丙肝病毒与糖尿病：病毒直接引起胰岛素抵抗

流行病学研究提示，2型糖尿病与慢性丙肝病毒（HCV）感染之间具有相关性。但是，肥胖、高龄、肝硬化等其它因素使得人们无法建立这两种疾病之间的确切关系。东京大学医学研究院的Kazuhiko Koike博士及其同事应用HCV核心基因转基因小鼠模型对此进行了深入的研究。

葡萄糖耐量实验显示，虽然不具有统计学意义，但核心基因转基因小鼠在包括空腹状态在内的全部时间点的血浆葡萄糖水平均高于对照小鼠。与此相反，胰岛素耐量实验发现，转基因小鼠出现明显的胰岛素抵抗，基础血清胰岛素水平显著升高。采用高脂食物喂养时，转基因小鼠发生显性糖尿病，但对照小鼠未发生显性糖尿病。与人类慢性丙肝患者一样，转基因小鼠的肿瘤坏死因子-α水平升高，它可能通过阻碍胰岛素受体底物-1的酪氨酸磷酸化，成为转基因小鼠发生胰岛素抵抗的原因之一。此外，给予抗肿瘤坏死因子α抗体能够恢复胰岛素敏感性。

Koike博士等认为，与慢性丙肝患者相同，HCV转基因小鼠体内胰岛素降低血浆葡萄糖水平的能力受损。这些结果为HCV引起HCV感染患者的胰岛素抵抗、最终导致2型糖尿病的理论提供了直接的实验依据。

Gastroenterology. 2004 Mar;126(3):840-8.

Hepatitis C virus infection and diabetes: Direct involvement of the virus in the development of insulin resistance.

Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, Moriya K, Koike K.

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.

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