Effects of S 15511, a therapeutic metabolite of the insulin-sensitizing agent S 15261, in the Zucker Diabetic Fatty rat
Effects of S 15511, a therapeutic metabolite of the insulin-sensitizing agent S 15261, in the Zucker Diabetic Fatty rat
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DOI：
10.1111/j.1463-1326.2006.00586.x
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发表时间：
2007-01-01
影响因子：
5.8
通讯作者：
Wilding, J. P. H.
中科院分区：
文献类型：
--
作者：
Pickavance, L. C.;Wilding, J. P. H.
目的：S15261是一种新型口服降糖药，具有促胰岛素分泌和胰岛素增敏作用。该研究旨在确定其两个主要代谢产物S 15511和Y 415的生物活性，以及它们是否具有累加效应。Zucker糖尿病肥胖大鼠用S 15511处理28天（10 mg/kg）、Y 415（10 mg/kg）或相同剂量的组合持续4周的时间，从6-7周龄开始。结果：单独使用S15511和与Y 415联合使用S15511可减少能量摄入和体重增加（与对照组相比为-13%，p均< 0.01）。通过S15511、S15511 + Y 415和配对喂养（p <0.01），在整个治疗期间维持基线空腹血糖水平（p <0.01）。基线胰岛素仅通过配对喂养维持，而所有其他治疗组变为高胰岛素血症（+110-276%; p < 0.05）。胰岛素敏感性的恶化[稳态模型评估（HOMA）-IR：+239%; p < 0.01]被S15511、S15511 + Y 415和配对喂养减弱（p < 0.01），并被改善的胰岛素分泌补偿（HOMA-β; p < 0.01）。在第0、14和28天进行的口服葡萄糖耐量试验显示，所有组都有受损的胰岛素反应，但到第28天，与未处理对照组的进行性恶化相比，S15511、S15511 + Y 415和成对喂养改善了葡萄糖处置结论：在2型糖尿病的遗传模型中用这些药剂治疗揭示，与赋形剂治疗的对照的进行性恶化相比，它们都具有瞬时效应。然而，观察到S 15511对葡萄糖代谢的改善是显著的，这表明它比S 15261的Y 415代谢产物具有更高的治疗活性。它与糖尿病进展频率较低相关;即Y 415单独发挥非显著作用，与S 15511联合使用时无显著叠加作用。S 15511的作用机制可能是通过增加胰岛素敏感性和保持β细胞反应至第21天。因此，之前报道的胰岛素促分泌作用可能归因于母体化合物。
Aim: S 15261 is a novel oral antihyperglycaemic drug with both insulin secretagogue and insulin-sensitizing effects. The study was designed to determine the biological activity of its two major metabolites, S 15511 and Y 415, and whether or not they have an additive effect.Methods: Zucker Diabetic Fatty rats were treated for 28 days with S 15511 (10 mg/kg), Y 415 (10 mg/kg), or a combination at the same doses for a period of 4 weeks starting at 6-7 weeks of age. An additional group was pair-fed to the level of S 15511-treated animals to determine if possible effects were due to reduced food intake.Results: S 15511 alone and combined with Y 415 reduced energy intake and weight gain (-13% vs. controls; both p < 0.01). Baseline fasting plasma glucose levels were maintained by S 15511, S 15511 + Y 415 and pair-feeding (p < 0.01) for the entire treatment period (p < 0.01). Baseline insulin was maintained by pair-feeding only, whereas all other treated groups became hyperinsulinaemic (+110-276%; p < 0.05). Deterioration in insulin sensitivity [homeostasis model assessment (HOMA)-IR: + 239%; p < 0.01] was attenuated by S 15511, S 15511 + Y 415 and pair-feeding (p < 0.01) and was compensated for by improved insulin secretion (HOMA-beta; p < 0.01). Oral glucose tolerance tests, performed on days 0, 14 and 28, showed that all groups had an impaired insulin response, but by day 28, S 15511, S 15511 + Y 415 and pair-feeding had improved glucose disposal compared to the progressive deterioration in untreated controls (-44% to -48% vs. controls; p < 0.01), associated with progression to frank diabetes in these animals.Conclusion: Treatment with these agents in a genetic model of type 2 diabetes reveals that they all have a transient effect compared to the progressive worsening of vehicle-treated controls. The improvements in glucose metabolism observed with S 15511 are significant, however, suggesting it has more therapeutic activity than the Y 415 metabolite of S 15261. It is associated with less frequent progression to diabetes; i.e. Y 415 exerts a non-significant effect alone and no significant additive effect when combined with S 15511. The mechanism of action of S 15511 may be via increased insulin sensitivity and beta-cell response preservation up to day 21. Thus, previously reported insulin secretagogue effects are likely to be attributable to the parent compound.