Proinflammatory Cytokines, Insulin Resistance, and Insulin Secretion in Chronic Hepatitis C Patients: A Case-Control Study : Response to Petit et al.

We thank Petit et al. (1) for their interest in our study, in which we suggest that insulin resistance mediated by proinflammatory cytokines, but not a deficit of insulin secretion, is the primary pathogenic mechanism implicated in the development of diabetes associated with hepatitis C virus (HCV) infection (2). Based on the results of our study, these authors measured tumor necrosis factor (TNF)-soluble receptors (TNF-RI and TNF-RII) and homeostasis model assessment (HOMA) in 68 noncirrhotic subjects with chronic hepatitis C. They found that HOMA was significantly lower in patients with genotype 3 (n = 13) than in patients with genotype non-3 (n = 55), and there were no significant differences between the two groups regarding age, BMI, and serum levels of TNF-RI and TNF-RII. The authors concluded that the HCV genotype must be included when evaluating insulin resistance in HCV-infected patients and suggest that other factors apart from TNF-α could be involved in the development of insulin resistance during HCV chronic infection. This letter deserves the following comments. First, we would like to specify that all the patients included in our study were genotype 1 (which is largely the most prevalent), and, therefore, a potential bias due to this issue can be absolutely ruled out. Second, and more importantly, it should be stressed that in our study, both groups of patients (anti-HCV negative and anti-HCV positive) were closely matched by the degree of liver fibrosis and several indexes of hepatic insulin extraction. In our view, this is a crucial point that should be considered when comparing patients with liver disease. The HOMA model is based on circulating insulin levels, and, therefore, the higher the degree of hepatic fibrosis the lower the rate of insulin extraction and, in consequence, the higher HOMA. Therefore, the measurement of hepatic insulin extraction should be provided before suggesting any influence of the HCV genotype in insulin resistance measured by HOMA. Finally, it should be noted that apart from TNF-α soluble receptors, we had also determined interleukin-6, and it was significantly higher in anti-HCV–positive than in anti-HCV–negative patients. Therefore, we agree with Petit et al. (1) that other factors apart from TNF-α could be implicated in the insulin resistance associated with HCV infection. In this regard, further studies to evaluate the contribution of other proinflammatory cytokines in the development of insulin resistance associated with HCV infection are warranted.