Insulin resistance

Insulin resistance (IR) is the pathogenic foundation underlying metabolic syndrome, steatosis and cirrhotic-NASH, and possibly HCC. The interplay between genetic and environmental risk factors ultimately leads to the development of IR. Obesity is considered a major risk factor, with dysregulation of levels of secreted adipokines from distended adipose tissue playing a major role in IR. HCV-induced IR may be due to the HCV core protein inducing proteasomal degradation of IRS 1 and 2, impairing expression of IRS 1 and 2 and blocking intracellular insulin signalling. The latter is mediated by increased levels of both TNF-α and suppressor of cytokine signalling 3 (SOC-3). IR, through different mechanisms, plays a role in the development of steatosis and its progression to steatohepatitis, cirrhosis, and even HCC. In addition, it has a role in impairing IFN signalling cascade (JAK → STAT → IFN genes), as insulin activates PI3K thus blocking STAT-1 translocation, avoiding the antiviral effect of interferon.