Brain-Heart Axis in Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disease characterized by insulin resistance and persistent hyperglycemia. Beyond disturbances in glucose metabolism, T2DM has profound effects on the central nervous system, autonomic nervous system, cardiovascular function, cognition, and mental health. Previous studies have demonstrated that individuals with T2DM have an increased risk of cognitive decline, cardiac autonomic neuropathy, reduced functional capacity, and psychological disorders such as depression and anxiety. Although electroencephalography (EEG) and heart rate variability (HRV) have independently been used to evaluate neural and autonomic dysfunction in T2DM, few studies have investigated these parameters simultaneously within the framework of the brain-heart axis.

The brain-heart axis describes the bidirectional interaction between cortical neural activity and autonomic cardiovascular regulation. Metabolic abnormalities associated with T2DM may alter cortical electrical activity, impair autonomic balance, and consequently influence cognitive performance, physical function, and psychological well-being. A comprehensive evaluation integrating these multidimensional outcomes may improve understanding of the systemic consequences of T2DM and identify potential biomarkers for early neurocardiac dysfunction.

The primary objective of this cross-sectional study is to investigate the relationships between metabolic status and brain-heart axis function in adults with T2DM. Specifically, the study will evaluate whether metabolic abnormalities are associated with alterations in EEG-derived brain activity and HRV-derived autonomic function and whether these neurophysiological changes are related to functional capacity, cognitive performance, physical activity level, and mental health.

Approximately 50 adults aged 40-65 years with a confirmed diagnosis of T2DM will be recruited from participating clinical centers. Eligible participants must be able to complete all study assessments and provide written informed consent. Individuals with neurological, psychiatric, orthopedic, or other severe systemic disorders that may interfere with study assessments, recent surgery, or cognitive impairment preventing completion of evaluations will be excluded.

Demographic and clinical characteristics will be collected from medical records, including age, medication use, medical history, HbA1c, fasting blood glucose, lipid profile, C-reactive protein, erythrocyte sedimentation rate, and other routine clinical parameters. No invasive procedures will be performed specifically for this study.

Cardiac autonomic function will be assessed using resting heart rate variability (HRV) recordings obtained with a Polar heart rate sensor. Time-domain parameters (including RMSSD, SDNN, pNN50, mean RR interval, and total power) and frequency-domain parameters (LF, HF, LF/HF ratio, LF peak, and HF peak) will be analyzed according to established recommendations.

Brain electrical activity will be evaluated using resting-state electroencephalography (EEG) performed under standardized laboratory conditions. EEG recordings will be obtained using the international 10-20 electrode placement system. After artifact removal and signal preprocessing, spectral analyses will be performed to quantify delta, theta, alpha, and beta frequency bands. Additional analyses will include frontal alpha asymmetry, theta/alpha ratio, and, when appropriate, functional connectivity between cortical regions.

Functional capacity will be evaluated using the 1-Minute Sit-to-Stand Test and the 6-Minute Walk Test according to standardized international procedures. Cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA). Physical activity level will be measured with the International Physical Activity Questionnaire-Short Form (IPAQ-SF), while psychological status will be evaluated using the Depression Anxiety Stress Scale (DASS-21) and the Hospital Anxiety and Depression Scale (HADS). All assessments will be completed during a single visit lasting approximately 60 minutes.

Statistical analyses will be performed using IBM SPSS Statistics and AMOS software. Descriptive statistics will summarize participant characteristics. Pearson or Spearman correlation analyses will initially examine associations among metabolic markers, HRV, EEG parameters, functional capacity, cognition, physical activity, and psychological measures. Path analysis will subsequently be performed to investigate the direct and indirect effects of metabolic status on functional capacity through autonomic function and cortical activity. Structural equation modeling (SEM) will be used to evaluate the hypothesized brain-heart axis model, with model fit assessed using χ²/df, Comparative Fit Index (CFI), Tucker-Lewis Index (TLI), Root Mean Square Error of Approximation (RMSEA), and Standardized Root Mean Square Residual (SRMR). Statistical significance will be defined as p < 0.05.

The findings of this study are expected to improve understanding of the neurophysiological mechanisms linking metabolic dysfunction with autonomic regulation, cognition, functional performance, physical activity, and mental health in T2DM. Furthermore, identifying brain-heart axis alterations associated with metabolic control may contribute to earlier detection of neurocardiac dysfunction and support the development of more comprehensive rehabilitation and disease management strategies.