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Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance

Lookup NU author(s): Professor Mike TrenellORCiD


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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.

Publication metadata

Author(s): Milner KL, van der Poorten D, Trenell MI, Jenkins AB, Xu A, Smythe G, Dore G, Zekry A, Weltman M, Fragomeli V, George J, Chisholm DJ

Publication type: Article

Publication status: Published

Journal: Gastroenterology

Year: 2010

Volume: 138

Issue: 3

Pages: 932-41

Print publication date: 01/03/2010

ISSN (print): 0016-5085

ISSN (electronic): 1528-0012

Publisher: W.B. Saunders Co.


DOI: 10.1053/j.gastro.2009.11.050


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