Incretin Therapy and Exercise in Type 2 Diabetes

Type 2 diabetes (T2D) is associated with alterations in cognitive function, mental health, and the regulation of appetite and food intake. Incretin-mimetic therapies are increasingly used in the management of T2D and improve glycemic control while reducing appetite and body mass. However, their effects on brain health remain poorly understood. In addition, body mass loss during incretin-mimetic therapy can include loss of lean tissue, which may have implications for metabolic health and physical function. Exercise is a cornerstone of T2D management and has beneficial effects on glycemic control, body composition, physical function, cognitive function, and mental health. Whether structured exercise provides additional brain-health benefits during incretin-mimetic therapy while helping to preserve lean tissue and physical function remains unclear.

The primary objective of this randomized controlled trial is to characterize changes in brain health during incretin-mimetic therapy and determine whether the addition of structured exercise provides additional benefit. Brain health will be considered across three complementary domains: cognitive performance, mental health, and brain-mediated appetite regulation. The study will also examine changes in body composition and metabolic and physical health to determine whether exercise helps preserve lean tissue and physical function during incretin-mimetic therapy.

A secondary objective is to investigate the microbiota-gut-brain axis (MGBA) and motor-cortex neuroplasticity as potential mechanistic correlates of brain-health responses. The MGBA represents bidirectional communication between the gut and brain and may influence cognitive and mental health as well as homeostatic and hedonic regulation of food intake. Gut microbial communities will be characterized using 16S rRNA gene sequencing and bioinformatics to examine changes in microbial diversity and composition.

Motor-cortex neuroplasticity will be assessed using transcranial magnetic stimulation (TMS). A standardized stimulation protocol will be used to induce changes in motor-cortex excitability, with changes in motor-evoked responses used to quantify the neuroplastic response. These measures will be used to investigate whether changes in motor-cortex neuroplasticity are associated with changes in brain-health outcomes.

Together, the study will examine the complementary effects of pharmacological and exercise-based approaches to T2D management and investigate biological factors that may contribute to brain-health responses during treatment.

Inclusion criteria

• adults aged 18 years or older
• diagnosed with pre diabetes or type 2 diabetes
• prescribed incretin-based therapy (e.g., semaglutide or tirzepatide)
• able and willing to participate in the study assessments and, if randomized to the exercise group, the 24-week structured exercise program
• able to provide informed consent

Exclusion criteria

• current use of incretin-based therapy outside the study-defined enrollment window
• pregnant or planning to become pregnant during the study period
• any other medical condition or circumstance that, in the opinion of the research team, would interfere with safe participation or completion of study procedures