This review indicates that patients with HCV infections were at higher risk of developing type 2 DM compared with patients with HBV infection. Findings of this review are comparable with a previous review[14
], and a large sample-individual study[56
]. In the 2008 review[14
] an excess risk of type 2 DM in HCV-infected cases was observed in comparison to HBV-infected controls (summary OR: 1.63, 95% CI: 1.11-2.39). In the present analysis, this is also encountered (summary OR: 1.92, 95% CI: 1.41-2.62) and the association becomes stronger over time.
As both these viruses can replicate in extra-hepatic sites they can produce β-cell damage resulting in diabetes[10,61
]. The lower risk in HBV infection could be explained by two factors: (1) Hepatitis B has been controlled in most developed countries, with active HBV vaccination programme; the occurrence of chronic HBV and its complications in these countries is very low; and (2) The disease progression is rather fast in HBV infection and therefore very few patients reach the level of cirrhosis and thus diabetes frequency is lower in this population[61
An excess risk of type 2 DM in HCV infected cases was also observed in comparison to non-HCV infected controls in the present analysis (summary OR: 1.63, 95% CI: 1.11-2.39). The evidence of heterogeneity in these studies could be explained by variation in definition of case and control subjects and in the sample size of the primary studies.
Available studies had suggested that an expression of the HCV core protein induces hepatic insulin resistance through alterations in signaling in the insulin receptor substrate-1 pathway. This, along with other factors such as diet and obesity, can result in expression of the diabetic phenotype[38,61,68-70
]. When insulin resistance reaches extents no longer compensated by the β-cell, insulin secretion declines and hyperglycemia emerges[10,68,70
]. The complex interaction of chronic HCV infection with the host hepatic glucose and lipid metabolism has not been fully understood[10,65,67,70
] and it remains to be determined.
In the studies identified, anti-HCV antibody was assessed only at the entry point of the study. Anti-HCV is considered as time-varying[43
]. As such, there may be a likelihood of changes in serological status of anti-HCV over the study period. Liver disease and endocrine disorders, both common in the general population, have a bidirectional and complex relationship[69
]. In addition, it is conceivable that patients with an earlier stage of chronic HCV infection have β-cell dysfunction but that diabetes does not become established until cirrhosis has supervened. Thus, a combination of β-cell dysfunction and insulin resistance is required for overt expression of diabetes mellitus[2,10,45
]. Patients in some of the primary studies were not confirmed for the absence of cirrhosis by liver biopsy which is the best predictor of disease progression[2
]. As such, we were unable to rigorously exclude cirrhosis individuals from the present analysis, and including these patients in the analysis may have exaggerated the association estimated. Of interest, it has been postulated that HCV has a permissive rather than a direct effect on the development of diabetes and acts in concert with other determinants to lead to diabetes[70
]. Recent animal model evidence suggests a more direct effect of HCV infection on insulin resistance in the liver[38
] indicating the role of hepatic tumor necrosis factor-α in affecting insulin signaling in this animal model of HCV infection[71
]. In the present review, as cross-sectional and longitudinal prospective studies both show the same evidence, an excess type 2 DM risk in HCV-infected persons suggests a direct role of HCV in inducing derangement of glucose metabolism[9,10,45
]. Further, there may be other factors influencing the development of type 2 DM in HCV infected patients which is not possible to address in the present analysis.
There are limitations to the present study. Most, if not all, observational studies have the potential for ascertainment bias[10,70
] particularly for the studies in which diabetes status was defined by self report. Thus, there may be biased estimates of association. Moreover, recall bias is a factor in case-control studies. Although confounding factors were addressed in many of these observational studies, it is likely that there may be unmeasured confounding factors which may introduce bias into our findings. Further, as patient level data were not available for each study, we could not make further adjustments for important factors such as genotype that were not included in most of the primary studies.
Findings of those prospective studies[42,53,66
] which have measured HCV prior to diagnosis of type 2 DM support evidence for a temporal relationship between exposure and outcome. In a study[43
], a significant link between viral load and diabetes was found and it supported the diabetogenic role of HCV infection. The influence of viral load on the progression rate of type 2 DM was not examined in most of the studies. More research is needed to assess a dose-response association. It is also recommended that surveillance of HCV could indicate whether trends in its incidence continue to reflect changes in the prevalence of type 2 DM in the defined group.
Public health implications
If the associations do support temporality, the early detection and provision of aggressive antiviral treatment for HCV could prevent the development of type 2 DM, particularly in patients at high risk of HCV.
Nevertheless, the findings of the current analysis, to a certain extent, represent the HCV endemic countries. The present study has significant strengths in two ways: (1) It is comprehensive, including most recent studies; and (2) It addresses traditional risk factors (age, gender, BMI, family history of diabetes) which could potentially affect the outcome. As the prevalence of obese patients obtained in the group of HCV-positive patients with type 2 DM was significantly lower than that in diabetic HCV-negative patients found in an independent study[8
] and also in the present meta-analysis, it is suggesting the pathogenesis of diabetes in HCV infection could be different from that in the general population.