Exercise and Diabetes Interventions to Improve Brain Health in Older Adults With Type 2 Diabetes

Metabolic Optimization and Training InterVentions for Aging and Type 2 Diabetes to Enhance Cognition: the MOTIVATE Study

Type 2 diabetes and low levels of physical activity are associated with an increased risk of cognitive decline in older adults. Improving blood sugar control and engaging in regular exercise may help support brain health and physical function in this population.

The MOTIVATE study is a randomized clinical trial designed to examine the effects of supervised exercise and diabetes treatment with semaglutide, alone or in combination, on cognitive function, physical health, and brain-related outcomes in older adults with Type 2 diabetes. Participants will be assigned to one of four study groups involving exercise training, control exercise, semaglutide treatment, or standard diabetes care.

Participants will complete supervised exercise sessions three times per week for 32 weeks, with some participants also receiving weekly semaglutide injections for 16 weeks. Assessments will include cognitive testing, physical and functional measures, blood-based metabolic markers, and brain imaging. This study aims to improve understanding of how exercise and diabetes treatments may support brain health in older adults with Type 2 diabetes.

Type 2 diabetes (T2D) and lack of engagement in physical activity are common in Canada, significantly increasing the risk of dementia among older adults. High blood sugar levels in people living with T2D are linked to poorer cognitive performance and faster cognitive decline. Even those at risk for T2D, due to slightly elevated blood sugar levels or being overweight, show signs of cognitive decline and brain abnormalities. Studies show that improving blood sugar control, losing weight, and engaging in physical activity can enhance cognitive function in long-term and spatial memory and decision-making.

Semaglutide is primarily used to lower blood sugar levels, while resistance exercise is known to improve brain health and physical fitness. Thus, short-term pharmacotherapy in adjunct to RE may serve as a powerful therapy for older adults with T2D to achieve and sustain clinically relevant improvements in cognitive function and glycemic control, and to facilitate a healthier lifestyle.

The present trial is a 32-week, real-world, randomized, open-label waitlist-controlled trial designed to show improvements in cognitive function and compare the effect of injectable semaglutide once-weekly versus standard of care as a short-term (16-weeks) adjunct to resistance exercise (RE) (32 weeks) versus its active control (balance-and-tone training (BAT)) in older adults with T2D. Participants will be randomly put into one of four groups: 1) drug and exercise, 2) no drug and exercise, 3) standard of care and non- intense exercise, or 4) standard of care and non-intense exercise. Exercise will be conducted in classes involving either resistance exercise (weighted movements using exercise machines) or an active control, balance and tone exercise (stretching and core).

Cognitive function will be assessed using tasks of memory, learning, flexibility, and processing of information. Brain structure and function will be examined through magnetic resonance imaging (MRI) scans. Blood samples will be analyzed for markers of brain health and inflammation. After randomization, all outcome assessors will remain blinded to the study drug and exercise groups.

Inclusion Criteria:

1. Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.
2. Community-dwelling
3. Male or female
4. Age ≥ 65 at the time of signing informed consent
5. Glycated hemoglobin levels of ≥7% (i.e., A1c levels high enough to see intervention-related changes and increase eligibility for recruitment, but can exercise safely)
6. Eligible for the Ontario Drug Benefit (inadequate glycemic control and on max tolerated dose of metformin or metformin contraindicated or inappropriate)
7. Score >24/30 on the Mini-Mental State Exam (MMSE)
8. Score >6/8 on the Lawton Instrumental Activities of Daily Living Scale (IADL)
9. Have visual acuity of >20/40 with or without corrective lenses
10. Speak and understand English fluently
11. Complete the Physical Activity Readiness Questionnaire (PAR-Q+) and obtain physician clearance to start a supervised exercise program
12. Comfortable with a blood draw
13. Not currently engaging in structured resistance exercise more than once per week

Exclusion Criteria:

1. Have a medical condition for which semaglutide or exercise is contraindicated
2. Use of a GLP-1 receptor agonist in the past 6 months (i.e., offers removal of Semaglutide from the system as it has a half-life of around 1 week; thus, 8-10 weeks are required for a washout.

3) Have engaged regularly (>1/week) in aerobic or RE within the past 6 months 4) Have a neurodegenerative disease (i.e., dementia) or psychiatric condition 5) Have had untreated depression in the past 6 months (6) Have experienced a recent vascular incident (i.e., stroke, myocardial infarction in the last 6 months.) (7) Have severe peripheral neuropathy, an active foot wound, or severe musculoskeletal/joint disease (8) Active or untreated retinopathy (9) Taking psychotropic medications (excluding those for the treatment of depression)