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ORIGINAL ARTICLE
Year : 2017  |  Volume : 44  |  Issue : 2  |  Page : 100-105

Insulin resistance and tumor necrosis factor-α in chronic viral hepatitis C in Makurdi, Nigeria


1 Department of Chemical Pathology, Federal Medical Centre, Makurdi, Nigeria
2 Department of Medical Laboratory Science, Chemical Pathology Unit, University of Calabar, Calabar, Nigeria

Date of Web Publication11-Oct-2017

Correspondence Address:
Ayu Agbecha
Department of Chemical Pathology, Federal Medical Centre, Makurdi
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jss.JSS_25_17

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  Abstract 

Background: Type 2 diabetes mellitus has been reported by studies as an extrahepatic manifestation of chronic hepatitis C (CHC). Aim: The present study aimed at determining the impact of CHC disease on insulin resistance (IR) and its correlation with tumor necrosis factor-α (TNF-α) in this infection. Materials and Methods: The present case–control study adopted purposive sampling technique in selecting 36 CHC and 36 anthropometrically matched apparently healthy individuals, who fulfilled the inclusion criteria. CHC was defined as persistent infection without remission for a period up to 1 year. Results: A statistically significant (P < 0.02) elevated TNF-α, fasting serum insulin (FSI), fasting plasma glucose, and homeostasis model of insulin resistance (HOMA-IR) were observed in CHC compared with the controls. The liver function profile of CHC group showed that plasma total protein and albumin were significantly low when compared to controls, whereas significant high aspartate and alanine aminotransferase levels were observed in the CHC group compared to controls. There was a statistically significant (P < 0.001) positive correlation between TNF-α and HOMA-IR (r = 0.751) and TNF-α and FSI (r = 0.694) in CHC patients. Conclusion: CHC disease could induce increased IR, partly mediated by TNF-α. We recommend metabolic profiling of chronic viral hepatitis C patients during disease management.

Keywords: Chronic hepatitis C disease, insulin resistance, tumor necrosis factor-α


How to cite this article:
Agbecha A, Usoro CO, Etukudo MH. Insulin resistance and tumor necrosis factor-α in chronic viral hepatitis C in Makurdi, Nigeria. J Sci Soc 2017;44:100-5

How to cite this URL:
Agbecha A, Usoro CO, Etukudo MH. Insulin resistance and tumor necrosis factor-α in chronic viral hepatitis C in Makurdi, Nigeria. J Sci Soc [serial online] 2017 [cited 2020 Sep 18];44:100-5. Available from: http://www.jscisociety.com/text.asp?2017/44/2/100/216495


  Introduction Top


Hepatitis C virus (HCV) is among the major causes of viral hepatitis in the world.[1] Individuals who fail to spontaneously or naturally clear the virus after acute infection become chronic carriers of the viruses.[2] Chronic hepatitis C (CHC) infection has been described as a disease with numerous extrahepatic manifestations including type 2 diabetes mellitus (T2DM), B-cell lymphoma, mixed cryoglobulinemia, porphyria, and glomerulonephritis.[3]

Insulin actions involve cell signaling comprising a series of complex events. The binding of insulin to its receptor is followed by the phosphorylation of insulin receptor substrate (IRS) proteins, which are linked to the activation of two main signaling pathways: the phosphatidylinositol 3-kinase–Akt/protein kinase B pathway, which is responsible for the majority of the metabolic actions of insulin, and the Ras–mitogen-activated protein kinase pathway, which controls cell growth and differentiation.[4] Pathogenesis of insulin resistance (IR) has been shown to be due to impairment of insulin signaling, predominantly mediated by regulators or modulators of insulin receptor function.[5]

Previous studies have reported an increasing incidence of T2DM in CHC individuals.[6],[7],[8],[9] Studies in Nigeria have also reported incident T2DM in HCV patients.[10],[11],[12] Several studies have linked IR to the incident T2DM, also confirming it to be an extrahepatic manifestation of CHC.[8],[13] Besides causing T2DM, IR in CHC has been shown to be associated with poor outcome of the disease, therapeutic resistance, and development of liver cancer.[14],[15]

Tumor necrosis factor-α (TNF-α) is a cytokine with many functions.[16],[17] Overexpression of pro-inflammatory cytokines has been reported to be stimulated by HCV.[18] Animals exposed to TNF-α on a long-term basis developed IR through modulation of insulin receptor function.[19] Neutralization of TNF-α in the animals resolved the IR.[19] Hotamisligil et al., in 1993, reported the first evidence of a link between TNF-α and IR.[20] Their study revealed that obese animal's adipocytes expressed raised TNF-α level which caused IR. In this scenario too, neutralization of TNF-α with soluble receptors was followed by an improvement in IR in the animals. TNF-α has been reported to be the driving force of IR and glucose metabolism toward the development of T2DM in the obese.[21] This study aimed at determining the impact of CHC disease on IR and its correlation with TNF-α.


  Materials and Methods Top


Selection of participants

This case–control study was conducted over a period of 6 months, in a selected hospital in Makurdi, Nigeria, after ethical approval was obtained from the Institutional Ethics Committee. Informed consent was sought from the individual patients by educating them on the need and relevance of the study. Participants, who agreed to partake in the research, were orally interviewed using the same structured questions to obtain information about bio data and lifestyle in addition to clinical history. The information obtained formed part of the selection criteria for both the test and control groups. The inclusion criteria comprised viral hepatitis C patients, who continuously tested positive for anti-HCV antibody for up to 1 year during their periodic visit to the clinic, as chronic HCV patients. Apparently healthy individuals with desired blood pressure (BP) and anthropometric indices (body mass index [BMI], waist circumference [WC], and age) seronegative for hepatitis B surface antigen (HBsAg) and anti-HCV antibody were included as the controls. The exclusion criteria comprised individuals with conditions that predispose to elevated IR and TNF-α, patients on drugs that affect glucose metabolism, human immunodeficiency virus (HIV)-infected patients, patients with malignancy, and those who were unwilling to participate in the study. After fulfilling the selection criteria and determining the sample size according to the formula described by Daniel,[22] 36 chronic viral hepatitis C patients aged 18–55 years attending clinic in the hospital were purposefully selected as the test group. In addition, 36 apparently healthy anthropometrically matched individuals were randomly selected from the general population as the control group.

Anthropometric measurements

Height and WC were noted using a measuring tape (to the nearest 0.1 cm), with the participants wearing light clothes and no shoes. WC was measured at the midpoint between lower border of the rib cage and the iliac crest. Weight was measured to the nearest 0.1 kg using a mechanical weighing machine. BMI, defined as mass in kilograms divided by the square of height in meters, was calculated.

Sample collection and processing

Fasting venous blood samples were collected from the selected participants. Six milliliters of blood was drawn from each participant aseptically and dispensed as follows: 2 ml of whole blood into fluoride oxalate bottles and plasma extracted for the determination of fasting plasma glucose (FPG). Four milliliters of the whole blood was dispensed into plain tubes and centrifuged after clot retraction. The serum was extracted aseptically and transferred into three labeled separate screw-capped aliquot sample containers. Two of the serum containers were stored frozen separately; serum for enzyme-linked immunoassay (ELISA) TNF-α at −70°C and −20°C for serum ELISA insulin and anti-HCV antibody HBsAg, respectively. The serum in the third container was used for the rapid screening of anti-HCV antibody, anti-HIV antibody, human chorionic gonadotropin, and HBsAg. The serum was also used for liver function profile (total protein, albumin, alkaline phosphatase [ALP], aspartate aminotransferase [AST], and alanine aminotransferase [ALT]).

Determination of analytes

The TNF-α and insulin immunoassay kits, obtained from DRG International, Inc., California, USA, were used for the assay of serum TNF-α and insulin levels, based on the ELISA sandwich principle. Anti-HCV antibody ELISA kit was obtained from Diapro Diagnostic Bioprobes Srl Milano, Italy, were used for the determination of antibodies to HCV in serum. The determination of anti-HCV antibody was based on the ELISA sandwich principle. The reagent kits for the determination of plasma glucose, total proteins, albumin, AST/ALT, and ALP were obtained from Randox Laboratories Ltd., United Kingdom. The Barham and Trinder glucose oxidase method was used in the determination of plasma glucose.[23] The Biuret end point method was used in determining serum total proteins.[24] Serum albumin was determined by the bromocresol green end point method.[25] The aminotransferase enzymes were assayed using the colorimetric end point method of Reitman and Frankel.[26] The reagent kit for the determination of ALP was obtained from Quimica Clinica Aplicada, S.A., Spain, and was determined using the phenolphthalein monophosphate substrate end point method.[27]

Homeostatic model assessment method (HOMA), which has been validated as a reliable measure of insulin sensitivityin vivo in humans, was used to estimate IR (HOMA-IR). IR was determined using a standardized Microsoft Excel HOMA 2 calculator, based on formula proposed by Matthews et al.[28]

Statistical analysis

The statistical package SPSS version 21, IBM Armonk, New York, United States, was used in analyzing the data generated. Descriptive statistics were used in determining the means and standard deviations of the parameters measured. The Student's t-test was used in comparing the means of parameters in CHC and control groups. Pearson's correlation analysis was used to determine the association between parameters measured in the viral hepatitis patients. A two-tailed P < 0.05 was indicative of a statistical significance.


  Results Top


[Table 1] shows the BP, age, WC, BMI, TNF-α, fasting serum insulin (FSI), FPG, and HOMA-IR values. There was no statistically significant (P > 0.05) difference between the mean systolic BP, diastolic BP, age, WC, and BMI of CHC patients and controls. There was a statistically significant (P < 0.02) elevated TNF-α, FSI, FPG, and HOMA-IR in CHC patients than the controls. The liver function profile summarized in [Table 1] shows a statistically significant decrease (P = 0.000) in TP and albumin and statistically significant rise (P = 0.000) in AST and ALT levels in CHC group compared to controls. However, no statistically significant difference (P > 0.05) was observed in ALP levels of CHC and control group.
Table 1: Blood pressure, anthropometric measurements, tumor necrosis factor-α, insulin, fasting plasma glucose, homeostasis model assessment of insulin resistance, and liver function parameters in chronic hepatitis C patients and controls

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[Figure 1] and [Figure 2], respectively, show the correlation between TNF-α and HOMA-IR and TNF-α and FSI in CHC patients. There was a statistically significant (P < 0.001) direct correlation between TNF-α and HOMA-IR (r = 0.751) and TNF-α and FSI (r = 0.694) in CHC patients.
Figure 1: Correlation of tumor necrosis factor-α with homeostasis model of insulin resistance in chronic hepatitis C patients. Y = 0.014x + 1.176, r = 0.751, n = 36, P < 0.001

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Figure 2: Correlation of tumor necrosis factor-α with insulin in chronic hepatitis C patients. Y = 0.865x + 64.10, r = 0.694, n = 36, P < 0.001

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  Discussion Top


Previous studies have reported and confirmed incidental T2DM in CHC disease. Experimental studies have observed IR, a major inducer of metabolic syndrome as a link to incidental T2DM. Based on these unconfirmed findings, previous studies have proposed incidental IR in CHC disease. Studies are ongoing to determine the mechanistic link between CHC disease and IR.[29] Observation by studies regarding the independent association of TNF-α with IR in the obese [16] influenced our choice of this candidate cytokine in the investigation of possible mediators of IR in CHC patients. Immunological TNF-α, synthesized and secreted in large amounts by immune cells in viral infections, has been reported by studies.[18] We hypothesized and proposed this immunological cytokine to be one of the mediators of IR in CHC disease. Our study, therefore, seeks to establish incident IR and further determine the relationship between TNF-α and IR in CHC patients.

Our study found elevated TNF-α, FSI, FPG, and HOMA-IR in CHC patients compared to controls. The study also observed a positive correlation between TNF-α and HOMA-IR and TNF-α and FSI. Hyperinsulinemia and higher fasting IR in CHC imply incident IR in viral hepatitis disease. The positive correlation between TNF-α and IR implies that elevated TNF-α could be the cause of the IR observed in the viral hepatitis patients. The hyperinsulinemia and high IR observed in the CHC are consistent with the findings of Hui et al., Harrison, Shaheen et al., Moucari et al., and Lam et al., who in using the surrogate estimates of IR (HOMA and FSI) observed IR in CHC.[13],[30],[31],[32],[33] The elevated TNF-α observed in CHC in this study is consistent with the findings of Parvaiz et al., who reported the promotion of TNF-α release by HCV.[29] The direct correlation observed in this study between serum TNF-α and IR in CHC is consistent with the works of Maeno et al., Knobler et al., and Sayed-Ahmed et al. who observed and proposed TNF-α as a mediator of IR in CHC.[34],[35],[36] The liver function profile of CHC in this study reveals viral-induced hepatic injury in the CHC group, which is in consonance with confirmed reports.[37] There are reports of loss of liver function of any etiology accompanied with hepatogenous IR, which could result in hepatogenous diabetes in the setting of liver cirrhosis.[37] Thus, IR observed in our CHC group could partly result from viral-induced hepatic injury, independent of immunological TNF-α. The hyperinsulinemia observed in our study is compensatory, brought about by a positive feedback stimulation of the pancreatic β-cells to secrete more insulin into circulation to meet the increasing demands of the body cells in insulin-resistant state.[38] IR has been reported to be mediated by regulators or modulators of insulin receptor and postreceptor functions, which impair insulin signaling.[5]

Shintani et al., Kawaguchi et al., Hung et al., and Hung et al. have shown specific alterations in host metabolism uniquely associated with CHC infection.[39],[40],[41],[42] The structural and nonstructural proteins of HCV have been shown to either have direct or indirect effect on insulin signaling. HCV protein cores, nonstructural protein 3 (NS-3) and NS-5, have shown to be greatly involved in the impairment of insulin signaling.[29] Parvaiz et al reported molecular mechanisms involving direct impairment of HCV protein on insulin signaling. This involves the hypophosphorylation of IRS proteins, phosphorylation of Akt, and stimulation of the expression of gluconeogenic genes.[29]

The indirect effect of HCV proteins on insulin signaling has been shown to be mediated through modulation of TNF-α and other cellular gene expressions, whose products subsequently impair insulin signaling.[29] Promotion of TNF-α release by host immune cells is generally enhanced by viral particles.[17] However, HCV core protein has been shown to increase the expression level of TNF-α, in addition to the stimulatory release of the cytokine.[43] Steinberg et al. reported the impairment of insulin signaling in skeletal muscles by TNF-α through TNF receptor.[44] According to the report, TNF-α action stimulates the synthesis of protein phosphatase 2C, which inactivates activated AMP-protein kinase (AMPK). The enzyme AMPK catalyzes the phosphorylation and activation of acetyl-CoA carboxylase (ACC). The enzyme ACC stimulates free fatty oxidation. Absence or inactivation of ACC results in elevated free fatty acids with the subsequent formation and accumulation of diacylglycerol-mediating IR in skeletal muscles. In adipose tissues, TNF-α has been shown to suppress the expression of many intracellular proteins that are needed for insulin-mediated glucose uptake in adipocytes, such as the insulin receptor, IRS-1, and glucose transporter 4 (GLUT-4).[45] Among the first transcription factors shown to be targeted by TNF-α signaling in adipocytes was the PPARγ. TNF-α suppresses PPARγ activity by inhibiting the expression of PPARγ mRNA or by the suppression of its transcriptional activity and by enhancing the phosphorylation of PPARγ.[45] TNF-α can suppress GLUT-4 expression through suppression of PPARγ activity. Another target gene that is upregulated by TNF-α in adipocytes implicated in adipocyte IR is suppressor of cytokine signaling 3, which inhibits the tyrosine phosphorylation of IRS-1, thereby suppressing insulin-mediated glucose uptake.[45]


  Conclusion Top


The present study shows that CHC disease induces IR, affirmed as the hallmark of metabolic syndrome mediating T2DM. Incident IR in CHC is evidenced by elevated TNF-α which is known to impair insulin actions at the cellular level. More studies are required to determine the direct impact of HCV proteins on insulin signaling pathways in relation to insulin sensitivity. We recommend the assessment of metabolic profile of chronic viral hepatitis C patients during disease management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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