Chronic hepatitis C (CHC) has been associated with the development insulin resistance (IR) and type 2 diabetes. Albeit hepatitis C virus (HCV) infects only hepatocytes, peripheral IR is also observed in HCV infected patients. In the frame of this thesis we aimed to investigate the liver-to-periphery crosstalk mechanisms involved in the pathogenesis of HCV-driven IR. To this goal, we conducted a proof-of-concept clinical study in CHC patients and generated HCV-based experimental models. Altogether, our results show that (i) viral suppression in CHC patients leads to a significant improvement of peripheral insulin sensitivity and modifies a subset of factors potentially accounting for peripheral IR; (ii) the expression of HCV-3a core protein in the hepatocytes is able to cause IR in the muscle; and that (iii) the soluble factor Angiopoietin-like 4 might be a mediator involved in HCV-related IR. Our work demonstrates that HCV infection affects the hepatokine secretion profile to induce peripheral IR.