Insulin resistance and liver injury in hepatitis C is not associated with virus-specific changes in adipocytokines

Abstract

The role of tumor necrosis factor ␣, interleukin 6, leptin, and adiponectin in the pathogenesis of hepatitis C virus (HCV)-associated insulin resistance (IR) remains controversial. We tested the hypothesis that these adipocytokines contribute to chronic HCV-associated IR and liver injury by first comparing their serum levels and homeostasis model assessment of insulin resistance (HOMA-IR) in 154 untreated, non-diabetic, HCV-infected male subjects with fibrosis stage 0-2, to that in 75 healthy volunteers matched for age, body mass index (BMI), and waist-hip ratio (WHR). We next examined whether the adipocytokine levels were associated with the extent of hepatic steatosis, portal/periportal inflammation and fibrosis in our total cohort of 240 HCVinfected male subjects. Significantly higher levels of HOMA-IR (2.12 versus 1.63, P ‫؍‬ 0.01), TNF␣ (1.28 versus 0.60 pg/ml, P < 0.001) and IL6 (2.42 versus 1.15 pg/ml, P ‫؍‬ 0.001) were noted in the HCV cohort compared with healthy controls respectively, but there were no significant differences in leptin and adiponectin concentrations. C hronic hepatitis C virus (HCV) infection is associated with the development of hepatic steatosis 1-5 and unique, virus-specific alterations in host metabolism leading to the development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). [6][7][8][9] We and others have shown that chronic HCV infection is associated with the development of IR in the absence of overt T2DM, irrespective of the presence or absence of cirrhosis. 6,10 Further, IR as assessed by the homeostasis model (HOMA-IR) 11 was independently associated with virally-mediated portal inflammation and an increased rate of fibrosis progression, indicating that IR is a cause rather than a consequence of hepatic fibrosis in HCV infection. 6 Despite recent recognition of the important role of IR in the progression of liver injury in HCV infection [12][13][14] and the response to antiviral therapy, 12,14,15 the mechanism of HCV-induced IR is not known. There is an abundance of literature to suggest that adipose tissue-derived cytokines (adipocytokines) may play a key role in the development of obesity-related IR. 16,17 TNF␣, IL6 and leptin are proinflammatory cytokines that can directly alter glucose and lipid metabolism. [16][17][18] In contrast, adiponectin, the most abundant of all the adipocytokines has an opposite effect, increasing insulin sensitivity [16][17][18] and having anti-steatotic, 19 anti-inflammatory 20 and antifibrotic effects. 21 In nonalcoholic fatty liver disease, it has been shown that serum levels of the various adipocyto-

Molecular mechanisms of insulin resistance in chronic hepatitis C

“…Serum levels of the adipocytokines leptin and adiponectin were likewise independently associated with IR (adiponectin inversely), but not with HCV infection itself. The authors therefore concluded that these adipocytokines could not account for the increased IR seen in HCV-infected subjects [65] .…”

“…Early human studies were conflicting but more recent studies have shown that HCV-induced IR is NOT due to alterations in serum inflammatory cytokines or adipokines [65] . Rather, IR in CHC seems to be due to direct virus-specific effects on insulin signaling.…”

“…Thus, initial studies noted increased serum levels of TNF-α in subjects with CHC [66][67][68] or showed a correlation with IR [69] but did not adequately correct for potential confounders. A later well-controlled study compared 154 HCV-infected non-diabetic males with 75 matched uninfected controls [65] . In that study, as expected, serum levels of TNF-α and IL-6 were higher in HCV-infected patients than controls but levels did not correlate with IR [65] .…”

“…A later well-controlled study compared 154 HCV-infected non-diabetic males with 75 matched uninfected controls [65] . In that study, as expected, serum levels of TNF-α and IL-6 were higher in HCV-infected patients than controls but levels did not correlate with IR [65] . Serum levels of the adipocytokines leptin and adiponectin were likewise independently associated with IR (adiponectin inversely), but not with HCV infection itself.…”

Serum leptin and plasma ghrelin concentrations in patients with chronic hepatitis C virus with steatosis: Their effect on the response to antiviral therapy

“…However, Cua et al [27] found that insulin resistance and liver injury in HCV are not associated with virus-specific changes in adipocytokines. Nkontchou et al [17] found that IR but not serum leptin levels predicts outcome of viral hepatitis C. In addition, other studies reported that, the structural and nonstructural proteins of HCV may directly cause steatosis by provoking oxidative stress [28,29].…”