Hepatitis C virus infection and diabetes: Direct involvement of the virus in the development of insulin resistance
Hepatitis C virus infection and diabetes: Direct involvement of the virus in the development of insulin resistance
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DOI：
10.1053/j.gastro.2003.11.056
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发表时间：
2004-03-01
期刊：
影响因子：
29.4
通讯作者：
Koike, K
中科院分区：
文献类型：
--
作者：
Shintani, Y;Fujie, H;Koike, K
背景与目的：流行病学研究表明，2型糖尿病与慢性丙型肝炎病毒感染之间存在关联。然而，肥胖、衰老或肝硬变等其他因素的存在阻碍了在这两种情况之间建立明确的关系。方法：采用丙型肝炎病毒核心基因转基因小鼠模型。结果：在糖耐量试验中，核心基因转基因小鼠的血糖水平在包括空腹状态在内的所有时间点均高于对照组，但差异无统计学意义。相比之下，胰岛素耐量试验显示，转基因小鼠表现出显著的胰岛素抵抗，以及显著更高的基础血清胰岛素水平。在转基因小鼠中，喂食高脂肪食物会导致显性糖尿病的发生，但在对照组小鼠中则不会。高度的肿瘤坏死。在人类慢性丙型肝炎患者中也观察到了α因子，它被认为是转基因小鼠胰岛素抵抗的基础之一，它通过干扰胰岛素受体底物1的酪氨酸磷酸化来发挥作用。此外，注射抗肿瘤坏死因子-α抗体可恢复胰岛素敏感性。结论：与慢性丙型肝炎患者一样，转基因丙型肝炎小鼠胰岛素降低血糖水平的能力受到损害。这些结果为丙型肝炎病毒在人丙型肝炎病毒感染的胰岛素抵抗发展中的作用提供了直接的实验证据，最终导致2型糖尿病的发生。
Background & Aims: Epidemiological studies have suggested a linkage between type 2 diabetes and chronic hepatitis C virus (HCV) infection. However, the presence of additional factors such as obesity, aging, or cirrhosis prevents the establishment of a definite relationship between these 2 conditions. Methods: A mouse model transgenic for the HCV core gene was used. Results: In the glucose tolerance test, plasma glucose levels were higher at all time points including in the fasting state in the core gene transgenic mice than in control mice, although the difference was not statistically significant. In contrast, the transgenic mice exhibited a marked insulin resistance as revealed by the insulin tolerance test, as well as significantly higher basal serum insulin levels. Feeding with a high-fat diet led to the development of overt diabetes in the transgenic mice but not in control mice. A high level of tumor necrosis. factor-alpha, which has been also observed in human chronic hepatitis C patients, was considered to be one of the bases of insulin resistance in the transgenic mice, which acts by disturbing tyrosine phosphorylation of insulin receptor substrate-1. Moreover, administration of an anti-tumor necrosis factor-alpha antibody restored insulin sensitivity. Conclusions: The ability of insulin to lower the plasma glucose level in the HCV transgenic mice was impaired, as observed in chronic hepatitis C patients. These results provide a direct experimental evidence for the contribution of HCV in the development of insulin resistance in human HCV infection, which finally leads to the development of type 2 diabetes.