2006 Fiscal Year Final Research Report Summary
MOLECULAR MECHANISMS FOR THE DEVELOPMENT OF HEPATITIS C VIRUS-RELATED INSULIN RESISTANCE
| Project/Area Number |
16590648
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Kurume University |
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Principal Investigator |
SATA Michio Kurume University School of Medicine, Department of Medicine, Professor, 医学部, 教授 (10162398)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAGUCHI Takumi Kurume University School of Medicine, Department of Digestive Disease Information & Research, Assistant, 医学部, 助手 (00320177)
YOSHIDA Takafumi Kurume University School of Medicine, Department of Medicine, Assistant, 医学部, 助手 (30368899)
HARADA Masaru Kurume University School of Medicine, Department of Medicine, Assistant Professor, 医学部, 講師 (00241175)
NAGAO Yumiko Kurume University School of Medicine, Department of Digestive Disease Information & Research, Associate Professor, 医学部, 助教授 (90227992)
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| Project Period (FY) |
2004 – 2006
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| Keywords | Hepatitis C virus / Insulin resistance / HOMA-IR / HCV core / Interferon / Intracellular insulin signaling / Insulin receptor substrate / HepG2 cell |
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| Research Abstract |
Insulin resistance is frequently seen in patients with liver disease. However, molecular mechanisms for the development of insulin resistance remain unclear. We examined changes in glucose metabolisms in patients with various hepatobiliary disorders and disclosed following 4 findings : 1) Insulin resistance (HOMA-IR) is significantly increased in patients with hepatitis C virus (HCV) infection compare to that in healthy controls or patients with other hepatobiliary disorders. 2) Insulin resistance (HOMA-IR) was decreased in patients showing sustained virological response to interferon therapy. 3) Insulin resistance was severer in patients with positive result of serum HCV core than those with negative result of serum HCV core. 4) The relative risk for the development of diabetes mellitus was 5.6 times higher in inhabitants with high levels of serum HCV core compare to those with low levels of serum HCV core. These findings indicate the involvement of HCV core in the development of insulin resistance in patients with HCV infection.
In order to investigate the molecular mechanisms for the development of insulin resistance, we transfected cDNA of HCV core into HepG2 cells and examined the changes in insulin signaling molecules. In gene-transfected HepG2 cells, insulin-induced phosphorylation of both PI3K and Akt, and glucose up-take were also impaired, suggesting that HepG2 cells showed insulin resistance. Insulin receptor substrate (IRS)1/2 was down-regulated in gene-transfected HepG2 cells. Furthermore, Similarly, down-regulation of IRS1/2 was seen in liver tissues from both HCV core transgenic mice and human liver. In conclusion, we found that insulin resistance was significantly increased in patients with HCV infection. HCV itself was involved in the development of insulin resistance and one of the its mechanisms is that HCV core down-regulates IRS 1/2, central molecules for intracellular insulin signaling.
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