Abstract:
Background: Type 2 Diabetes Mellitus (T2DM) is associated with an increased risk of cognitive decline, yet the combined influence of disease duration, cardiorespiratory fitness, and circulating biomarkers of inflammation and neurotrophic support is not fully elucidated.?
Objectives: This study examined differences in cognitive performance, exercise capacity, and neurobiological biomarkers between individuals with early versus longer?duration T2DM and identified clinical and biomarker correlates of global cognition.?
Methods: In this cross?sectional study, adults with T2DM were categorized into early (≤5 years since diagnosis) and longer?duration (>5 years) groups. Cognitive function was assessed using the Addenbrooke’s Cognitive Examination–III (ACE?III), Montreal Cognitive Assessment (MoCA), and Mini?Mental State Examination (MMSE). Exercise capacity and physical function were evaluated by maximal oxygen uptake (VO?max), 6?minute walk distance (6MWD), and handgrip strength. Serum concentrations of interleukin?6 (IL?6), dopamine, serotonin (5?HT), insulin?like growth factor?1 (IGF?1), and S100B were quantified. Between?group differences were analyzed using appropriate parametric or non?parametric tests, and associations between cognitive scores, exercise measures, and biomarkers were explored using Pearson correlation and multivariable linear regression adjusted for age, sex, education, diabetes duration, body mass index, and HbA1c.?
Results: Participants with longer?duration T2DM showed significantly lower global cognitive scores, including ACE?III and MoCA, compared with those with early T2DM, alongside reduced VO?max and shorter 6MWD. The longer?duration group also demonstrated a more pro?inflammatory and neurotrophically adverse biomarker profile, with higher IL?6 and S100B and lower IGF?1. Across the entire cohort, better cognitive performance correlated positively with VO?max and 6MWD, and negatively with IL?6 while positively with IGF?1. In multivariable models, VO?max, IL?6, and IGF?1 emerged as independent predictors of ACE?III scores, whereas the effect of diabetes duration was attenuated after adjustment for these variables.?
Conclusions: Longer?duration T2DM is associated with poorer cognitive function, diminished cardiorespiratory fitness, and an unfavourable inflammatory and neurotrophic biomarker profile. Cardiorespiratory fitness and specific biomarkers of inflammation and neurotrophic support show independent links with global cognition, supporting intervention strategies that enhance fitness and modulate inflammatory pathways to help preserve cognitive health in individuals with T2DM.?
