Gastroenterology
Volume 138, Issue 3 , Pages 932-941.e3, March 2010

Chronic Hepatitis C Is Associated With Peripheral Rather Than Hepatic Insulin Resistance

  • Kerry–Lee Milner

      Affiliations

    • Garvan Institute for Medical Research, University of New South Wales, Sydney, Australia
    • ,
  • David van der Poorten

      Affiliations

    • Storr Liver Unit, Westmead Millenium Institute, University of Sydney, Sydney, Australia
    • ,
  • Michael Trenell

      Affiliations

    • Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
    • ,
  • Arthur B. Jenkins

      Affiliations

    • School of Health Sciences, University of Wollongong, Wollongong, Australia
    • ,
  • Aimin Xu

      Affiliations

    • Department of Medicine and Pharmacology and Research Center of Heart, Brain, Hormone and Healthy Ageing, University of Hong Kong, Hong Kong, China
    • ,
  • George Smythe

      Affiliations

    • Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, Australia
    • ,
  • Gregory J. Dore

      Affiliations

    • National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
    • ,
  • Amany Zekry

      Affiliations

    • St George Hospital Clinical School, University of New South Wales, Sydney, Australia
    • ,
  • Martin Weltman

      Affiliations

    • Department of Gastroenterology and Hepatology, Nepean Hospital and University of Sydney, Western Clinical School, Sydney, Australia
    • ,
  • Vincent Fragomeli

      Affiliations

    • Department of Gastroenterology and Hepatology, Nepean Hospital and University of Sydney, Western Clinical School, Sydney, Australia
    • ,
  • Jacob George

      Affiliations

    • Storr Liver Unit, Westmead Millenium Institute, University of Sydney, Sydney, Australia
    • ,
  • Donald J. Chisholm

      Affiliations

    • Garvan Institute for Medical Research, University of New South Wales, Sydney, Australia
    • Corresponding Author InformationReprint requests Address requests for reprints to: Donald Chisholm, MBBS, FRACP, Diabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. fax: (61) 2 9295 8201

Received 4 May 2009; accepted 20 November 2009. published online 07 December 2009.

Background & Aims

Chronic hepatitis C (CHC) is associated with insulin resistance (IR), liver steatosis (genotype 3), and increased diabetes risk. The site and mechanisms of IR are unclear.

Methods

We compared cross-sectionally 29 nonobese, normoglycemic males with CHC (genotypes 1 and 3) to 15 adiposity and age-matched controls using a 2-step hyperinsulinemic-euglycemic clamp with [6,6-2H2] glucose to assess insulin sensitivity in liver and peripheral tissues and 1H-magnetic resonance spectroscopy to evaluate liver and intramyocellular lipid. Insulin secretion was assessed after intravenous glucose.

Results

Insulin secretion was not impaired in CHC. Peripheral insulin sensitivity was 35% higher in controls vs CHC (P < .001) during high-dose (264.3 ± 25 [standard error] mU/L) insulin (P < .001); this was negatively associated with viral load (R2 = .12; P = .05) and subcutaneous fat (R2 = .41; P < .001). IR was similar in both genotypes despite 3-fold increased hepatic fat in genotype 3 (P < .001). Hepatic glucose production (P = .25) and nonesterified free fatty acid (P = .84) suppression with insulin were not different between CHC and controls inferring no adipocyte IR, and suggesting IR is mainly in muscle. In CHC, intramyocellular lipid was nonsignificantly increased but levels of glucagon (73.8 ± 3.6 vs 52.8 ± 3.1 ng/mL; P < .001), soluble tumor necrosis factor receptor 2 (3.1 ± 0.1 vs 2.3 ± 0.1 ng/mL; P < .001), and Lipocalin-2 (36.4 ± 2.9 vs 19.6 ± 1.6 ng/mL; P < .001) were elevated.

Conclusions

CHC represents a unique infective/inflammatory model of IR, which is predominantly in muscle, correlates with subcutaneous, not visceral, adiposity, and is independent of liver fat.

Keywords: Chronic Hepatitis C, Insulin Resistance, Hyperinsulinemic-Euglycemic Clamp, Liver Steatosis

Abbreviations used in this paper: AFABP, adipocyte fatty acid-binding protein, AUC, area under the curve, BMI, body mass index, CHC, chronic hepatitis C, HCV, hepatitis C virus, EGP, endogenous glucose production, HOMA-IR, homeostasis model assessment of insulin resistance, IL, interleukin, IR, insulin resistance, sTNFR2, soluble tumor necrosis factor receptor 2, TGD, total glucose disposal, TNF-α, tumor necrosis factor α

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 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by grants from the National Health and Medical Research Council of Australia (Grant 358398), GESA postgraduate medical research scholarship, Robert W. Storr Bequest to the University of Sydney, a University of Sydney Grant and Hong Kong Research Council CRF (HKU 2/07C to A.X.). K.M. is supported by a National Health and Medical Research Council Postgraduate scholarship. M.T. is supported by a Diabetes UK RD Lawrence Fellowship.

PII: S0016-5085(09)02102-7

doi:10.1053/j.gastro.2009.11.050

Gastroenterology
Volume 138, Issue 3 , Pages 932-941.e3, March 2010

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