Oakes, Jörgen Ostling, Lennart Svensson, Germán Camejo |
Journal | Journal of lipid research
(J Lipid Res)
Vol. 43
Issue 11
Pg. 1855-63
(Nov 2002)
ISSN: 0022-2275 [Print] United States |
PMID | 12401884
(Publication Type: Journal Article)
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Chemical References |
- Alkanesulfonates
- Cinnamates
- Fatty Acids
- Phenylpropionates
- Receptors, Cytoplasmic and Nuclear
- Transcription Factors
- tesaglitazar
- Glucose
- Bezafibrate
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Topics |
- Alkanesulfonates
- Animals
- Bezafibrate
(pharmacology)
- Carbohydrate Metabolism
- Cinnamates
(metabolism)
- Diabetes Mellitus
(metabolism)
- Fatty Acids
(metabolism)
- Glucose
(metabolism)
- Humans
- Insulin Resistance
(physiology)
- Lipid Metabolism
- Male
- Mass Spectrometry
- Mice
- Mice, Obese
- Molecular Structure
- Obesity
- Phenylpropionates
- Rats
- Rats, Zucker
- Receptors, Cytoplasmic and Nuclear
(agonists, metabolism)
- Transcription Factors
(agonists, metabolism)
- Tumor Cells, Cultured
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