Health impact of seven herpesviruses on (pre)diabetes incidence and HbA1c: results from the KORA cohort

Abstract

Aims/hypothesis: The prevalence of type 2 diabetes is increasing worldwide, and previous studies have suggested that it is higher in individuals who are seropositive for herpesviruses. This study examines the prospective association of herpesviruses with (pre)diabetes to evaluate their potential role in diabetes aetiology.

Methods: Two follow-up examinations of the German population-based KORA cohort (F4 and FF4) were used to identify participants with normal glucose tolerance at baseline, thus being at risk for (pre)diabetes (n = 1257). All participants had repeated OGTTs and antibody measurements for herpes simplex virus (HSV) 1 and 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus (CMV) and human herpesvirus 6 and 7. Regression models were used to evaluate the association between serostatus with (pre)diabetes incidence after a 7 year follow-up and HbA_1c.

Results: HSV2 and CMV were associated with (pre)diabetes incidence after adjustment for sex, age, BMI, education, smoking, physical activity, parental diabetes, hypertension, lipid levels, insulin resistance and fasting glucose. Seropositivity of both viruses was also cross-sectionally associated with higher HbA_1c at baseline, with the association of HSV2 being independent of confounders, including the prevalence of (pre)diabetes itself. While seropositivity for multiple herpesviruses was associated with a higher incidence of (pre)diabetes, this association was not independent of confounders.

Conclusions/interpretation: The associations of HSV2 and CMV serostatus with (pre)diabetes incidence indicate that these herpesviruses may contribute to the development of impaired glucose metabolism. Our results highlight the link between viral infection and (pre)diabetes, and the need for more research evaluating viral prevention strategies.

Keywords: Cytomegalovirus (CMV); Epstein–Barr virus (EBV); HbA1c; Herpes simplex virus 1 (HSV1); Herpes simplex virus 2 (HSV2); Human herpes virus 6 (HHV6); Human herpes virus 7 (HHV7); Incidence; Prediabetes; Varicella-zoster virus (VZV).

Fig. 1

Associations of herpesvirus seropositivity with incidence of (pre)diabetes using the serostatus of each virus separately as the predictor in logistic regression models (n = 1257, except for VZV for which n = 986; 95% CI in brackets). Results are presented for unadjusted models and for models adjusted for: (1) sex and age, (2) adjusted 1 plus BMI, education, smoking and physical activity, (3) adjusted 2 plus parental diabetes, hypertension, triacylglycerols, total cholesterol/HDL-C and HOMA-IR, and (4) adjusted 3 plus fasting glucose. *p≤0.05, **p≤0.01

Fig. 2

Selection proportion of viruses and confounders in two logistic LASSO models on (pre)diabetes incidence (n = 1257 participants). The first model (blue) only includes the serostatus for the seven assayed herpesviruses, and the second model (red) further includes confounders. We report the selection proportion calculated over 1000 calibrated models fitted on 80% of the full population, each including the same proportion of incident cases. For each model, the penalty was calibrated using fivefold cross-validation. The selection proportion of each variable was derived by summing the number of times it was included across the 1000 models β (95% CI)

Fig. 3

Association of each herpesvirus serostatus separately with HbA_1c. Results are reported for the serostatus and HbA_1c measured at baseline (n = 1967 participants, except for VZV for which n = 1540). We report the regression coefficients (β and 95% CI) for unadjusted models and models adjusted for: (1) sex and age, (2) adjusted 1 plus BMI, education, smoking and physical activity, (3) adjusted 2 plus parental diabetes, hypertension, triacylglycerols, total cholesterol/HDL-C and HOMA-IR, and (4) adjusted 3 plus prevalence of (pre)diabetes. **p≤0.01, ***p≤0.001

Fig. 4

(a) Number of viruses that participants were seropositive for at baseline in relation to (pre)diabetes incidence (n = 1257). (b) Baseline viral co-occurrence with the 15 most common combinatorial patterns representing 1032 of 1257 at-risk participants in bars coloured by (pre)diabetes incidence; p=0.072 by χ² test. Combinations with fewer than 20 participants each are not shown and account for the remaining 225 participants. *p≤0.05