Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C.
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 x minute(-1) x kg(-1)) coupled with infusion of tracers ([6,6-(2)H(2)]glucose, [(2)H(5)]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.


CONCLUSIONS
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.
Vanni
Ester
E
Division of Gastro-Hepatology, San Giovanni Battista Hospital, University of Turin, Turin, Italy.
Abate
Maria Lorena
ML
Gentilcore
Elena
E
Hickman
Ingrid
I
Gambino
Roberto
R
Cassader
Maurizio
M
Smedile
Antonina
A
Ferrannini
Ele
E
Rizzetto
Mario
M
Marchesini
Giulio
G
Gastaldelli
Amalia
A
Bugianesi
Elisabetta
E
D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D005260:Female; D015309:Glucose Clamp Technique; D019698:Hepatitis C, Chronic / Q000503:physiopathology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D020382:Interleukin-18 / Q000096:biosynthesis; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D007328:Insulin; D020382:Interleukin-18; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha