Russell J C, Ravel D, Pégorier J P, Delrat P, Jochemsen R, O'Brien S F, Kelly S E, Davidge S T, Brindley D N
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
J Pharmacol Exp Ther. 2000 Nov;295(2):753-60.
S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P <.05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.
S15261是一种开发用于口服治疗II型糖尿病的化合物，它被酯酶裂解为片段Y415和S15511。目的是确定S15261、裂解产物、曲格列酮和二甲双胍在JCR:LA-cp大鼠（一种肥胖/胰岛素抵抗综合征动物模型，表现出相关的血管病变和心血管疾病）中的胰岛素增敏作用。用S15261或S15511对8至12周龄的动物进行治疗导致食物摄入量和体重下降，而Y415没有作用。曲格列酮使食物摄入量略有增加（P<0.05）。用S15261或S15511治疗可降低喂食大鼠的血浆胰岛素水平，并在进餐耐量试验中防止餐后胰岛素水平峰值出现。Y415对胰岛素水平没有影响。曲格列酮使对试验餐的胰岛素反应减半，但二甲双胍没有改善作用。S15261降低了磷酸烯醇式丙酮酸羧激酶和葡萄糖-6-磷酸酶的表达，并刺激了乙酰辅酶A羧化酶和酰基辅酶A合酶的表达。S15261还降低了肉碱棕榈酰转移酶I和羟甲基戊二酰辅酶A合酶的表达。S15261而非曲格列酮降低了肠系膜阻力血管对去甲肾上腺素的过度收缩反应，并增加了最大一氧化氮介导的舒张作用。S15261通过S15511增加胰岛素敏感性、降低胰岛素水平并减轻JCR:LA-cp大鼠的血管病变。因此，S15261可能为胰岛素抵抗综合征及其相关血管并发症提供有效的治疗方法。
