Diabetes and Infections-Hepatitis C: Is There Type 2 Diabetes Excess in Hepatitis C Infection?

Abstract

Individual epidemiologic studies as well as the pooled analysis of observational studies have indicated the association between type 2 diabetes (T2D) and hepatitis C virus infection (HCV). Whether HCV infection is the cause of diabetes or diabetic patients are more prone to get HCV infection is still in question. The objective of the present review was to provide answers to this issue, based on available evidence from epidemiologic, molecular, experimental and therapeutic studies. Our current understanding of how chronic HCV infection could induce T2D is incomplete, but it seems twofold based on both direct and indirect roles of the virus. HCV may directly induce insulin resistance (IR) through its proteins. HCV core protein was shown to stimulate suppressor of cytokine signaling, resulting in ubiquitination and degradation of tyrosine kinase phosphorylated insulin receptor substrates (IRS1/2) in proteasomes. HCV-nonstructural protein could increase protein phosphatase 2A which has been shown to inactivate the key enzyme Akt by dephosphorylating it. Insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to IR, which leads to the development of T2D in patients with HCV infection. The peroxisome proliferator-activated receptors (PPARs) are also implicated. PPARα/γ, together with their obligate partner RXR, are the main nuclear receptors expressed in the liver. PPARα upregulates glycerol-3-phosphate dehydrogenase, glycerol kinase, and glycerol transport proteins, which allows for glucose synthesis during fasting states. Decreased activity of PPARs could attribute to HCV-induced IR. Immune-mediated mechanisms may be involved in the indirect role of HCV in inducing IR. It is speculated that TNF-alpha plays a major role in the pathogenesis of IR through lowering IRS1/2. Furthermore, HCV infection- triggered ER stress could lead to the activation of PP2A, which inhibits both Akt and the AMP-activated kinase, the regulators of gluconeogenesis. In summary, we illustrate that HCV infection is accompanied by multiple defects in the upstream insulin signaling pathway in the liver that may contribute to the observed prevalence of IR and diabetes. Future studies are needed to resolve this issue.

Hepatitis C Virus Infection and Kidney Transplantation in 2014: What’s New?

“…We found a significant association between HCV infection and impaired insulin sensitivity in nondiabetic kidney transplant recipients, without any significant differences in insulin secretion and hepatic insulin uptake . The precise pathogenic mechanism leading to insulin resistance in HCV‐infected patients is still unclear and has been reviewed recently .…”

Endoplasmic reticulum stress induces liver cells apoptosis after brain death by suppressing the phosphorylation of protein phosphatase 2A

“…Phosphorylation decreased the catalytic activation of PP2a (37). There have been many studies that have revealed that activation of erS and PP2a may have a synergistic effect on cell damage under different pathological states (38)(39)(40). according to a study on neurodegenerative disorders, after rat brain endothelial cells were exposed to okadaic acid, a well-known inhibitor of PP2a, inhibition of PP2a and an increase in erS markers expression were observed, which suggests that inhibition of PP2a affected erS (41).…”

Matched population‐based study examining the risk of type 2 diabetes in people with and without diagnosed hepatitis C virus infection

“…The effect modification could explain some of the heterogeneity that both meta analyses found, since few of the reviewed studies stratified by gender and none by social deprivation. However, widely accepted biological models of the effects of HCV infection on T2DM risk do not explain the observed effect modification. Moreover, while gender, social deprivation and year of birth were included in our matched analysis to increase efficiency of the study , the analysis of effect modification by gender, social deprivation, year and age was purely exploratory.…”