Diabetes and infections-hepatitis C: is there type 2 diabetes excess in hepatitis C infection?

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.

Meta-analysis: the association between HIV infection and extrapulmonary tuberculosis.

BACKGROUND: Extrapulmonary tuberculosis has been an AIDS-defining condition. Individual studies that highlight the association between HIV and extrapulmonary TB are available. Our objectives were to synthesis evidence on the association between extrapulmonary tuberculosis and HIV and to explore the effective preventive measures of these two diseases. METHODS: This is a meta-analysis of observational studies reporting effect estimates on how HIV is associated with extrapulmonary tuberculosis. We searched for the eligible studies in the electronic databases using search terms related to HIV and extrapulmonary tuberculosis. Where possible, we estimated the summary odds ratios using random effects meta-analysis. We stratified analysis by the type of study design. We assessed heterogeneity of effect estimates within each group of studies was assessed using I (2) test. RESULTS: Nineteen studies (7 case control studies and 12 cohort studies) were identified for the present study. The pooled analysis shows a significant association between HIV and extrapulmonary tuberculosis (summary odds ratio: 1.3; 95 % confidence interval (CI) 1.05-1.6; I (2): 0 %). In a subgroup analysis with two studies, a significant association was found between CD4+ count less than 100 and the incidence of extrapulmonary tuberculosis (summary OR: 1.31; 95 % CI 1.02-1.68; I (2): 0 %). CONCLUSIONS: Findings show evidence on the association between extrapulmonary tuberculosis and HIV, based on case control studies. Further studies to understand the mechanisms of interaction of the two pathogens are recommended.

Relationship between hepatitis C virus infection and type 2 diabetes mellitus: meta-analysis.

AIM: To investigate the association between hepatitis C infection and type 2 diabetes mellitus. METHODS: Observational studies assessing the relationship between hepatitis C infection and type 2 diabetes mellitus were identified via electronic and hand searches. Studies published between 1988 to March 2011 were screened, according to the inclusion criteria set for the present analysis. Authors performed separate analyses for the comparisons between hepatitis C virus (HCV) infected and not infected, and HCV infected and hepatitis B virus infected. The included studies were further subgrouped according to the study design. Heterogenity was assessed using I(2) statistics. The summary odds ratios with their corresponding 95% CIs were calculated based on a random-effects model. The included studies were subgrouped according to the study design. To assess any factor that could potentially affect the outcome, results were further stratified by age group (proportion of ≥ 40 years), gender (proportion of male gender), body mass index (BMI) (proportion of BMI ≥ 27), and family history of diabetes (i.e., self reported). For stability of results, a sensitivity analysis was conducted including only prospective studies. RESULTS: Combining the electronic database and hand searches, a total of 35 observational studies (in 31 articles) were identified for the final analysis. Based on random-effects model, 17 studies (n = 286,084) compared hepatitis C-infected patients with those who were uninfected [summary odds ratio (OR): 1.68, 95% CI: 1.15-2.45]. Of these 17 studies, 7 were both a cross-sectional design (41.2%) and cohort design (41.2%), while 3 were case-control studies (17.6%). Nineteen studies (n = 51,156) compared hepatitis C-infected participants with hepatitis B-infected (summary OR: 1.92, 95% CI: 1.41-2.62). Of these 19 studies, 4 (21.1%), 6 (31.6%) and 9 (47.4%) were cross-sectional, cohort and case-control studies, respectively. A sensitivity analysis with 3 prospective studies indicated that hepatitis C-infected patients had a higher risk of developing type 2 diabetes compared with uninfected controls (summary odds ratio: 1.41, 95% CI: 1.17-1.7; I(2) = 0%). Among hepatitis C-infected patients, male patients (OR: 1.26, 95% CI: 1.03-1.54) with age over 40 years (summary OR: 7.39, 95% CI: 3.82-9.38) had an increased frequency of type 2 diabetes. Some caution must be taken in the interpretation of these results because there may be unmeasured confounding factors which may introduce bias. CONCLUSION: The findings support the association between hepatitis C infection and type 2 diabetes mellitus. The direction of association remains to be determined, however. Prospective studies with adequate sample sizes are recommended.