Molecular mechanisms of insulin resistance in obesity-induced IRS-1 heterozygous knockout mice.

IRS-1是胰岛素受体的主要底物之一。IRS-1基因多态性已在2型糖尿病患者中以杂合方式被发现，并且一些突变的IRS-1在体外表现出胰岛素信号受损。然而，目前尚不清楚IRS-1多态性如何促进人类2型糖尿病的发展，因为杂合子IRS-1敲除（IRS-1 +/-）小鼠未显示异常。在这项研究中，我们通过给药金硫葡萄糖（GTG）制造肥胖的IRS-1 +/-小鼠，研究IRS-1表达降低对肥胖相关胰岛素抵抗的影响。在IRS-1 +/-小鼠以及野生型（WT）小鼠中给予GTG，与注射盐水的对照组相比，体重增加了约30%。肥胖的IRS-1+/-和肥胖的WT均显示空腹胰岛素水平高于瘦对照组，空腹血糖无显著差异。肥胖者IRS-1+/-胰岛素水平比肥胖者WT高1.5倍（p<0.05）。在葡萄糖负荷下，肥胖组的血糖水平明显高于瘦对照组，肥胖IRS-1 +/-组的血糖水平明显高于肥胖WT组。肥胖的IRS-1 +/-与肥胖的WT相比，表现出严重的胰岛素抵抗。肥胖的IRS-1 +/-小鼠的胰岛大小约为肥胖WT的1.4倍。与肥胖的WT相比，肥胖的IRS-1 +/-显示肝脏胰岛素受体和肌肉IRS-1的表达减少，这可以部分解释肥胖的IRS-1 +/-存在严重的胰岛素抵抗。这些结果支持了IRS- 1基因是2型糖尿病的可疑基因的观点，其在人类中的多态性可能会在肥胖等其他因素存在的情况下加重胰岛素抵抗。

IRS-1 is one of the major substrates for insulin receptor. IRS-1 gene polymorphisms have been identified m type 2 diabetes patients in a heterozygous manner, and some mutant IRS-1 show impaired insulin signal in vitro. However, it is unclear how the IRS-1 polymorphisms contribute to the development of type 2 diabetes in human, since the heterozygous IRS-1 knockout (IRS-1 +/-) mice showed no abnormality. In this study, we created obese IRS-1 +/- mice by administration of gold-thioglucose (GTG) and studied the impact of reduced IRS-1 expression in obesity-linked insulin resistance. GTG administration in IRS-1 +/- mice as well as in wild type (WT) mice, acieved 〜30 % body weight gain from their saline-injected controls. Both obese IRS-1+/- and obese WT revealed elevated fasting insulin levels compared to their lean controls with no significant difference in fasting glucose. The insulin level in obese IRS-1+/- was 1.5-fold higher than that in obese WT (p<0.05). The blood glucose levels upon glucose load were significantly elevated in obese groups when compared with their lean controls, and which were significantly higher in obese IRS-1 +/- than in obese WT. In insulin tolerance test, obese IRS-1 +/- revealed profound insulin resistance compared to obese WT. The size in islets of obese IRS-1 +/- mice were about 1.4-fold larger than that in obese WT. Obese IRS-1 +/- showed a decrease in expression of insulin receptor in the liver and IRS-1 in the muscle compared from obese WT mice, which could in part explain profound insulin resistance in obese IRS-1 +/-. These results support the idea that IRS- 1 gene is the suspectable gene for type 2 diabetes and its polymorphisms in human could worsen insulin resistance in the presence of additional factors, such as obesity.