Gastroenterology

Gastroenterology

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

Clinical—Liver, Pancreas, and Biliary Tract
Chronic Hepatitis C Is Associated With Peripheral Rather Than Hepatic Insulin Resistance

https://doi.org/10.1053/j.gastro.2009.11.050Get rights and content

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.

Section snippets

Materials and Methods

See additional information regarding methods in the Supplementary Materials and Methods.

Baseline Characteristics of Subjects

CHC subjects (n = 29) and controls (n = 15) were selected to be matched for age, weight, BMI, and were similar for abdominal fat (visceral and subcutaneous fat). There was a higher frequency of smokers and methadone users in CHC subjects (Table 1). Among CHC subjects, methadone users and smokers, compared to nonusers, had similar baseline characteristics except for higher waist-to-hip ratios (P = .04) in methadone users and higher highly sensitive C-reactive protein (P = .02) and low-density

Discussion

This study demonstrates that nonobese male subjects with CHC and mild liver disease had significant IR compared to healthy controls of similar age, BMI, and physical activity and that this IR is principally in the periphery, contrasting with previous suggestions of impaired hepatic insulin action,33 although there may be a small contribution from the liver. This observation is supported by the decreased insulin stimulated glucose disposal at high insulin dose clamp (when endogenous glucose

Acknowledgments

Drs George and Chisholm contributed equally to this work and are joint senior authors.

Clinical trials registry no: NCT00707603.

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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.

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