Chronic hepatitis C virus (HCV) infection is associated with 50% incidence of insulin resistance (IR) that is fourfold higher than that in non-HCV population. IR impairs the outcome of antiviral treatment. The molecular mechanisms of IR in HCV are not entirely clear. Experimental and clinical data suggested that hepatitis C virus per se is diabetogenic. However, presence of HCV alone does not affect IR. It was proposed that IR is mediated by proinflammatory cytokines, mainly by TNF-alpha. TNF-alpha potentiates interferon-gamma-induced transcriptional activation of indoleamine 2,3-dioxygenase, the rate-limiting enzyme of tryptophan- (TRP-) kynurenine (KYN) metabolism. Upregulation of TRP-KYN metabolism was reported in HCV patients. KYN and some of its derivatives affect insulin signaling pathways. We hypothesized that upregulation of TRP-KYN metabolism might contribute to the development of IR in HCV. To check this suggestion, we evaluated serum concentrations of TRP and KYN and HOMA-IR and HOMA-beta in 60 chronic HCV patients considered for the treatment with IFN-alpha. KYN and TRP concentrations correlated with HOMA-IR and HOMA-beta scores. Our data suggest the involvement of KYN and its metabolites in the development of IR in HCV patients. TRP-KYN metabolism might be a new target for prevention and treatment of IR in HCV patients. 1. Introduction Hepatitis C patients have fourfold higher incidence of insulin resistance (IR) than non-HCV population, that is, healthy controls or chronic hepatitis B patients [1]. IR is the major feature of the metabolic syndrome (diabetes type 2, obesity, hypertension, and cardiovascular disorders). HCV-associated IR may lead to resistance to antiviral therapy, hepatocarcinogenesis, and extrahepatic complications [2, 3]. The molecular mechanisms whereby HCV infection leads to IR are not entirely clear. Experimental and clinical findings indicated that hepatitis C virus per se is diabetogenic [4, 5]. However, presence of HCV alone does not affect IR [6]. It was suggested that increased production of proinflammatory cytokines, especially TNF-alpha, contributes to the development of IR in HCV patients [7]. TNF-alpha potentiates interferon-gamma- (IFNG-) triggered transcriptional induction of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of tryptophan- (TRP-) kynurenine (KYN) metabolism [8]. Upregulated IDO expression in the dendritic cells [9] and in the liver [10] and increased serum KYN？:？TRP ratio (KTR) [10] were reported for HCV patients. Review of clinical and experimental data suggested that KYN and some
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