Effect of home-based exercise training on muscle microvascular dysfunction in type 2 diabetes.

This study is a single-site two-armed, parallel, randomized controlled trial comparing the effect of 3 months of home-based exercise training to usual care. Pre-intervention testing: Clinical chemistries and anthropometrics: Fasting clinical chemistries (glucose, insulin, lipid profile, HbA1c, lactate) and body composition (height, weight, hip and waist circumferences and lean/fat mass by DEXA) will be measured. Medical, lifestyle, quality of life, and dietary questionnaires will be used to assess overall health, physical activity, quality of life, and dietary habits. A 6-minute walk test and a 2-minute step test will be conducted to assess functional exercise capacity. Vascular function and metabolic responses to both exercise stress testing and mixed nutrient meal ingestion will be performed before and after a 3-month intervention (home-based exercise training or usual care). Exercise Doppler-echocardiogram: Graded exercise testing will be performed on an exercise bike/treadmill using standard cardiopulmonary stress equipment and symptom limited graded exercise test protocol. Resting and post-exercise echocardiographic assessment will be performed using a commercial ultrasound machine at rest and during exercise testing. Microvascular responses in skeletal muscle during exercise and after mixed nutrient meal ingestion: Microvascular blood flow responses will be tested via contrast enhanced ultrasound imaging of thigh muscle at rest, at the end of the exercise stress tests, and during and after ingesting a mixed nutrient meal. Large artery function and central haemodynamics: Femoral artery blood flow will be assessed using 2D and Doppler imaging at rest, at the end of the exercise stress tests, and during and after ingesting a mixed nutrient meal. Mixed nutrient meal: Participants will be provided a mixed nutrient meal to consume within 5 minutes. The mixed meal nutrient meal constitutes approximately 21.6 g protein, 4.9 g fat, and 40 g carbohydrate with 1256 kJ of total energy. Muscle capillary density/biochemistry: A vastus lateralis muscle biopsy will be performed before and after mixed nutrient meal ingestion. The number of capillaries per mm2 and per muscle fibre will be determined by histology. Oxidative enzyme capacity (e.g. citrate synthase) and cell signalling linked to muscle function and exercise adaptation will be performed via western blot. 3-month Intervention: Following baseline testing, participants will be randomised to either i) usual care or ii) home-based (remote) exercise training for 3 months. Groups will be matched for age, BMI, sex and LV filling pressure (assessed as E/e’ by echo). Randomisation will be in accordance with CONSORT guidelines for non-pharmacological trials, and all researchers performing outcome measures will be blinded to group allocation. i) Home-based exercise training: Participants will be asked to undergo three 35 minute exercise sessions per week, for 3 months. Exercise intensity will be prescribed based of heart rate reserve (HRR; Intensity * (HR peak - HR rest) + HR rest], and can include any type of exercise that elicits the target heart rate (e.g., fast pace walking, jogging, running, walking uphill, cycling). The exercise protocol will include four 4-minute walking/jogging intervals of high-intensity exercise at 80-85% HRR, with each interval separated by 3 minutes of low-intensity exercise at 50% HRR. All exercise sessions will include a 5-minute warm-up and 5-minute cool-down at 50% of HRR. The first week of the home-based exercise training program (three complete exercise sessions) will be conducted at the research facility and will be supervised by an exercise physiologist to help familiarise the participant with this type of exercise and help answer any questions about adapting the exercise for home use/outside the clinic (e.g., using plastic aerobic steps in the house or in their local park, or incorporating other types of aerobic exercise to elicit the target heart rate intensity). Participants will complete the remainder of the training program at home/outside the clinic (i.e., under free living conditions). Research staff will check-in with participants (email, phone, and/or text message) after each training day for the first two weeks of home-based exercise training, and then once a week for the remainder of the training program. Heart rate data after each exercise session will be recorded and uploaded to the commercial Polar Flow online servers using a wearable heart rate strap provided to participants which will be connected to a smart phone (either participant owned or a loaned smartphone). The researchers will then access this server to download the heart rate data to confirm that the prescribed workload (heart rate intensity) was achieved, and to confirm the number of sessions completed over the course of the exercise program (compliance). An android phone will be loaned to participants in the event participants do not have a mobile phone, or would prefer not to use their personal phone for the research study. ii) Usual care: Those participants randomised to this group will be instructed to maintain their normal lifestyle habits, while following usual care (but refrain from increasing physical activity levels). Mid-intervention exercise tolerance testing (after 6 weeks): After 6 weeks of the exercise program or usual care, participants will be asked to attend a single session at the research facility to undergo a 6-minute walk test, 2-minute step test, and a maximal exercise test on a gym bike/treadmill. No ultrasound measures or blood will be taken during this visit. Aerobic capacity (exercise tolerance) will be measured via a face-mask during the maximal exercise test. Post-intervention mixed meal challenge and Cardiopulmonary Exercise Tests: Participants will repeat the same mixed meal challenge and exercise tests as performed in the pre-intervention visits. These visits will be conducted a minimum of 48 hours after the final training session to eliminate the effects of acute exercise. Medical, lifestyle, quality of life, and dietary questionnaires will be completed after the intervention to assess overall health, physical activity, quality of life, and dietary habits.