Insulin resistance and hepatitis C

Abstract

Insulin resistance is the major feature of the metabolic syndrome and depends on insulin secretion and insulin sensitivity. In chronic hepatitis C, insulin resistance and type 2 diabetes mellitus are more often seen than in healthy controls or chronic hepatitis B patients. Hepatitis C virus (HCV) infection promotes insulin resistance, mainly by increased TNF production together with enhancement of suppressor of cytokine (SOC-3); both events block PI3K and Akt phosphorylation. Two types of insulin resistance could be found in chronic hepatitis C patients: "viral" and "metabolic" insulin resistance. Insulin resistance in chronic hepatitis C is relevant because it promotes steatosis and fibrosis. The mechanisms by which insulin resistance promotes fibrosis progression include: (1) steatosis, (2) hyperleptinemia, (3) increased TNF production, (4) impaired expression of PPARgamma receptors. Lastly, insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics, overweight, HIV coinfected and Afro-American. Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin. Indeed, in genotype 1, the sustained response rate was twice (60%) in patients with HOMA < or = 2 than patients with HOMA > 2. In experiments carried out on Huh-7 cells transfected by full length HCVRNA, interferon alpha blocks HCV replication. However, when insulin (at doses of 128 microU/mL, similar that seen in the hyperinsulinemic state) was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished. In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance, steatosis and fibrosis progression.

Figure 1

Prevalence of type 2 diabetes mellitus in patients with chronic hepatitis C and chronic hepatitis B.

Figure 2

Interaction between insulin and peginterferon alpha signalling pathway. The phosphatidil-inositol-3-kinase (PI3K) activated by insulin seems to be responsible for the block of STAT 1 translocation avoiding antiviral effect of interferon. Dotted lines represent inhibition, continuous lines represent activation.