Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C #

• DOI: 10.1002/hep.23031
• Publication Date: 2009-04-19T15:12:12Z
• Authors: Ester Vanni; Maria Lorena Abate; Elena Gentilcore; Ingrid Hickman; Roberto Gambino; Maurizio Cassader; Antonina Smedile; Ele Ferrannini; Mario Rizzetto; Giulio Marchesini; Amalia Gastaldelli; Elisabetta Bugianesi
• Keywords: Adult; Male; 0301 basic medicine; 571; 920109 Infectious Diseases; Suppressor of Cytokine Signaling Proteins; 920106 Endocrine Organs and Diseases (excl. Diabetes); VIRUS-INFECTION; 970111 Expanding Knowledge in the Medical and Health Sciences; 110306 Endocrinology; 03 medical and health sciences; C1; Humans; Insulin; 920104 Diabetes; 111201 Cancer Cell Biology; RECEPTOR; ENDOGENOUS GLUCOSE-PRODUCTION; Tumor Necrosis Factor-alpha; Interleukin-18; NECROSIS-FACTOR-ALPHA; DIABETES-MELLITUS; GLUCONEOGENESIS; QUANTIFICATION; Hepatitis C, Chronic; Middle Aged; Lipid Metabolism; PREVALENCE; 3. Good health; MODEL; Diabetes Mellitus, Type 2; Suppressor of Cytokine Signaling 3 Protein; OBESITY; 970106 Expanding Knowledge in the Biological Sciences; Glucose Clamp Technique; Female; Insulin Resistance

Abstract Chronic hepatitis C (CHC) has been associated with type 2 diabetes and insulin resistance, but the extent of impairment in insulin action, the target pathways involved, and the role of the virus per se have not been defined. In this study, we performed a euglycemic hyperinsulinemic clamp (1 mU · minute−1 · kg−1) coupled with infusion of tracers ([6,6-2H2]glucose, [2H5]glycerol) and indirect calorimetry in 14 patients with biopsy-proven CHC, who were selected not to have any features of the metabolic syndrome, and in seven healthy controls. We also measured liver expression of inflammatory cytokines/mediators and tested their association with the metabolic parameters. Compared to controls, in patients with CHC: (1) total glucose disposal (TGD) during the clamp was 25% lower (P = 0.003) due to impaired glucose oxidation (P = 0.0002), (2) basal endogenous glucose production (EGP) was 20% higher (P = 0.011) and its suppression during the clamp was markedly reduced (P = 0.007), and (3) glycerol appearance was not different in the basal state or during the clamp, but lipid oxidation was less suppressed by insulin (P = 0.004). Lipid oxidation was higher in patients with CHC who had more steatosis and was directly related to EGP, TGD, and glucose oxidation. The decreased insulin-stimulated suppression of EGP was associated with increased hepatic suppressor of cytokine signaling 3 (SOCS3; P < 0.05) and interleukin-18 (P < 0.05) expression. Conclusion: Hepatitis C infection per se is associated with peripheral and hepatic insulin resistance. Substrate competition by increased lipid oxidation and possibly enhanced hepatic expression of inflammatory cytokines/mediators could be involved in the defective glucose regulation. (Hepatology 2009.)