Diabetes and Hepatitis C: A Two-Way Association

Abstract

Diabetes and hepatitis C infection are both prevalent diseases worldwide, and are associated with increased morbidity and mortality. Most studies, but not all, have shown that patients with chronic hepatitis C are more prone to develop type 2 diabetes (T2D) compared to healthy controls, as well as when compared to patients with other liver diseases, including hepatitis B. Furthermore, epidemiological studies have revealed that patients with T2D may also be at higher risk for worse outcomes of their hepatitis C infection, including reduced rate of sustained virological response, progression to fibrosis and cirrhosis, and higher risk for development of hepatocellular carcinoma. Moreover, hepatitis C infection and mainly its treatment, interferon α, can trigger the development of type 1 diabetes. In this review, we discuss the existing data on this two-way association between diabetes and hepatitis C infection with emphasis on possible mechanisms. It remains to be determined whether the new curative therapies for chronic hepatitis C will improve outcomes in diabetic hepatitis C patients, and conversely whether treatment with Metformin will reduce complications from hepatitis C virus infection. We propose an algorithm for diabetes screening and follow-up in hepatitis C patients.

Keywords: hepatitis C; hepatitis C virus; hepatocellular carcinoma; insulin resistance; interferon alpha; outcomes; treatment; type 1 diabetes; type 2 diabetes.

Figure 1

Potential mechanisms by which HCV directly affects the insulin signaling cascade. HCV infection of liver cells can lead to (1) decreased insulin receptor (IR in the figure) auto phosphorylation; (2) decreased IRS-1 activation due to increased serine-phosphorylation of IRS-1; (3) decreased IRS-1 levels due to increased ubiquitin-mediated proteasomal degradation induced by SOCS 3/7 and mTOR upregulation; (4) reduced Akt activity due to increased threonine-phosphorylation of Akt; (5) decreased GLUT4 expression; and (6) increased gluconeogenic enzymes (GC6P and PCK2). IR, insulin receptor; IRS-1, insulin receptor substrate-1; SOCS 3/7, suppressor of cytokine signaling; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; GC6P, glucose-6-phosphatase; PCK2, phosphoenolpyruvate carboxykinase 2.

Figure 2

Mechanisms by which IFNα affects beta cells to trigger islet autoimmunity. PDCs produce IFNα in response to infection. Binding to IFN type I receptor, IFNα or therapeutic IFNα, activates Jak/STAT pathways – inducing transcription of IFN-inducible genes leading to (1) production of proinflammatory cytokines, (2) increase expression of HLA class I, (3) stimulation of cytotoxic T cells. IFNα also induces ER stress, and epigenetic modification of genes involved in the pathogenesis of type 1 diabetes.

Figure 3

Possible mechanisms linking diabetes to accelerated cancer development. Binding of insulin to the insulin receptor (IR in the figure), likely IR-A and/or binding of IGF-1 to the IGF-1 receptor activate MAPK and PI3K/AKT signaling pathways leading to increased cell proliferation and decreased apoptosis. Hyperglycemia and chronic inflammation also contribute to cancer progression through other mechanisms. The mechanisms by which HCV promotes the development of HCC were not included in this figure. IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1 receptor; IR-A, insulin receptor A; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B.

Figure 4

Algorithm for screening for diabetes in hepatitis C patients. (1) Screen for DM: fasting blood sugar (FBS) and/or oral glucose tolerance test (OGTT). HbA ₁c might be considered if the measurement methods are well established. (2) High risk Type 1 diabetes patients are defined as individuals with first degree relatives with type 1 diabetes (T1D); patients with other autoimmune conditions; or patients might be considered as high risk, if IFNα therapy is considered. (3) Fasting C-peptide levels. (4) Islet antibodies include autoantibodies to glutamic-acid decarboxylase (GAD65), autoantibodies to insulin (IAA2), autoantibodies to the tyrosine phosphatase IA-2 and IA2B, autoantibodies to zinc transporter 8 (ZnT8), (5) IFNα may induce autoimmunity and therefore measure­ment of islet antibodies should be considered before and after IFNα therapy in high risk patients, and in patients with suspicion of T1D after initiation of IFNα.