Can personalised antioxidant screening and prescription improve cardiovascular and metabolic health in individuals with pre-diabetes and type 2 diabetes: PRESCRIBE.

Clinical Trial Registry This study is a single-site, parallel, randomized controlled trial comparing the effect of 3 months of personalised antioxidant treatment to generic antioxidant treatment and placebo. 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 dual-energy X-ray absorptiometry) will be measured. Medical, lifestyle and dietary questionnaires will be used to assess overall health, physical activity and dietary habits. Vascular function and metabolic responses to exercise (maximal and functional capacity) and mixed nutrient meal ingestion will be performed before and after the 3-month intervention (personalised antioxidant treatment, generic antioxidant treatment, and placebo). Maximal and functional exercise capacity: Maximal exercise capacity will be assessed using a symptom limited graded exercise test on a treadmill and standard cardiopulmonary stress equipment. Functional exercise capacity will be assessed with a 6-minute walk test and 2-minute step test. Mixed nutrient meal test: Participants will be provided a mixed nutrient meal to consume within 5 minutes. The mixed meal constitutes 1256 kJ of total energy (approximately 21.6 g protein, 4.9 g fat, 40 g carbohydrate). Vascular measures: Resting and post-exercise echocardiographic assessment will be performed using a commercial ultrasound machine. Microvascular blood flow in skeletal muscle will be measured via contrast enhanced ultrasound imaging of the thigh muscle. Femoral artery blood velocity, diameter and flow will be assessed using 2D and Doppler imaging. Quality of life will be assessed via EuroQol five-dimensional questionnaire (EQ5D) and the 36-Item Short Form Health Survey (SF-36). 3-MONTH INTERVENTION Vitamin C levels will be assessed during the screening phase. Participants will be classified as having either “low vitamin C” (less than 28 µmol/L) or “normal vitamin C” (greater than or equal to 28 µmol/L) using standard clinical cut-offs for vitamin C levels. Both a low vitamin C group and a normal vitamin C group will be split and randomised to undergo either 3 months of personalised antioxidant treatment, generic antioxidant treatment, or placebo. Groups will be matched for age, BMI, sex, glucose management (HbA1c levels) and exercise capacity (VO2peak). The “low vitamin C” groups that undergo personalised, generic, and placebo treatment, will be counterbalanced to ensure that individuals with a vitamin C deficiency of less than 11 µmol/L will be similar across groups. Individuals with low vitamin C level will be randomised to: • Personalised antioxidant treatment (n = 26): Oral vitamin C (2 x 500 mg/day) for 12 weeks, as previously done in healthy adults. • Placebo treatment (n = 26): Oral placebo capsules containing an inert powder (Avicel) (2 x 500 mg/day). Individuals with normal vitamin C level will be randomised to: • Generic antioxidant treatment (n = 26): Oral vitamin C (2 x 500 mg/day) for 12 weeks, as previously done in healthy adults. • Placebo treatment (n = 26): Oral placebo capsules containing an inert powder (Avicel) (2 x 500 mg/day). Capsule counting will be conducted to measure compliance of the antioxidant and placebo intervention. Note: Vitamin C supplementation in individuals with normal vitamin C levels is considered generic treatment as it is not targeting a specific deficiency, and therefore hypothesised to be less effective at improving health outcomes.