hepatitis c patients have fourfold higher incidence of insulin resistance ( ir ) than non - hcv population , that is , healthy controls or chronic hepatitis b patients . 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 ] . experimental and clinical findings indicated that hepatitis c virus per se is diabetogenic [ 4 , 5 ] . it was suggested that increased production of proinflammatory cytokines , especially tnf - alpha , contributes to the development of ir in hcv patients . 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 . upregulated ido expression in the dendritic cells   and in the liver   and increased serum kyn  :  trp ratio ( ktr )   were reported for hcv patients . review of clinical and experimental data suggested that kyn and some of its derivatives affect biosynthesis , release , and activity of insulin . we suggested that upregulated trp - kyn metabolism might be one of the mechanisms of ir in hcv patients . to check this suggestion , we evaluated serum trp and kyn concentrations and ir and pancreatic beta - cell function in hcv patients . participants were recruited from hcv patients considered for starting a treatment with pegylated interferon - alpha and ribavirin . the study was approved by tufts medical center irb , and written consents were obtained for participation in the study . ido activation results in decrease of trp and increase of kyn and , therefore , in elevation of ktr that is used as a marker of ido activity in clinical studies . however , there are some peculiarities related to the use of ktr as a marker of ido activity in hcv patients . increased ktr was reported in hcv patients but without data on serum trp and kyn levels . on the other hand , the decreased concentrations of both trp and kyn in serum and macrophages and , consequently , decreased ktr were observed in hcv . in the largest , so far , study , concentrations of kyn in 176 patients were significantly higher those than in healthy controls , whereas the levels of trp were comparable in the two groups . authors suggested that in hcv patients serum kyn level can be used as a marker of ido activity . serum trp , kyn , and kynurenic acid ( kyna ) concentrations were evaluated by hplc - uv - fluorimetric method . ir was assessed by homeostatic model assessment index , version 2 ( homa2-ir ) , and pancreatic beta - cell function by homa - beta index , based on fasting glucose and insulin levels , using the computer - based solution of the model provided by the diabetes trials unit , oxford center for diabetes , endocrinology , and metabolism ( http://www.dtu.ox.ac.uk/index.php?maindoc=/homa/history.php ) . serum glucose was measured using an enzymatic , kinetic reaction on the olympus au400e with olympus glucose reagents ( oscr6121 ) ( olympus america inc . , serum insulin is measured using the immulite 1000 insulin kit ( lkin1 ) on the immulite 1000 ( siemens medical solutions diagnostics , los angeles , ca , usa ) . quantitative data are presented using median ( 50th percentile ) and minimum - maximum range . nonparametric tests ( wilcoxon and mann - whitney u ) were used to assess correlations for nonnormally distributed data . there were 42 male and 18 female american caucasian hcv patients , 52.2  7.45 years of age . forty - eight patients had hcv genotype 1 or 4 , and twelve patients had hcv genotype 2 or 3 . serum kyn concentrations correlated with scores of homa2-ir and homa - beta ( table 1 ) . trp ( kyn precursor ) but not kyna ( immediate metabolite of kyn ) [ 17 , 18 ] correlated with homa2-ir and homa - beta . serum kyna concentrations correlated with kyn but not with trp concentrations ( table 1 ) . the major findings of the present study are the correlations between serum concentration of kyn and scores of homa2-ir and homa - beta in hcv patients . as far as we are aware , this is the first observation of such a correlation . considering that serum kyn concentrations used an index of ido activity in hcv patients , our data suggested a possible involvement of upregulated of trp - kyn metabolism in the development of ir in hcv patients . we did not find correlation between ir indexes and ktr , a marker of ido activity in clinical studies . as it was indicated earlier ( see section 2 ) , in hcv patients , serum kyn concentrations might be considered as an index of ido activity . present finding of correlation between serum kyn and trp with both homa-2-ir and homa - beta is in line with the reported induction of ir by surplus dietary trp in pigs   and with recent observation of increased serum kyn in diabetes retinopathy patients . association between elevated kyn and trp concentrations and ir might be a result or a cause of ir . recent review of clinical and experimental data suggested the involvement of kyn pathway of trp metabolism in the development of ir since kyn and some of its derivatives affect biosynthesis , release , and activity of insulin .   diabetogenic effect of kyn and its derivatives , xa , 3-hk , and kyna , ( figure 1 ) may be mediated by inhibition of pro - insulin synthesis in isolated rat pancreatic islets   and of insulin release from rat pancreas . however , the effective concentrations ( millimolar ) of kyna were much higher than its concentrations ( micromolar ) in pig 's pancreatic juice . the most plausible candidate for mediation of diabetogenic effect of upregulated try - kyn metabolism is xa . increased urine excretion of xa was reported in type 2 diabetes patients in comparison with healthy subjects , while xa induced experimental diabetes in rats . xa might contribute to the development of diabetes via formation of chelate complexes with insulin ( xa - in ) [ 26 , 27 ] and induction of pathological apoptosis of pancreatic beta cells through caspase-3-dependent mechanism [ 28 , 29 ] . formation of xa from 3-hk depends on the vitamin b6 since its active metabolite , pyridoxal 5-phosphate ( p5p ) , is a cofactor of kynureninase , the enzyme , catalyzing 3-hk metabolism to nad+ ( figure 1 ) . evaluation of xa should be included in future studies of the role of trp - kyn metabolism in mechanisms of hcv - associated ir . mechanisms of ir in hcv might be different from those in non - hcv patients . thus , we observed in agreement with previous finding that a positive correlation between homa - ir and homa - beta was reported in hcv patients , in comparison with negative correlation between hoam-2ir and homa - beta in non - hcv patients . in the present study , a strong positive correlation between hoam-2ir and homa - beta was observed as well ( table 1 ) . our data of correlation between kyn and ir suggested the involvement of trp - kyn metabolism in the development of ir in hcv patients . detection and treatment of hcv - associated ir are of importance considering that hcv - associated ir may lead to resistance to antiviral therapy , hepatocarcinogenesis , and extrahepatic manifestations , including an increased risk of cardiovascular disorders . trp - kyn metabolism might be a new target for prevention and treatment of ir in hcv patients .