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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
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2006: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
KeywordsHepatitis C virus / Insulin resistance / HOMA-IR / HCV core / Interferon / Intracellular insulin signaling / Insulin receptor substrate / HepG2 cell / insulin receptor substrate / ウイルス駆除 / トランスジェニックマウス / 免疫染色 / C型慢性肝炎 / 2型糖尿病 / ケース・コホート研究 / C型肝炎ウイルス高感染地区 / 一般住民 / C型肝炎ウイルスコア抗原 / SOCS-3 / インスリンシグナル伝達分子
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.

Report

(4 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (51 results)

All 2007 2006 2005 2004

All Journal Article (46 results) Book (5 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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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 Gatrol. 102・3

      Pages: 570-576

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Insulin resistance and lichen planus in patients with HCV-infectious liver diseases.2007

    • Author(s)
      Nagao Y.
    • Journal Title

      J Gastroenterol Hepatol (in press)

    • Related Report
      2006 Annual Research Report
  • [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

    • NAID

      130000097829

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [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

    • NAID

      130000097829

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

    • Author(s)
      Taniguchi E
    • Journal Title

      Gastroenterology 130・2

      Pages: 521-531

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Pro-inflammatory signaling by Jun-N-terminal kinase in inflammatory bowel disease.2006

    • Author(s)
      Mitsuyama K
    • Journal Title

      Int J Mol Med 17・3

      Pages: 449-455

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Increased circulating concentrations of growth-related oncogene (GRO)-alpha in patients with inflammatory bowel disease.2006

    • Author(s)
      Mitsuyama K
    • Journal Title

      Dig Dis Sci. 51・1

      Pages: 173-177

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A form of circulating interleukin-6 receptor component soluble gp130 as a potential interleukin-6 inhibitor in inflammatory bowel disease.2006

    • Author(s)
      Mitsuyama K
    • Journal Title

      Clin Exp Immunol 143・1

      Pages: 125-131

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Activation of c-Jun N-terminal kinase (JNK) signalling in experimentally induced gastric lesions in rats.2006

    • Author(s)
      Mitsuyama K
    • Journal Title

      Clin Exp Immunol. 143・1

      Pages: 24-29

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Timing of interferon therapy and sources of infection in patients with acute hepatitis C.2006

    • Author(s)
      Ogata K
    • Journal Title

      Hepatol Res. 34・1

      Pages: 35-40

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Attenuation of experimental colonic injury by thiazolidinedione agents2006

    • Author(s)
      Takaki K
    • Journal Title

      Inflamm Res 55・1

      Pages: 10-15

    • Related Report
      2005 Annual Research Report
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Demonstration of reversed flow in segmental branches of the portal vein with hand-held color Doppler ultrasonography after hematopoietic stem cell transplantation.2005

    • Author(s)
      Hashiguchi M
    • Journal Title

      Bone Marrow Transplant. 36・12

      Pages: 1071-1075

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Bifidogenic growth stimulator for the treatment of active ulcerative colitis : a pilot study2005

    • Author(s)
      Suzuki A
    • Journal Title

      Nutrition 22・1

      Pages: 76-81

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification of hepatitis C virus 1b-derived peptides recognized by both cellular and humoral immune systems in HCV1b(+) HLA-A24(+) patients.2005

    • Author(s)
      Tamura M
    • Journal Title

      Hepatol Res 32・4

      Pages: 227-234

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Determination of thrombopoietin-derived peptides recognized by both cellular and humoral immunities in healthy donors and patients with thrombocytopenia.2005

    • Author(s)
      Takedatsu H
    • Journal Title

      Stem Cells. 23・7

      Pages: 975-982

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Extrahepatic manifestations and insulin resistance in an HCV hyperendemic area.2005

    • Author(s)
      Nagao Y
    • Journal Title

      Int J Mol Med. 16・2

      Pages: 291-296

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Clinical course of patients with chronic hepatitis B with viral breakthrough during long-term lamivudine treatment.2005

    • Author(s)
      Ide T
    • Journal Title

      J Gastroenterol 40・6

      Pages: 625-630

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Diminished cytokine signalling against bacterial components in mononuclear leucocytes from ulcerative colitis patients after leukocytapheresis.2005

    • Author(s)
      Mitsuyama K
    • Journal Title

      Clin Exp Immunol. 41・1

      Pages: 130-140

    • Related Report
      2005 Annual Research Report
  • [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・1

      Pages: 109-114

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Immunological evaluation of vaccination of peptides derived from epithelial cancer-related antigens in two patients with hematological malignancy.2005

    • Author(s)
      Takedatsu H
    • Journal Title

      Int J Oncol. 26・6

      Pages: 1605-1612

    • Related Report
      2005 Annual Research Report
  • [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・2

      Pages: 471-482

    • Related Report
      2005 Annual Research Report
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Hepatitis C virus down-regulates insulin receptor substrate 1 and 2 through up-regulation of suppressor of cytokine signaling 3.2004

    • Author(s)
      Kawaguchi T
    • Journal Title

      Am J Pathol 165・5

      Pages: 1499-1508

    • Related Report
      2004 Annual Research Report
  • [Book] 患者さんの質問に答える慢性肝疾患診療2006

    • Author(s)
      佐田通夫
    • Total Pages
      193
    • Publisher
      南山堂
    • Related Report
      2006 Annual Research Report
  • [Book] C型肝炎患者が専門医に聞く88の質問2006

    • Author(s)
      長尾由実子
    • Total Pages
      129
    • Publisher
      新興医学出版社
    • Related Report
      2006 Annual Research Report
  • [Book] C型肝炎はなぜ恐いのか2006

    • Author(s)
      佐田通夫
    • Total Pages
      159
    • Publisher
      五絃舎
    • Related Report
      2006 Annual Research Report
  • [Book] NASH and Nutritional Therapy2005

    • Author(s)
      Ueno T
    • Total Pages
      114
    • Publisher
      Springer-Verlag
    • Related Report
      2005 Annual Research Report
  • [Book] 臨床消化器病学2005

    • Author(s)
      長尾由実子
    • Total Pages
      654
    • Publisher
      朝倉書店
    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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