Despite the controversy surrounding their association, type 2 diabetes (T2D) and hepatitis C virus (HCV) infection are related in a number of ways. Diabetes is defined as an endocrine disorder, and chronic HCV infection manifests as a variety of disorders, including endocrinological diseases. Diabetes and HCV also share associations with insulin resistance, the primary pathogenic mechanism linking both diseases.

In a review of studies, the prevalence of HCV infection in patients with T2D was higher than in controls who were nondiabetic, and chronic HCV infection was associated with an increased risk of developing T2D.1 Understanding the comorbid relationship between diabetes and HCV infection and the role of insulin resistance in their pathophysiology can help inform an integrated approach to treatment.

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The comorbid impact of diabetes and HCV infection

Patients with HCV infection are at higher risk of developing diabetes, and diabetics are at higher risk for HCV infection. Recent research shows that the associated pathogenesis of T2D and HCV infection proceeds through insulin resistance. 2

Whereas the mechanism of insulin resistance in T2D is well defined, in HCV infection, the association is primarily with peripheral insulin resistance, which can further lead to the development of T2D. HCV mostly attacks hepatocytes, but it can also impair insulin sensitivity in extrahepatic cells, specifically muscle and adipose tissue.2

In fact, excess morbidity and mortality related to HCV is often derived from extrahepatic disorders, which include insulin resistance and T2D.2 Progression of chronic HCV infection to cirrhosis and hepatocellular carcinoma is notably more rapid in concomitant diabetes.3

The Underlying Mechanism of Insulin Resistance in HCV

Patients with chronic HCV infection have significantly greater C-peptide and homeostatic model assessment insulin resistance levels, which are primary markers. Whereas HCV-induced changes to insulin-mediated signal transduction have been observed in the liver, it is thought that the proteins secreted by infected hepatocytes also interfere with the extrahepatic insulin signaling cascade and may even proceed independently of liver inflammation.1

Insulin resistance — with or without concomitant diabetes — affects long-term outcomesin chronic HCV infection by accelerating the progression of liver disease to cirrhosis or hepatocellular carcinoma.1 As mentioned, the presence of T2D (characterized by abnormalities resulting in insulin resistance) further increases the risk for disease progression and even has a selective impact on hepatocellular carcinoma development.1

In fact, several studies have indicated that diabetes along with insulin resistance are independent risk factors for the development of hepatocellular carcinoma through altered homeostasis of the liver.4 Hepatocellular carcinoma is thought to be related to the proliferative effects of insulin, implicating the oncogenic impact of hyperglycemia, hyperinsulinemia, and activation of insulin-like growth factor signaling pathways.4

Identifying shared risk factors in diabetes and HCV

Many factors can influence diabetes risk in patients with HCV infection and vice versa. In addition to the role of insulin resistance, research has pointed to the involvement of beta cell dysfunction and immune-mediated disorders.1 Knowledge of these pathogenic mechanisms can help providers identify patients at risk for diabetes or HCV infection and guide treatment options.

In a setting of chronic HCV infection, identifying patients at risk of developing T2D is of particular importance. Studies show that the identification of these patients helps to decelerate the progression of liver disturbances, decrease the incidence of hepatocellular carcinoma, reduce transplant-related morbidity and mortality, and improve the response to antiviral therapies.1

These associations underscore the need to implement preventative measures to reduce the risk of developing diabetes or HCV infection in diabetic patients. Lifestyle modifications are recommended for all at-risk individuals, and anti-HCV positive persons should be regularly screened for T2D. Clinical analyses should further be performed on risk factors known to accelerate the progression of both chronic HCV infection and diabetes, including obesity, dyslipidemia, and alcohol consumption.1

Integrated management of concomitant HCV and diabetes

The desired outcome of HCV therapies is sustained virological response, which has been demonstrated by pretreating insulin resistance and diabetes, and which has also shown to ameliorate insulin resistance and improve beta cell function.1 This provides further insight into the comorbid association of HCV infection and diabetes (and underlying insulin resistance) and illuminates the potential for integrated pharmacological management.

Whereas treatment with interferon (IFNα) is a mainstay of anti-HCV therapies, and IFNα is effective at reducing whole body insulin resistance, it can be contraindicated in certain patient populations. Researchers hypothesize that newly available IFNα-free regimens may provide new options with greater improvement in extrahepatic manifestations of HCV infection, including diabetes.

Studies show complete viral suppression can be achieved through IFNα-free regimens and further demonstrate significantly improved extrahepatic (but not hepatic) insulin activity.2 Besides reduced insulin resistance, improved glucose homeostasis was reported by patients treated with IFNα-free regimens. This indicates tremendous benefit for patients with concomitant diabetes, in which they may be able to reduce the number of diabetic medications needed to maintain glycemic control.

Not only is it important to recognize the associations between HCV infection, T2D, and insulin resistance from a risk standpoint, it is also useful to understand how integrated treatment approaches use preventive management and antiviral therapies to act on the underlying pathogenic mechanisms and inhibit overall disease progression.

References

  1. Fabiani S, Fallahi P, Ferrari SM, Miccoli M, Antonelli A. Hepatitis C virus and development of type 2 diabetes mellitus: systematic review and meta-analysis of the literature. Rev Endocr Metab Disord. 2018;19(4):405-420.
  2. Gastaldi G, Gomes D, Schneiter P, et al. Treatment with direct-acting antivirals improves peripheral insulin sensitivity in non-diabetic, lean chronic hepatitis C patients [published online June 6, 2019]. PLoS ONE. doi: 10.1371/journal.pone.0217751
  3. Kombi PK, Agasa SB, Mukonkole, JPM, Bome LB, Bokele CA, Tschilumba CK. Seroprevalence of hepatitis B and C virus infections among diabetic patients in Kisangani (North-eastern Democratic Republic of Congo) [published online November 2, 2018]. Pan Afr Med J. doi: 10.11604/pamj.2018.31.160.17176
  4. Li X, Wang X, Gao P. Diabetes mellitus and risk of hepatocellular carcinoma [published online December 12, 2017]. Biomed Res Int. doi: 10.1155/2017/5202684