C型肝炎病毒E2蛋白對於胰島素作用相關分子的影響

C型肝炎病毒感染發病的過程可從初期的急性感染時期漸漸演變成較嚴重的肝臟疾病，長期的慢性感染甚至會演變成肝硬化或肝癌的形成。臨床上發現，C型肝炎往往併發一些非肝臟性的症狀，其中第二型糖尿病就是常見的一種。研究顯示胰島素阻抗是第二型糖尿病最主要的致病原因，而目前無論在流行病學研究或胰島素相關分子機制層面研究皆有強烈的證據顯示C型肝炎病毒感染和胰島素阻抗有高度相關性。C型肝炎病毒E2蛋白在病毒的感染過程中扮演重要的角色，與第二型糖尿病的致病機制卻尚未被研究，因此此研究希望探討E2蛋白是否有導致胰島素阻抗的能力，更進一步的探討E2蛋白對於胰島素訊息傳遞路徑相關分子的影響。經由RT-RCR、Real-time PCR以及western blot等分析方式，我們發現當E2蛋白在Huh-7肝癌細胞表現時並不會影響胰島素訊息傳遞路徑上游因子IR和IRS-1的mRNA和蛋白質的表現量；接著再搭配胰島素處理並利用western blot分析，發現E2蛋白卻會抑制胰島素誘導的Akt/PKB Ser473磷酸化和GSK3beta Ser9磷酸化，因此我們推測E2蛋白可能會藉由某些路徑間接抑制葡萄糖的吸收和肝醣的合成，最終導致胰島素阻抗而促使第二型糖尿病的發生。

關鍵字

C型肝炎病毒；套膜蛋白；胰島素阻抗；第二型糖尿病

並列摘要

Hepatitis C virus (HCV) infection may cause liver diseases of various severities ranging from primary acute infection to life-threatening diseases. Long-term chronic infection even leads to cirrhosis or hepatocellular carcinoma (HCC) with poor prognosis. According to clinical finding, HCV infection may also cause some extra-hepatic symptoms, including type 2 diabetes mellitus (DM). Since insulin resistance is the major etiology for type 2 diabetes mellitus and there are numerous evidences showed that HCV infection may be highly associated with insulin resistance, the involvement of E2 in the pathogenesis of type 2 DM and underlying mechanisms of insulin signaling pathway was investigated in this study. Results showed that without any influence on mRNA and protein levels of IR and IRS-1, the expression of E2 protein in Huh-7 could impair insulin-induced Ser473 phosphorylation of Akt/PKB and Ser9 phosphorylation of GSK3beta which may inhibit glucose uptake and glycogen synthesis, respectively, to lead to insulin resistance. Therefore, E2 may indeed involve in the pathogenesis of type 2 DM by inducing insulin resistance.

並列關鍵字

HCV ； E2 ； insulin resistance ； type 2 diabetes mellitus

參考文獻

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Aytug S, Reich D, Sapiro LE, Bernstein D, Begum N. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology. 2003; 38: 1384-1392.

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C型肝炎病毒E2蛋白對於胰島素作用相關分子的影響

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