Association Between Liver Fibrosis and Insulin Sensitivity in Chronic HCV
In this study, we investigated the insulin sensitivity and β-cell function in HCV-infected patients with normal fasting glucose, although there was no control group for these analyses. Using a 75 g OGTT, impaired glucose tolerance and diabetes were found in 50% of the studied subjects. Additionally, insulin resistance (HOMA-R ≥2.5) was detected in 40 of 83 HCV patients and 77% of the insulin resistance group had severe liver fibrosis (F3 and F4). In the multivariate analysis, liver fibrosis was the only independent factor associated with insulin resistance. Furthermore, HOMA-R in subjects with severe fibrosis (F3 and F4) was significantly higher than in those with mild fibrosis (F1 and F2). Furthermore, WBISI in the subjects with severe fibrosis was significantly lower than in those with mild fibrosis. These results indicate that the development of liver fibrosis in chronic hepatitis C is associated with insulin resistance, although this finding might be due to a Berkson's bias that individuals seeking medical care are likely to show a high rate of association between two medical conditions, which may be independent in the general population.
Insulin resistance is known to be an important pathogenic factor for nonalcoholic fatty liver disease. Recently, several investigators have demonstrated that the severity of liver fibrosis in chronic hepatitis C was related to insulin resistance, although the pathogenesis of glucose intolerance in HCV-infected patients remains a matter of controversy. Several studies have demonstrated that obesity and steatosis were related to insulin resistance in chronic HCV infection. Furthermore, a recent report found that weight loss could improve insulin resistance in HCV-infected patients. Most notably, our study demonstrated that BMI and steatosis had no significant association with insulin resistance. This may be attributable to the small number of subjects with severe obesity or severe steatosis. However, the lack of such association also suggests that additional factors other than obesity and steatosis are involved in the incidence of insulin resistance in HCV-infected patients. Although BMI is commonly used as a marker for obesity, waist-to-hip circumference ratio and abdominal height, which were not available in this study, are better indicators of metabolic disorders with insulin resistance. These anthropometric measurements might have provided an important view on insulin resistance in the studied patients.
Shintani et al. showed that insulin resistance preceded the onset of steatosis in transgenic mice expressing HCV core protein. This resulted in greater levels of tumor necrosis factor alpha (TNF-α), which prevented tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Moreover, this impaired IRS-1 signaling has been observed in liver biopsies of HCV patients. These data suggest that TNF-α-mediated alterations in IRS-1 signaling are relevant to HCV-induced insulin resistance. In the present study, HBV-infected patients had a similar incidence of insulin resistance to that in HCV-infected patients. It is unknown whether insulin resistance in HBV infection is induced by the TNF-α-mediated mechanism, although activation of the TNF-α system occurs in both HCV and HBV infection.
Despite the small sample size and heterogeneity of the study group, our study showed that greater insulin resistance in HCV-infected patients is associated with the stage of fibrosis. Hyperinsulinemia, which is closely related to insulin resistance, commonly results from cirrhosis for several reasons, including impaired insulin degradation in particular (as reviewed elsewhere.) To avoid the confounding effect of end-stage liver disease on the interpretation of the insulin and insulin resistance data, we excluded patients with Child-Pugh grade B or C. Furthermore, there was no significant difference in serum insulin level between patients with mild fibrosis and those with severe fibrosis. Accordingly, it is unlikely that impairment of insulin clearance induced by worsening liver fibrosis accounted for insulin resistance in our patients. Conversely, it is conceivable that insulin resistance contributes to the progression of liver fibrosis, because hyperinsulinemia has been shown to directly stimulate hepatic stellate cell proliferation and increase expression of connective tissue growth factor, a key factor in the progression of fibrosis. Our data that the development of liver fibrosis in chronic hepatitis B was also associated with insulin resistance support this hypothesis. Alternatively, it is possible that factors influencing both insulin resistance and liver fibrosis are involved in their association. Again, TNF-α plays an important role not only in the development of insulin resistance but also in hepatic fibrogenesis, and thus this cytokine may provide one of the pathogenic links between insulin resistance and liver fibrosis in chronic HCV infection.
Although insulin resistance is a major issue in HCV-infected patients with glucose intolerance, previous studies have not demonstrated a relationship between liver fibrosis and β-cell function. In this study, HOMA-β was significantly elevated in HCV-infected patients with severe fibrosis compared with those with mild fibrosis. However, the Δ-insulin/Δ-glucose 30 showed no significant difference in stage of liver fibrosis. Moreover, insulin secretion did not differ between patients with mild fibrosis and those with severe fibrosis. Accordingly, we could not show a clear relationship between liver fibrosis and β-cell function in chronic hepatitis C.
In conclusion, we demonstrated in the present study that the development of liver fibrosis is associated with insulin resistance in HCV-infected patients. Further studies are needed to determine the underlying cause of this association.
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