Sustained virological response following chronic hepatitis <scp>C</scp> treatment is associated with improvement in insulin resistance

Chan, Chin Hong; Hansen, Ross; Gilliver, Rosie; Jones, Brett E.

doi:10.1111/imj.12136

Cited by 7 publications

(8 citation statements)

References 37 publications

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“…Previous studies have suggested that IR in patients with chronic hepatitis C accelerates the process of liver disease and impaired sustained virological response to the standard therapy of peginterferon and ribavirin [ 7 ]. Thus, dysregulated PTEN expression caused by HCV infection may affect hepatic insulin sensitivity, but may also lead to progression to severe liver malignancies, of which PTEN is frequently mutated or deleted.…”

Section: Discussionmentioning

confidence: 99%

“…IR is a systemic pre-diabetic disorder wherein an increased level of insulin needs to maintain normal glucose levels in peripheral tissues, especially in muscle and adipose tissue [ 4 ]. Previous studies have shown that IR is the major factor leading to hepatic steatosis and fibrosis, weakened host immune response to viral infection, and is involved in the development of HCC [ 5 - 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of IRS-1 by hepatitis C virus infection leads to insulin resistance in a PTEN-dependent manner

Gao

Qin

Ren

et al. 2015

Virol J

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BackgroundHepatitis C virus (HCV) infection was recently recognized as an independent risk factor for insulin resistance (IR), the onset phase of type 2 diabetes mellitus (T2DM). Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates PI3K/Akt signaling pathway, which is critical for IR development and progression of cirrhosis to hepatocellular carcinoma (HCC). Here, we investigate the role of PTEN in HCV-associated IR and explored the mechanisms by which HCV regulates PTEN.MethodsWestern blotting was used to detect the levels of insulin signaling pathway components, including insulin receptor substrate-1 (IRS-1), phosphorylated IRS-1 (pIRS-1) at serine 307 (Ser307), both phosphorylated Akt (pAkt) and total Akt. A time-course experiment measuring activation of the insulin signaling pathway was performed to assess the effect of HCV infection on insulin sensitivity by examining the phosphorylation levels of Akt and GSK3β, a downstream target of Akt. Huh7.5.1 cells were transduced with a lentiviral vector expressing PTEN or PTEN shRNA, and IRS-1 and pIRS-1 (Ser307) levels were determined in both HCV-infected and uninfected cells. The pc-JFH1-core plasmid was constructed to explore the underlying mechanisms by which HCV regulated PTEN and therefore IRS-1 levels.ResultsHCV infection inhibited the insulin signaling pathway by reducing the levels of IRS-1 and pAkt/Akt while increasing phosphorylation of IRS-1 Ser307. In addition, HCV infection decreased the sensitivity to insulin-induced stimulation by inhibiting Akt and GSK3β phosphorylation. Furthermore, PTEN mRNA and protein levels were reduced upon HCV infection as well as transfection with the pc-JFH1-core plasmid. The reduction in IRS-1 level observed in HCV-infected cells was rescued to a limited extent by overexpression of PTEN, which in turn slightly reduced pIRS-1 (Ser307) level. In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser-307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon HCV infection occurred in a PTEN-dependent manner.ConclusionsHCV infection suppresses the insulin signaling pathway and promotes IR by repressing PTEN, subsequently leading to decreased levels of IRS-1 and increased levels of pIRS-1 at Ser307. The findings provide new insight on the mechanism of HCV-associated IR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of IRS-1 by hepatitis C virus infection leads to insulin resistance in a PTEN-dependent manner

Gao

Qin

Ren

et al. 2015

Virol J

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“…The proposed mechanisms involve direct interference of HCV with insulin signalling, resulting in metabolic disturbances, impaired glucose tolerance and hepatic steatosis . The first evidence of improved insulin sensitivity after SVR came from an Australian study demonstrating decreased HOMA‐IR values . Moreover, a retrospective analysis of a US Veterans cohort, based on Cox proportional hazards regression analysis, showed that patients achieving SVR had a significantly lower risk of developing DM2 …”

Section: Extrahepatic Benefits Of Hcv Curementioning

confidence: 99%

“…41,50 The first evidence of improved insulin sensitivity after SVR came from an Australian study demonstrating decreased HOMA-IR values. 51 Moreover, a retrospective analysis of a US Veterans cohort, based on Cox proportional hazards regression analysis, showed that patients achieving SVR had a significantly lower risk of developing DM2. 52 Fatigue is another major problem for chronic HCV patients.…”

Section: Extrahepatic Benefits Of Hcv Curementioning

confidence: 99%

The benefits of hepatitis C virus cure: Every rose has thorns

Salmon

Mondelli

Matičič

et al. 2018

Journal of Viral Hepatitis

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To examine mid-term benefits on hepatic complications, extrahepatic clinical syndromes and quality of life associated with HCV cure; to review the few safety issues linked to oral direct-acting antivirals (DAAs); and to discuss the potential population benefits of reducing the burden of HCV infection. DAAs cure HCV infection in more than 95% of patients. The halting of liver inflammation and fibrosis progression translates into both hepatic and extrahepatic benefits and reduces the need for liver transplantation. A reduction in the frequency of extrahepatic manifestations such as mixed cryoglobulinaemia and vasculitis and improvements in quality of life and fatigue have also been described. A few safety issues linked to DAAs such as the potential recurrence of aggressive HCC, the flares of hepatitis B virus in patients with overt or occult HBV infection are been discussed. Curing HCV infection also has a high potential to reduce the burden of HCV infection at the population level. With widespread scaling up of HCV treatment, several modeling studies suggest that major reductions in HCV prevalence and incidence are possible, and that elimination of viral hepatitis is an achievable target by 2030.

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“…The HOMA-IR score has been indicated to be a predictor of liver fibrosis and may be used as a surrogate marker for SVR at EOT (33). A previous meta-analysis of 13 studies reported that elevated HOMA-IR (regardless of cut-off value, as well as with the cut-off value set at >2) was associated with lower SVR rates after IFN-based therapy in patients infected with HCV of the genotype 1, 2 or 3 (36).…”

Section: Discussionmentioning

confidence: 99%

Effect of HCV treatment response on insulin resistance: A systematic review and meta‑analysis

Chang

Liu

et al. 2019

Exp Ther Med

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Sustained virological response (SVR) in hepatitis C virus (HCV) patients treated with pegylated interferon α-2a and ribavirin is associated with reduced insulin resistance (IR), measured as a reduction of homeostasis model assessment (HOMA) scores after 24 weeks of therapy, and reduced fasting serum insulin and serum glucose levels. The present meta-analysis aimed to evaluate the effect of HCV treatment response on IR in HCV patients who achieved SVR and those who did not (non-SVR) after receiving interferon (IFN)-based therapy. The PubMed, Cochrane and Embase databases were searched using combinations of the following search terms: ‘HCV’, ‘hepatitis C’, ‘interferon’, ‘antiviral’, ‘treatment response’ and ‘insulin resistance’. The incidence of IR, HOMA-IR and HOMA-β, as well as fasting glucose and fasting insulin levels, were summarized in terms of basal values and values after the end of treatment for each study. A total of 8 studies were included in the final analysis. There was no significant difference in the reduction in IR between the SVR and non-SVR groups (odds ratio, 0.995; 95% CI=0.613–1.616; P=0.984). However, the SVR group had a significantly higher mean reduction in HOMA-IR (difference in means=−0.485; 95%CI=−0.713 to −0.256; P<0.001) and HOMA-β (difference in means=−15.448; 95%CI=−23.326 to −7.570; P<0.001) compared to the non-SVR group. In conclusion, HCV patients who achieved SVR after IFN-based therapy exhibited improvement in HOMA-IR and HOMA-β. The present results suggest that clinical management of IR and serum glucose levels may be an important way to impact the therapeutic response in HCV patients.

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Sustained virological response following chronic hepatitis C treatment is associated with improvement in insulin resistance

Cited by 7 publications

References 37 publications

Inhibition of IRS-1 by hepatitis C virus infection leads to insulin resistance in a PTEN-dependent manner

Inhibition of IRS-1 by hepatitis C virus infection leads to insulin resistance in a PTEN-dependent manner

The benefits of hepatitis C virus cure: Every rose has thorns

Effect of HCV treatment response on insulin resistance: A systematic review and meta‑analysis

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