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Proinflammatory Cytokines, Insulin Resistance, and Insulin Secretion in Chronic Hepatitis C patients

A case-control study

¹ Diabetes Research Unit, Endocrinology Division, Institut de Recerca, Hospital Univeritari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
² Liver Unit, Institut de Recerca, Hospital Univeritari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

Address correspondence and reprint requests to Dr. Rafael Simó, Diabetes Research Unit. Endocrinology Division, Hospital Universitari Vall d’Hebron, Pg. Vall d’Hebron 119-129, 08035 Barcelona, Spain. E-mail: rsimo{at}ir.vhebron.net

OBJECTIVE—The purpose of this study was to explore the initial pathogenic mechanisms of diabetes associated with hepatitis C virus (HCV) infection.

RESEARCH DESIGN AND METHODS—Insulin resistance, proinflammatory cytokines, and ß-cell function were evaluated in a case-control study. A total of 28 consecutive nondiabetic patients with chronic hepatitis C were included in the study (anti-HCV⁺). Fourteen patients with chronic hepatitis other than HCV infection served as the control group (anti-HCV^–). Both groups were closely matched by the main clinical variables associated with insulin resistance and the degree of liver fibrosis. In addition, there were no differences between groups regarding hepatic insulin extraction measured by calculating the ratio between C-peptide and insulin. Serum levels of proinflammatory cytokines (tumor necrosis factor [TNF]-, soluble TNF receptor [sTNFR] 1, soluble TNFR2, and interleukin-6) were measured by enzyme-linked immunosorbent assay. Insulin resistance (homeostasis model assessment [HOMA] of insulin resistance [HOMA-IR]) and insulin secretion at baseline (HOMA-ß) and after various stimulus (oral glucose tolerance test, standard food intake, and intravenous glucagon) were determined by previously validated mathematic indexes.

RESULTS—HOMA-IR was higher in anti-HCV⁺ than in anti-HCV^– patients (4.35 ± 2.27 vs. 2.58 ± 1.74; P = 0.01). All the proinflammatory cytokines analyzed were significantly higher in anti-HCV⁺ patients than in anti-HCV^– patients. In addition, sTNFR1 and sTNFR2 were directly correlated to HOMA-IR. HOMA-ß as well as insulin and C-peptide responses after the intravenous glucagon test were significantly higher in anti-HCV⁺ patients than in anti-HC^– patients.

CONCLUSIONS—Insulin resistance mediated by proinflammatory cytokines, but not a deficit in insulin secretion, could be the primary pathogenic mechanism involved in the development of diabetes associated with HCV infection.

Abbreviations: AUC, area under the curve • HCV, hepatitis C virus • HOMA, homeostasis model assessment • HOMA-IR, HOMA of insulin resistance • IL, interleukin • OGTT, oral glucose tolerance test • TNF, tumor necrosis factor • sTNFR, soluble TNF receptor

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