Scientists examine the impact of herpesviruses on (pre)diabetes

Scientists recently analyzed the association between herpes viruses and type 2 diabetes. This study is available in the journal Diabetology.

Study: Health impact of seven herpesviruses on the incidence of (pre)diabetes and HbA1c: results of the KORA cohort. Image Credit: Negro Elkha / Shutterstock

Herpesvirus and type 2 diabetes: background

Typically, humans are infected with eight different herpes viruses, namely herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus (VZV ), cytomegalovirus (CMV) and human herpes viruses (HHV). All of these viruses can cause lifelong latent infection after an initial mild systemic infection.

Type 2 diabetes is one of the most common metabolic diseases. A person is known to be prediabetic when diagnosed with impaired glucose tolerance (IGT) or impaired fasting blood sugar (IFG). Studies have shown that people with prediabetes are much more likely to develop type 2 diabetes than those with normal blood sugar levels. Additionally, several studies have identified both genetic factors as well as other relevant factors, such as obesity, poor diet, and inflammation, that increase the risk of type 2 diabetes.

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Researchers have found that type 2 diabetes reduces the body’s innate and adaptive immune abilities, thereby making an individual more susceptible to infections. A high volume of research has shown that diabetes increases the risk of viral infection. These studies have reported that people with diabetes are at greater risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hepatitis B and hepatitis C.

Recently, scientists have established an etiological link between viruses, namely enteroviruses and Coxsackieviruses, and type 1 diabetes. Interestingly, an increased prevalence of HHV8 has been observed in type 2 diabetic patients in several populations. Further longitudinal studies are therefore needed to understand the potential link between herpes virus infection and (pre)diabetes.

The link between viruses and diabetes – A new study

The present population-based longitudinal cohort study investigated the association of the seven herpes viruses, i.e., HSV1, HSV2, VZV, EBV, CMV, HHV6, and HHV7, with the incidence of ( pre)diabetes. In addition, the researchers cross-sectionally analyzed their relationship with HbA1c (average blood sugar measurement over the past two months).

The scientists obtained data from KORA, a population-based health research platform in Germany. They conducted follow-up studies of the KORA study cohort using the F4 (2006-2008) and FF4 (2013-2014) studies. The researchers identified candidates with normal glucose tolerance at baseline. These candidates had a higher risk of (pre)diabetes. All participants underwent extensive phenotyping, including viral multiplex serology for human herpesviruses, oral glucose tolerance test (OGTT), and HbA1c.

Proportion of virus selection and confounding factors in two LASSO logistic models on the incidence of (pre)diabetes (n = 1257 participants).  The first model (blue) includes only the serological status of the seven herpes viruses tested, and the second model (red) additionally includes confounders.  We report the proportion of selection calculated on 1000 calibrated models adjusted to 80% of the total population, each including the same proportion of incident cases.  For each model, the penalty was calibrated using fivefold cross-validation.  The proportion of selection for each variable was derived by summing the number of times it was included in the 1000 β models (95% CI)Proportion of virus selection and confounding factors in two LASSO logistic models on the incidence of (pre)diabetes (n = 1257 participants). The first model (blue) includes only the serological status of the seven herpes viruses tested, and the second model (red) additionally includes confounders. We report the proportion of selection calculated on 1000 calibrated models adjusted to 80% of the total population, each including the same proportion of incident cases. For each model, the penalty was calibrated using fivefold cross-validation. The proportion of selection for each variable was derived by summing the number of times it was included in the 1000 β models (95% CI)

Main findings

The researchers limited their studies to participants with normal glucose tolerance at baseline to reduce the risk of reverse causation. The current study reported a correlation between seropositivity for HSV2 and CMV, and the incidence of (pre)diabetes. Multivariate analysis revealed that the above viruses consistently influence the prevalence of (pre)diabetes, independent of education, age, smoking status, gender, BMI, physical activity, hypertension, insulin resistance, lipid levels and fasting blood glucose.

Scientists observed that HSV2 was cross-linked to HbA1c, independent of the confounding factors mentioned above. Although a marginal improvement in blood sugar levels in people without diabetes is unlikely to compromise the immune system, cross-sectional modeling was unable to distinguish between directions of causal effects.

Although previous studies have indicated that herpes viruses are persistent in the host, they might not be detected by blood antibody testing due to changes in the host’s immune system or the body’s immune system. viral activity. Scientists have stated that in most cases, herpes virus infection occurs in early childhood; however, infection at later ages is possible. Therefore, the seroconversion observed in this study indicates incident cases, which could be due to increased antibody reactivity of a previously undetectable virus. The researchers said an individual without HIV does not mean they are cured as the virus could be in its undetectable latency state.

Limitation of this current study

One of the limitations of the current study is that the serological analysis did not fully capture past infections. Generally, the level of antibodies is influenced by the severity of infection, the strength of immune responses during primary infection, the virus-host interaction, and the potential for recurrent infections. In this study, researchers observed inconsistencies in HIV status between two time points that were not explained by incident cases.

The scientists lacked relevant information about the acute herpesvirus manifestations of the study cohort, so they were unable to determine the underlying cause of the observed seroconversion. Another limitation of the study is that the viral multiplex test for HHV6 and HHV7 has not been validated. This is due to the lack of availability of a standardized multiplex test.

Conclusion

The current study linked HSV2 and CMV seropositivity with the incidence of (pre)diabetes after adjusting for confounding factors. It also documented a cross-sectional association of HSV2 serostatus with HbA1c, independent of confounding factors. In the future, the pathogenetic mechanisms associated with HSV2 and CMV in the development of (pre)diabetes should be investigated.

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