A novel peroxisome proliferator--activated receptor alpha/gamma dual agonist ameliorates dyslipidemia and insulin resistance in prediabetic rhesus monkeys.

Abstract

TAK-559, a newly developed non-thiazolidinedione, activates both peroxisome proliferator-activated receptors alpha and gamma. We investigated the effects of TAK-559 on dyslipidemia and insulin resistance in nonhuman primates. Five adult male obese prediabetic rhesus monkeys were studied on vehicle and after TAK-559 treatment (0.3, 1.0, 3.0 mg/kg per day) for a total of 12 weeks. No significant changes were observed in body weight and fasting plasma glucose, total plasma cholesterol, very low-density lipoprotein-triglyceride, and low-density lipoprotein cholesterol levels. TAK-559 treatment resulted in significant elevation of circulating high-density lipoprotein (HDL) cholesterol levels, consisting of an increase in large HDL particles and a decrease in small dense HDL particles. Nuclear magnetic resonance data exhibited a less atherogenic lipoprotein profile with treatment. Plasma triglyceride and apolipoprotein B-100 levels decreased, whereas apolipoprotein A-I increased during TAK-559 treatment. Hyperinsulinemia and insulin resistance (quantitative insulin sensitivity check index and homeostasis model assessment) were significantly corrected with the highest dose of 3.0 mg/kg per day in these prediabetic monkeys. In addition, no adverse effects on representative liver function parameters were observed during the study period. These results suggest that TAK-559 had beneficial effects on lipoprotein profiles and insulin sensitivity, without any side effect on body weight, which suggests that TAK-559 may provide a potentially safe approach for delaying the onset of type 2 diabetes mellitus and may reduce the risk of cardiovascular disease. The positive effects of TAK-559 in nonhuman primates have led to further clinical trials of TAK-559 in Europe and the United States.

• Authors: Shi-Ying Ding, Xenia T Tigno, Gheorghe T Braileanu, Katsuhiko Ito, Barbara C Hansen
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 56 Issue 10 Pg. 1334-9 (Oct 2007) ISSN: 0026-0495 [Print] United States
• PMID: 17884441 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (E)-4-(4-((5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy)benzyloxyimino)-4-phenylbutyric acid
• Apolipoproteins
• Blood Glucose
• Butyrates
• Cholesterol, HDL
• Hypolipidemic Agents
• Insulin
• Oxazoles
• PPAR alpha
• PPAR gamma

Topics

• Animals
• Apolipoproteins (blood)
• Blood Glucose (metabolism)
• Body Weight (drug effects)
• Butyrates (therapeutic use)
• Cholesterol, HDL (blood)
• Dyslipidemias (drug therapy, metabolism)
• Hypolipidemic Agents (pharmacology)
• Insulin (blood)
• Insulin Resistance (physiology)
• Liver Function Tests
• Macaca mulatta
• Male
• Oxazoles (therapeutic use)
• PPAR alpha (agonists)
• PPAR gamma (agonists)
• Prediabetic State (metabolism)
• Treatment Outcome