Age-related differences in T cell subsets and markers of subclinical inflammation in aging are independently associated with type 2 diabetes in the Health and Retirement Study.

AIMS: Age-related changes in adaptive immunity and subclinical inflammation are both important risk factors for diabetes in older adults. We evaluated the independent association between T cell subsets, subclinical inflammation, and diabetes risk in the Health and Retirement Study (HRS).

METHODS: We measured 11 T cell subsets, five pro-inflammatory markers, and two anti-inflammatory markers from the 2016 wave of HRS (baseline). Diabetes/prediabetes status was estimated at the 2016, 2018, and 2020 waves of HRS based on levels of blood glucose/HbA1C in plasma or self-reported status. We used survey generalized logit models to evaluate the cross-sectional associations and Cox proportional hazard models to evaluate longitudinal associations.

RESULTS: Among 8540 participants (age 56-107), 27.6% had prevalent type 2 diabetes and 31.1% had prediabetes in the 2016 survey. After adjusting for age, sex, race/ethnicity, education, obesity, smoking, comorbidity index and cytomegalovirus (CMV) seropositivity, individuals with type 2 diabetes had lower naïve T cells and higher memory and terminal effector T cells as compared to normoglycemic individuals. Among 3230 normoglycemic participants at the 2016 survey, the incidence of diabetes was 1.8% over four years of follow up. The baseline percentage of CD4+ effector memory T cells was associated with a lower risk of incident diabetes (HR=0.63; 95% CI [0.49, 0.80], p=0.0003) after adjustment for covariates. Baseline levels of Interleukin-6 (IL-6) was associated with risk of incident diabetes (HR=1.52; 95% CI [1.18, 1.97], p=0.002). The associations between age-related changes in CD4+ effector memory T cells and risk of incident diabetes remained unchanged after adjustment for subclinical inflammation, though adjusting for CD4+ effector memory T cells nullified the association between IL-6 and incident diabetes.

CONCLUSIONS: This study showed that the baseline percentage of CD4+ effector memory T cells was inversely associated with incident diabetes independent of subclinical inflammation, though CD4+ effector memory T cell subsets affected the relationship between IL-6 and incident diabetes. Further studies are needed to confirm and investigate mechanisms by which T cell immunity affects diabetes risk.