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2006 Fiscal Year Final Research Report Summary

MOLECULAR MECHANISMS FOR THE DEVELOPMENT OF HEPATITIS C VIRUS-RELATED INSULIN RESISTANCE

Research Project

Project/Area Number 16590648
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionKurume University

Principal Investigator

SATA Michio  Kurume University School of Medicine, Department of Medicine, Professor, 医学部, 教授 (10162398)

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)
Project Period (FY) 2004 – 2006
KeywordsHepatitis C virus / Insulin resistance / HOMA-IR / HCV core / Interferon / Intracellular insulin signaling / Insulin receptor substrate / HepG2 cell
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.

  • Research Products

    (26 results)

All 2007 2006 2005 2004

All Journal Article (26 results)

  • [Journal Article] Clearance of HCV Improves Insulin Resistance, Beta-Cell Function, and Hepatic Expression of Insulin Receptor Substrate 1 and 2.2007

    • Author(s)
      Kawaguchi T.
    • Journal Title

      Am J Gastrol. (In press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Clearance of HCV Improves Insulin Resistance, Beta-Cell Function, and Hepatic Expression of Insulin Receptor Substrate 1 and 2.2007

    • Author(s)
      Kawaguchi T et al.
    • Journal Title

      Am J Gastroenterol. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Appearance-specific satiety increases appetite and quality of life in patients with metastatic liver tumor : a case report.2006

    • Author(s)
      Kawaguchi T.
    • Journal Title

      Kurume Med J. 53

      Pages: 41-46

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Branched-chain amino acid supplementation complements conventional treatment for spontaneous bacterial peritonitis.2006

    • Author(s)
      Taniguchi E.
    • Journal Title

      Dig Dis Sci. 51

      Pages: 1057-1060

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors.2006

    • Author(s)
      Yoshida T.
    • Journal Title

      Oncogene 25

      Pages: 6056-6066

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Antibody to hepatitis B core antigen is associated with the development of hepatocellular carcinoma in hepatitis C virus-infected persons : a 12-year prospective study.2006

    • Author(s)
      Tanaka K.
    • Journal Title

      Int J Mol Med. 17

      Pages: 827-832

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Endothelial progenitor cell transplantation improves the survival following liver injury in mice.2006

    • Author(s)
      Taniguchi E.
    • Journal Title

      Gastroenterology 130

      Pages: 521-531

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Appearance-specific satiety increases appetite and quality of life in patients with metastatic liver tumor : a case report.2006

    • Author(s)
      Kawaguchi T et al.
    • Journal Title

      Kurume Med J. 53

      Pages: 41-6

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Branched-chain amino acid supplementation complements conventional treatment for spontaneous bacterial peritonitis.2006

    • Author(s)
      Taniguchi E et al.
    • Journal Title

      Dig Dis Sci. 51

      Pages: 1057-60

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors.2006

    • Author(s)
      Yoshida T et al.
    • Journal Title

      Oncogene. 25

      Pages: 6056-66

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Antibody to hepatitis B core antigen is associated with the development of hepatocellular carcinoma in hepatitis C virus-infected persons : a 12-year prospective study.2006

    • Author(s)
      Tanaka K et al.
    • Journal Title

      Int J Mol Med. 17

      Pages: 827-32

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Endothelial progenitor cell transplantation improves the survival following liver injury in mice.2006

    • Author(s)
      Taniguchi E et al.
    • Journal Title

      Gastroenterology. 130

      Pages: 521-31

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Extrahepatic manifestations and insulin resistance in an HCV hyperendemic area.2005

    • Author(s)
      Nagao Y.
    • Journal Title

      Int J Mol Med. 16

      Pages: 291-296

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Causal relationship between hepatitis C virus core and the development of type 2 diabetes mellitus in a hepatitis C virus hyperendemic area : a pilot study.2005

    • Author(s)
      Kawaguchi T.
    • Journal Title

      Int J Mol Med. 16

      Pages: 109-114

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Keratin-containing inclusions affect cell morphology and distribution of cytosolic cellular components.2005

    • Author(s)
      Hanada S.
    • Journal Title

      Exp Cell Res. 304

      Pages: 471-482

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Cholestasis in a rat model of graft-versus-host disease is accompanied by alteration of the expression and distribution of tight-junction-associated proteins.2005

    • Author(s)
      Sasatomi K.
    • Journal Title

      Int J Mol Med. 15

      Pages: 431-436

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The Wilson disease protein ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein.2005

    • Author(s)
      Harada M.
    • Journal Title

      Am J Pathol. 166

      Pages: 499-510

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Exacerbation of oral erosive lichen planus by combination of interferon and ribavirin therapy for chronic hepatitis C.2005

    • Author(s)
      Nagao Y.
    • Journal Title

      Int J Mol Med. 15

      Pages: 237-241

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Extrahepatic manifestations and insulin resistance in an HCV hyperendemic area.2005

    • Author(s)
      Nagao Y et al.
    • Journal Title

      Int J Mol Med. 16

      Pages: 291-6

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Causal relationship between hepatitis C virus core and the development of type 2 diabetes mellitus in a hepatitis C virus hyperendemic area : a pilot study.2005

    • Author(s)
      Kawaguchi T et al.
    • Journal Title

      Int J Mol Med. 16

      Pages: 109-14

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Keratin-containing inclusions affect cell morphology and distribution of cytosolic cellular components.2005

    • Author(s)
      Hanada S et al.
    • Journal Title

      Exp Cell Res. 304

      Pages: 471-82

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Cholestasis in a rat model of graft-versus-host disease is accompanied by alteration of the expression and distribution of tight-junction-associated proteins.2005

    • Author(s)
      Sasatomi K et al.
    • Journal Title

      Int J Mol Med. 15

      Pages: 431-6

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The Wilson disease protein ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein.2005

    • Author(s)
      Harada M et al.
    • Journal Title

      Am J Pathol. 166

      Pages: 499-510

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Exacerbation of oral erosive lichen planus by combination of interferon and ribavirin therapy for chronic hepatitis C.2005

    • Author(s)
      Nagao Y et al.
    • Journal Title

      Int J Mol Med. 15

      Pages: 237-41

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3.2004

    • Author(s)
      Kawaguchi T
    • Journal Title

      Am J Pathol. 165

      Pages: 1499-1508

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3.2004

    • Author(s)
      Kawaguchi T et al.
    • Journal Title

      Am J Pathol. 165

      Pages: 1499-508

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2008-05-27  

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