A role for iNOS in fasting hyperglycemia and impaired insulin signaling in the liver of obese diabetic mice
A role for iNOS in fasting hyperglycemia and impaired insulin signaling in the liver of obese diabetic mice
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DOI：
10.2337/diabetes.54.5.1340
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发表时间：
2005-05-01
期刊：
影响因子：
7.7
通讯作者：
Kaneki, M
中科院分区：
文献类型：
--
作者：
Fujimoto, M;Shimizu, N;Kaneki, M
慢性炎症被认为在胰岛素抵抗的发病机制中起重要作用。诱导型一氧化氮合酶（iNOS）与许多与炎症相关的人类疾病有关。iNOS缺乏被证明可以预防骨骼肌中高脂肪饮食引起的胰岛素抵抗，但在肝脏中没有。然而，在肥胖相关糖尿病中，iNOS在空腹高血糖和肝脏胰岛素抵抗中的作用仍有待研究。为了解决这个问题，我们研究了一种特定的iNOS抑制剂L-NIL对肥胖糖尿病小鼠（ob/ob）的影响。与野生型小鼠相比，ob/ob小鼠肝脏iNOS表达增加。在ob/ob小鼠中，iNOS抑制剂治疗可逆转空腹高血糖，同时改善高胰岛素血症和胰岛素敏感性。iNOS抑制剂还使胰岛素受体底物(IRS)-1和-2的蛋白表达分别增加1.5倍和2倍，并增强IRS-1和IRS-2介导的肝脏胰岛素信号转导。暴露于NO供体和异位表达的iNOS可降低培养肝细胞中IRS-1和-2的蛋白表达。这些结果表明，iNOS在ob/ob小鼠的空腹高血糖中起作用，并有助于肝脏胰岛素抵抗。
Chronic inflammation has been postulated to play an important role in the pathogenesis of insulin resistance. Inducible nitric oxide synthase (iNOS) has been implicated in many human diseases associated with inflammation. iNOS deficiency was shown to prevent high-fat diet-induced insulin resistance in skeletal muscle but not in the liver. A role for iNOS in fasting hyperglycemia and hepatic insulin resistance, however, remains to be investigated in obesity-related diabetes. To address this issue, we examined the effects of a specific inhibitor for iNOS, L-NIL, in obese diabetic (ob/ob) mice. iNOS expression was increased in the liver of ob/ob mice compared with wild-type mice. Treatment with iNOS inhibitor reversed fasting hyperglycemia with concomitant amelioration of hyperinsulinemia and improved insulin sensitivity in ob/ob mice. iNOS inhibitor also increased the protein expression of insulin receptor substrate (IRS)-1 and -2 1.5- and 2-fold, respectively, and enhanced IRS-1- and IRS-2-mediated insulin signaling in the liver of ob/ob mice. Exposure to NO donor and ectopically expressed iNOS decreased the protein expression of IRS-1 and -2 in cultured hepatocytes. These results suggest that iNOS plays a role in fasting hyperglycemia and contributes to hepatic insulin resistance in ob/ob mice.