Department of Pathology, Wake Forest University, Winston-Salem, North Carolina 27157, USA.
J Pharmacol Exp Ther. 2010 Jun;333(3):844-53. doi: 10.1124/jpet.110.166736. Epub 2010 Feb 26.
Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid and glucose metabolism. PPARgamma agonists improve insulin sensitivity and hyperglycemia and are effective in treating type 2 diabetes mellitus (T2DM), whereas PPARalpha agonists are used to treat dyslipidemia and atherosclerosis. The goal here was to examine the efficacy of a selective PPARalpha agonist {(S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP-900691} on lipid, glycemic, and inflammation indices in 14 cynomolgus monkeys 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. CP-900691 treatment increased plasma high-density lipoprotein cholesterol (HDLC) (33 +/- 3 to 60 +/- 4 mg/dL, p < 0.001) and apolipoprotein A1 (96 +/- 5 to 157 +/- 5 mg/dL, p < 0.001), reduced plasma triglycerides (547 +/- 102 to 356 +/- 90 mg/dL, p < 0.01), and apolipoprotein B (62 +/- 3 to 45 +/- 3 mg/dL, p < 0.01), improved the lipoprotein index (HDL to non-HDLC ratio; 0.28 +/- 0.06 to 0.79 +/- 0.16, p < 0.001), decreased body weight (p < 0.01) and C-reactive protein (CRP) (1700 +/- 382 to 304 +/- 102 ng/ml, p < 0.01), and increased adiponectin (1697 +/- 542 to 4242 +/- 1070 ng/ml, p < 0.001) compared with baseline. CP-900691 treatment reduced exogenous insulin requirements by approximately 25% (p < 0.04) while lowering plasma fructosamine from 2.87 +/- 0.09 to 2.22 +/- 0.17 mM (p < 0.05), indicative of improved glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in glycemic control, body weight, and CRP, suggest that CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations.
过氧化物酶体增殖物激活受体 (PPARs) 参与脂质和葡萄糖代谢的调节。PPARγ激动剂改善胰岛素敏感性和高血糖，对 2 型糖尿病 (T2DM) 有效，而 PPARα激动剂用于治疗血脂异常和动脉粥样硬化。本研究旨在研究选择性 PPARα激动剂 {(S)-3-[3-(1-羧基-1-甲基-乙氧基)-苯基]-哌啶-1-羧酸 4-三氟甲基-苄酯; CP-900691} 在 14 只接受每日胰岛素治疗的自发性 T2DM 恒河猴中对脂质、血糖和炎症指标的影响。猴子每日口服给予载体 (n = 7) 或 CP-900691 (3 mg/kg，n = 7) 治疗 6 周。CP-900691 治疗增加了血浆高密度脂蛋白胆固醇 (HDLC) (33 +/- 3 至 60 +/- 4 mg/dL，p < 0.001) 和载脂蛋白 A1 (96 +/- 5 至 157 +/- 5 mg/dL，p < 0.001)，降低了血浆甘油三酯 (547 +/- 102 至 356 +/- 90 mg/dL，p < 0.01) 和载脂蛋白 B (62 +/- 3 至 45 +/- 3 mg/dL，p < 0.01)，改善了脂蛋白指数 (HDL 与非-HDLC 比值; 0.28 +/- 0.06 至 0.79 +/- 0.16，p < 0.001)，降低了体重 (p < 0.01) 和 C 反应蛋白 (CRP) (1700 +/- 382 至 304 +/- 102 ng/ml，p < 0.01)，并增加了脂联素 (1697 +/- 542 至 4242 +/- 1070 ng/ml，p < 0.001) 与基线相比。CP-900691 治疗使外源性胰岛素需求减少约 25% (p < 0.04)，同时使血浆果糖胺从 2.87 +/- 0.09 降至 2.22 +/- 0.17 mM (p < 0.05)，表明血糖控制得到改善。载体组的上述任何参数均无变化。由于低 HDLC 和高甘油三酯是心血管疾病的公认危险因素，这些参数以及血糖控制、体重和 CRP 的显著改善表明 CP-900691 可能有益于糖尿病、肥胖或高脂血症患者。
