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- Title
A Novel Selective PPARα Agonist, CP900691, Improves Plasma Lipids, Lipoproteins, Glycemic Control and Reduces Body Weight in Diabetic Monkeys.
- Authors
Flynn, Mickey; Shadoan, Melanie K.; Kavanagh, Kylie; Zhang, Li; Auerbach, Bruce J.; Harwood, H. J.; Wagner, Janice D.
- Abstract
Peroxisome proliferator activated receptors (PPARs) are involved in regulation of lipid and glucose metabolism. PPAR-γ agonists improve insulin sensitivity and hyperglycemia and are effective in treatment of type 2 diabetes mellitus (T2DM), whereas PPAR-α agonists are used to treat dyslipidemia and atherosclerosis. The PPAR-α agonist fenofibrate has been shown to increase plasma HDL cholesterol (HDL-C) concentrations, ameliorate hyperinsulinemia and lower plasma triglyceride (TG) and LDL cholesterol (LDL-C) in obese rhesus monkeys. Here we examine the efficacy of a selective PPAR-α agonist (CP-900691) on lipid and glycemic indices in fourteen cynomolgus macaques with spontaneous T2DM maintained on daily insulin therapy. Monkeys were dosed orally with either vehicle (n=7) or CP-900691 (3 mg/kg, n=7) daily for 6 weeks. Plasma collected at baseline and 2, 4, and 6 weeks of treatment was analyzed for lipid and glycemic endpoints. Six weeks of CP-900691 treatment significantly increased plasma HDL-C and apolipoprotein A-l, from 33±4 to 60±6 mg/dL (p<0.001) and from 96±8 to 157±7 mg/dL (p<0.001), respectively. CP-900691 also markedly reduced plasma TG (from 547±144 to 356±127 mg/dL, p<0.01) and decreased plasma LDL-C (p=0.07) and body weight (p<0.05) compared to baseline. Exogenous insulin requirements in the CP-900691 treated monkeys treatment were reduced (p<0.05) without changes in fasting glucose, and plasma fructosamine decreased from 2.87±0.13 to 2.22±0.25 µmol/L (p<0.05), indicative of improved glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Since low plasma HDL-C and high plasma TG are well-established risk factors for cardiovascular disease, the marked improvements observed here in those parameters, as well as in glycemic control and body weight, suggest that PPAR-α agonism may be of benefit in diabetic patients, as well as in obese or hyperlipidemic populations.
- Subjects
NUCLEAR receptors (Biochemistry); BLOOD lipids; BLOOD sugar; HIGH density lipoproteins; TYPE 2 diabetes; TRIGLYCERIDES; BLOOD plasma
- Publication
Diabetes, 2007, Vol 56, pA138
- ISSN
0012-1797
- Publication type
Article