Gastroenterology
Volume 134, Issue 2 , Pages 619-622, February 2008

Hepatitis C Virus-Induced Insulin Resistance: Not All Genotypes Are the Same

  • Brent A. Neuschwander–Tetri

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Brent A. Neuschwander–Tetri, MD, Saint Louis University Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, 3635 Vista Avenue, Saint Louis, Missouri 63110.

Saint Louis University, Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, St. Louis, Missouri

Article Outline

 

See “Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis,” by Moucari R, Asselah T, Cazals–Hatem D, et al on page 416.

Genes, aging, overweight, and sedentary lifestyle all influence the action of insulin in various organs. Reduction in insulin sensitivity from obesity and a myriad of conditions (Figure 1) results in hyperinsulinemia, which promotes hepatocellular triglyceride accumulation in patients with nonalcoholic fatty liver disease (NAFLD). Basic research, clinical trials and epidemiological studies have provided evidence that the hepatitis C virus (HCV) can independently contribute to insulin resistance as well.1, 2, 3, 4, 5 Adding to this growing body of evidence and now providing genotypic association, Moucari et al6 implicate infection with viral genotypes 1 or 4 as an independent contributor to insulin resistance.

  • View full-size image.
  • Figure 1. 

    Insulin resistance (IR) has 4 major causes: genetic predisposition, aging, obesity (especially centripetal obesity), and a sedentary lifestyle. There are also genetic factors that predispose to obesity and possibly impaired muscle function, which could promote a sedentary lifestyle. The paper by Moucari et al6 and earlier data place HCV, especially genotypes 1 and 4, on the left-hand causative side of the diagram. Although there are mechanistic explanations why HCV-induced insulin resistance occurs at the cellular level, it is possible that the effect of HCV infection might be more indirect by promoting fatigue and a sedentary lifestyle in some patients. The consequences of insulin resistance are many and include NAFLD. Altered humoral responses to HCV infection caused by insulin resistance or the associated hyperinsulinemia may also impair the ability to clear the virus. Note that commonly used criteria for the metabolic syndrome include both a causative factor (centripetal obesity) and consequences of insulin resistance (hypertension, dyslipidemia, impaired fasting glucose) and thus the metabolic syndrome as it is currently conceived cannot be viewed as a consequence of insulin resistance.

What is “insulin resistance,” and how is it measured? Normally, the rise in insulin in the postprandial state inhibits gluconeogenesis and enhances glucose uptake into muscle and adipose tissue. Rising insulin levels also suppress lipolysis in adipose tissue. Insulin falls during fasting, and this, along with increasing levels of glucagon, epinephrine, and other “counterregulatory hormones,” stimulates glucose production and lipolysis. Obesity is the most common cause of insulin resistance and is characterized by failure of insulin to suppress glucose production, impaired glucose disposal, and postprandial hyperglycemia. As blood glucose levels rise, pancreatic β cells are stimulated to produce more insulin. Hyperinsulinemia in insulin-resistant states coupled with elevated hepatic fatty acid influx leads to fatty liver. Although the hyperinsulinemic–euglycemic clamp is often referred to as the “gold standard” test for assessing insulin resistance, this method is technically challenging and cannot be used in large studies. The Homeostatic Model Assessment (HOMA) offers an estimate of insulin resistance by multiplying the basal (fasting) glucose and insulin concentrations and dividing this product by 22.4 or 403 when the glucose concentration is expressed as millimolar or milligrams per deciliter, respectively. A HOMA score close to 1 indicates normal insulin sensitivity. Insulin resistance is associated with high HOMA scores. Alternatively, taking the log and then the inverse of the insulin and glucose product arrives at the Quantitative Insulin Sensitivity Check Index (QUICKI) score, a numerical transformation considered by some to be more advantageous because the values are more linearly correlated with insulin resistance measurements from the hyperinsulinemic glucose clamp.7 HOMA and QUICKI have the advantage of requiring only a single fasting plasma sample assayed for glucose and insulin, but the primary input data must be accurate and the lack of standardization of insulin assays can be a problem.

For the purposes of identifying significant insulin resistance in patients with hepatitis C, Moucari et al6 set the threshold high by requiring a HOMA of ≥3. The implication of this relatively stringent threshold is that some of the patients in this study were classified as not being insulin resistant when in fact they likely did have some degree of insulin resistance. Indeed, 4.8% of subjects meeting criteria for metabolic syndrome and 24% of diabetic patients in this study did not have a HOMA >3 at the time of their liver biopsy despite having these clinical sequelae of insulin resistance. The presence of NAFLD might be considered to be perhaps the most sensitive indicator of clinically significant insulin resistance.8 This could explain why in the population that they evaluated with hepatitis C, of whom 50.6% had biopsy evidence of NAFLD, only 32.4% met their HOMA threshold for insulin resistance, and 12.2% had insulin resistance long enough or with sufficient severity that they met the National Cholesterol Education Program criteria for the metabolic syndrome.

How HCV infection might cause insulin resistance remains an area of active investigation.9, 10 Studies in cultured cells transfected with viral proteins and transgenic mice expressing HCV proteins have established that these foreign proteins can interfere with both fat trafficking11 and insulin signaling.3 Cell culture studies of fat trafficking have further identified genotype-specific abnormalities with genotype 3 core protein more likely to cause cellular triglyceride accumulation than other genotype core proteins.12 This observation correlates with the clinical experience with HCV-infected patients in whom genotype 3 is associated with NAFLD independent of other risk factors, whereas the NAFLD found in patients infected with the other genotypes is associated with the commonly associated risk factors such as obesity and sedentary lifestyle.13, 14 In contrast with the studies of fat trafficking, genotype-specific abnormalities in postreceptor insulin signaling that could help explain the clinical associations found by Moucari et al6 have not been described in experimental systems.

What comes first in the absence of HCV infection—either NAFLD or insulin resistance—is not entirely clear. Much of the cardiovascular and endocrine literature has attributed insulin resistance to the presence of excessive triglyceride in organs such as the liver and muscle.15, 16 By contrast, accumulating data seem to indicate rather than causing insulin resistance, the presence of visible hepatocyte triglyceride droplets is a consequence of insulin resistance, hyperinsulinemia, and the resulting excessive flux of free fatty acids through the liver.3, 17, 18 In other words, triglyceride droplets may be inert with respect to promoting injury and altered cellular homeostasis and thus simply represent an easily identified morphologic epiphenomenon. In the genotype 3–infected patient, this seems to be the case because fat accumulation does not in itself cause insulin resistance and those patients who are insulin resistant typically have other causes such as obesity.1

If it is not the viral proteins causing NAFLD, which then cause insulin resistance, then a better understanding is needed to explain how viral proteins might directly impair insulin signaling. A study using transgenic mice expressing the genotype 1b HCV core protein demonstrated that the viral protein impaired insulin signaling, possibly through a mechanism involving circulating tumor necrosis factor (TNF)-α.3 Why TNF-α should cause insulin resistance in this model of liver disease and not in others remains unknown.19 Alternatively, HCV core protein expression has been shown to alter postreceptor insulin signaling through its interaction with endogenous P28γ, a protein involved in proteasome activation, HCV core protein degradation and insulin receptor substrate-1 (IRS-1) turnover.20 The contribution of altered IRS-1 turnover to hepatic insulin resistance is unclear because the role of P28γ in IRS-2 turnover was not described. Using the same genotype 1b core protein transgenic mice, Miyamoto et al21 found that knockout of P28γ expression normalized insulin sensitivity by correcting Akt signaling through IRS-2, a major pathway of hepatic postreceptor insulin signaling.21 Further evidence supporting this mechanism is that a small molecule proteasome inhibitor was found to block HCV core protein-induced IRS-1 and IRS-2 degradation in transfected hepatoma cells, this occurring in a pathway dependent on suppressor of cytokine signaling (SOCS) 3.22 A picture thus emerges of HCV genotype 1b core protein inducing SOCS3, which causes proteasomal degradation of IRS-1/2 and impaired insulin signaling.

The findings in these mouse experiments may have been corroborated by a clinical study demonstrating reduced IRS-1 phosphorylation in liver biopsies of HCV patients23 and a more recent study showing increases in IRS-1 and IRS-2 protein levels in liver biopsies and correspondingly improved insulin sensitivity in patients achieving a sustained virologic response to HCV therapy but not in those who failed to respond or relapsed.4 Needed now are investigations of the genotypic specificity of these virus–host interactions to determine if genotype-specific interactions lead to differences in SOCS-dependent IRS-1/2 turnover. Studies are also needed to separate out each genotype, and possibly even quasispecies, to further refine the nature of this interaction. Whereas Moucari et al lumped genotypes 1 and 4 to compare with genotypes 2 and 3 in their clinical study, the rationale for doing so is unclear and may be based on the known differences in treatment response between these groups rather than interactions between viral proteins and host signaling pathways.

Putting HCV infection on the causal side of insulin resistance has important therapeutic implications. Because the presence of insulin resistance has been associated with a reduction in the response rate of HCV infection to standard therapy,24 one approach has been to investigate whether improving insulin sensitivity before and during treatment of HCV improves the rate of sustained virologic response. If HCV infection is the cause of insulin resistance, and insulin resistance does not directly influence response to treatment, then this will be a failed approach. By contrast, ample experimental evidence exists to support the hypothesis that insulin resistance interferes with mechanisms of viral eradication and thus these remain studies worth pursuing.14

The paper by Moucari et al6 adds more texture to the complexity of the interaction between viral proteins and insulin signaling, providing new insight into the roles of genotype and host metabolic responses in progression of liver disease that need further explanation. Like many nuances of the virus–host relationship, understanding these interactions may not influence how we approach patients with our current therapeutic options, but it certainly adds to the foundation upon which future therapies for HCV and metabolic liver disease may be developed.

Back to Article Outline

References 

  1. Hui JM, Sud A, Farrell GC, et al. Insulin resistance is associated with chronic hepatitis C and virus infection fibrosis progression. Gastroenterology. 2003;125:1695–1704
  2. Mehta SH, Brancati FL, Strathdee SA, et al. Hepatitis C virus infection and incident type 2 diabetes. Hepatology. 2003;38:50–56
  3. Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126:840–848
  4. Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007;102:570–576
  5. Wang C-S, Wang S-T, Yao W-J, et al. Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. Am J Epidemiol. 2007;166:196–203
  6. Moucari R, Asselah T, Cazals-Hatem D, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134:416–423
  7. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85:2402–2410
  8. Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–1850
  9. Ratziu V, Heurtier A, Bonyhay L, et al. Review article: an unexpected virus-host interaction—the hepatitis C virus-diabetes link. Aliment Pharmacol Ther. 2005;22(Suppl 2):56–60
  10. Zekry A, McHutchison JG, Diehl AM. Insulin resistance and steatosis in hepatitis C virus infection. Gut. 2005;54:903–906
  11. Lai MM. Hepatitis C virus proteins: direct link to hepatic oxidative stress, steatosis, carcinogenesis and more. Gastroenterology. 2002;122:568–571
  12. Abid K, Pazienza V, de Gottardi A, et al. An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation. J Hepatol. 2005;42:744–751
  13. Romero-Gómez M, Castellano-Megias VM, Grande L, et al. Serum leptin levels correlate with hepatic steatosis in chronic hepatitis C. Am J Gastroenterol. 2003;98:1135–1141
  14. Hui JM, Kench J, Farrell GC, et al. Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection. J Gastroenterol Hepatol. 2002;17:873–881
  15. den Boer M, Voshol PJ, Kuipers F, et al. Hepatic steatosis: a mediator of the metabolic syndrome. Lessons from animal models. Arterioscler Thromb Vasc Biol. 2004;24:644–649
  16. Ryysy L, Häkkinen AM, Goto T, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes. 2000;49:749–758
  17. Buettner R, Ottinger I, Scholmerich J, et al. Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis. Am J Physiol Endocrinol Metab. 2004;286:E828–E833
  18. Monetti M, Levin MC, Watt MJ, et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab. 2007;6:69–78
  19. Weinman SA, Belalcazar LM. Hepatitis C: a metabolic liver disease. Gastroenterology. 2004;126:917–919
  20. Moriishi K, Okabayashi T, Nakai K, et al. Proteasome activator PA28g-dependent nuclear retention and degradation of hepatitis C virus core protein. J Virol. 2003;77:10237–10249
  21. Miyamoto H, Moriishi K, Moriya K, et al. Involvement of the PA28g-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J Virol. 2007;81:1727–1735
  22. Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165:1499–1508
  23. Aytug S, Reich D, Sapiro LE, et al. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology. 2003;38:1384–1392
  24. Harrison SA, Brunt EM, Qazi RA, et al. Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2005;3:604–609

PII: S0016-5085(07)02279-2

doi:10.1053/j.gastro.2007.12.041

Refers to article:

  • Insulin Resistance in Chronic Hepatitis C: Association With Genotypes 1 and 4, Serum HCV RNA Level, and Liver Fibrosis , 12 November 2007

    Rami Moucari, Tarik Asselah, Dominique Cazals–Hatem, Hélène Voitot, Nathalie Boyer, Marie–Pierre Ripault, Rodolphe Sobesky, Michèle Martinot–Peignoux, Sarah Maylin, Marie–Hélène Nicolas–Chanoine, Valérie Paradis, Michel Vidaud, Dominique Valla, Pierre Bedossa, Patrick Marcellin
    Gastroenterology February 2008 (Vol. 134, Issue 2, Pages 416-423)

Gastroenterology
Volume 134, Issue 2 , Pages 619-622, February 2008

Article Tools

* Image Usage & Resolution