We thank Gentilucci et al. (1) for their comments on our articles (2,3) regarding the pathogenic mechanisms of diabetes in patients with hepatitis C virus (HCV) infection. The authors question why an increased T-helper (Th)1 immune response can be simultaneously the major determinant of insulin resistance and responsible for a poor response to antiviral treatment. This question is based on the statement that Th1 immunoresponse favors HCV clearance. However, although a vigorous Th1 response could play an essential role in spontaneous viral clearance, this is not so evident after interferon treatment. It should be noted that in sustained responders, pretreatment intrahepatic mRNA levels of γ-interferon and tumor necrosis factor-α were lower than in nonsustained responders (4). In addition, a lower Th2 response during antiviral treatment (specifically a decrease in interleukin [IL]-10 rather than an increase of Th1) has been associated with a long-term virological response (5,6). Tsai et al. (7) and Eckels et al. (8) demonstrated that in vitro cytokine responses to recombinant HCV antigens were confined to IL-4 and IL-10 and proposed that such Th2 predominance might be conductive to viral persistence. Furthermore, Masaki et al. (9) reported that a lower Th1/Th2 ratio before interferon therapy may favor long-term virological response in patients with chronic hepatitis C. In addition, activation of naïve B-cells via CD81 has been involved in the immunological response triggered by HCV (10). Therefore, the immune mechanisms involved in the clearance of HCV after interferon therapy are complex and are far from being elucidated.
Low-grade inflammation mediated by activated innate immunity is an underlying pathogenic mechanism of insulin resistance and type 2 diabetes. Apart from the impairment of immune response, there is a cluster of alterations associated with insulin resistance such as obesity, ageing, hypertriglyceridemia, liver esteatosis, and fibrosis; these alterations are also risk factors for nonresponse to antiviral treatment. It has recently been demonstrated (11) that hyperinsulinemia blocks the inhibition of HCV virus replication by interferon. Therefore, it seems that there is a vicious circle in which insulin resistance facilitates the persistence of HCV and, alternatively, HCV favors insulin resistance.
Altogether, one can depict a complex scenario in which Th1 response is only one more of the actors. Future studies are needed to not only confirm that insulin resistance and type 2 diabetes are poor response predictors of antiviral treatment but also to unravel the mechanisms involved.