Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160 062, India.
Biochem Biophys Res Commun. 2010 Jul 23;398(2):260-5. doi: 10.1016/j.bbrc.2010.06.070. Epub 2010 Jun 19.
Impairment in the insulin receptor signaling and insulin mediated effects are the key features of type 2 diabetes. Here we report that S961, a peptide insulin receptor antagonist induces hyperglycemia, hyperinsulinemia ( approximately 18-fold), glucose intolerance and impairment in the insulin mediated glucose disposal in the Sprague-Dawley rats. Further, long-term S961 treatment (15day, 10nM/kg/day) depletes energy storage as evident from decrease in the adiposity and hepatic glycogen content. However, peroxysome-proliferator-activated-receptor-gamma (PPARgamma) agonist pioglitazone significantly (P<0.001) restored S961 induced hyperglycemia (196.73+/-16.32 vs. 126.37+/-27.07 mg/dl) and glucose intolerance (approximately 78%). Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. Further, results of the present study reconfirms and provide direct evidence to the crucial role of insulin receptor signaling in the glucose homeostasis and fuel metabolism.
胰岛素受体信号转导和胰岛素介导的作用受损是 2 型糖尿病的主要特征。在这里，我们报告 S961，一种肽类胰岛素受体拮抗剂，可诱导高血糖、高胰岛素血症（约 18 倍）、葡萄糖耐量受损和胰岛素介导的葡萄糖处置受损在 Sprague-Dawley 大鼠中。此外，S961 的长期治疗（15 天，10nM/kg/天）会耗尽能量储存，这从脂肪减少和肝糖原含量的减少中可以明显看出。然而，过氧化物酶体增殖物激活受体-γ（PPARγ）激动剂吡格列酮可显著（P<0.001）恢复 S961 诱导的高血糖（196.73+/-16.32 对 126.37+/-27.07 mg/dl）和葡萄糖耐量受损（约 78%）。吡格列酮改善高血糖和葡萄糖耐量的作用清楚地表明，S961 处理的大鼠可成功用于筛选具有通过受体非依赖性机制改善葡萄糖处置潜力的新型治疗干预措施。此外，本研究的结果进一步证实并提供了直接证据，证明胰岛素受体信号转导在葡萄糖稳态和燃料代谢中起着至关重要的作用。
