| Outcome Measures: |
Primary: Plasma concentration of 3-hydroxybutyrate, At visit 4 and visit 6, concentration of 3-hydroxybutyrate in plasma at baseline and during the visit (hourly for 8hr) will be measured by an enzymatic assay using PENTRA clinical chemistry analyser. The mean concentration of 3-hydroxybutyrate between 420-480 mins and the AUC of 3-hydroxybutyrate concentration time curve between 0-240 mins and 0-480 mins where the IMP was given at 0 mins in visits 4 and 6 will be calculated.The response will be compared following 4 weeks treatment with dapagliflozin versus placebo., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years | Secondary: Response to exercise testing: Plasma non-esterified fatty acid (NEFA) concentrations, At visit 3 and visit 5, plasma NEFA concentrations will be measured by an enzymatic assay using a clinical chemistry analyser (PENTRA). Plasma NEFA concentration measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) and will be compared following 4-weeks dapagliflozin versus placebo treatment., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Response to exercise testing: Plasma 3-hydroxybutyrate (BOHB) concentration, At visit 3 and visit 5, plasma BOHB concentrations will be measured by an enzymatic assay using a clinical chemistry analyser (PENTRA). Plasma BOHB concentration measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) and will be compared following 4-weeks dapagliflozin versus placebo treatment., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Response to exercise testing: Atrial natriuretic peptide, noradrenaline and adrenaline, At visit 3 and visit 5, plasma ANP, noradrenaline and adrenaline measured by ELISA assays. Atrial natriuretic peptide, noradrenaline and adrenaline concentrations will be measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) will be compared following 4-weeks dapagliflozin versus placebo treatment., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Response to exercise testing: Glucose concentration, insulin and growth hormone, At visit 3 and visit 5, plasma glucose concentration measured by an enzymatic assay on PENTRA, a clinical chemistry analyser and insulin and GH concentrations measured by respective radioimmune assays (RIA). Plasma glucose, insulin and growth hormone concentrations will be measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) and AUC (0-60 minutes)will be compared following 4-weeks dapagliflozin versus placebo treatment., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Response to exercise testing:ECG abnormality, At visit 3 and visit 5, ECG taken at rest and during exercise will be compared following 4-weeks dapagliflozin versus placebo, The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Response to exercise testing: BP, HR and Rate Pressure Product (RPP=HR*SBP), At visit 3 and visit 5, blood pressure (BP) and heart rate taken at rest and during exercise. BP, HR and Rate Pressure Product (RPP=HR\*SBP) will be measured at 0 minutes and at the end of each level of activity will be compared following 4-weeks dapagliflozin versus placebo, The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Response to exercise testing: Carbohydrate and fat oxidation, At visit 3 and visit 5, volumes of inhaled and expired air measured by a Cardio2 Med Graphics breath analyser, (VO2 and VCO2) taken at rest and at the end of each level of activity will allow calculation of carbohydrate and fat oxidation using established mathematical formula. These will be compared following 4-weeks dapagliflozin versus placebo, The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Response to exercise testing: whole blood capillary lactate concentration, At visit 3 and visit 5, whole blood capillary lactate concentration measured by single use test strips (lactate Pro) containing an enzyme coated electrode using a lactate analyser (Lactate Pro) in response to exercise at the end of each exercise activity level will be analysed following 4 weeks treatment with dapagliflozin versus Placebo., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Endogenous glucose production and glucose metabolic clearance rate, At visit 4 and visit 6, plasma glucose enrichment will be measured at basal and in in the last 30 minutes of 2H2-glucose infusion (450-480 min). Enrichment of 2H2glucose in plasma glucose will be measured using gas chromatography mass spectroscopy. Glucose production rate and MCR will be calculated from glucose enrichment data using standard isotope dilution equations. Glucose uptake will be determined by subtracting the rate of glucose excretion from the rate of glucose disappearance. Glucose concentration will be measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480 minutes), The main analysis will be conducted once all participants have completed the metabolic studies approximately within 2 years|Glycerol production rate, At visit 4 and visit 6, plasma glycerol enrichment will be measured at basal and in in the last 30 minutes of 2H5-glycerol infusion (450-480 min). Glycerol production rate and MCR will be calculated from glycerol enrichment data using standard isotope dilution equations., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Palmitate enrichment in plasma NEFA and TAG pools, At visit 4 and visit 6, following Folch extraction of the lipid moiety from plasma enrichment of 13C palmitate in NEFA and TAG pool will be measured by GCMS. The isotopic data for \[13C\] palmitate will be used to calculate the tracer concentration of \[13C\] palmitate in NEFA and TAG pool. • TAG concentration will be measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480) and mean of last three points 420, 450 and 480 minutes. • The tracer concentration of \[13C\] palmitate in NEFA and TAG pool, will be measured as (AUC 0-240) minutes and AUC (0-480 minutes) and mean of last three points 420, 450 and 480 minutes., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|[13C] 3-hydroxybutyrate enrichment relative to [13C] palmitate enrichment, At visit 4 and visit 6, perchloric acid treated plasma from the studies will be used to extract BOHB and the enrichment of 13C BOHB will be measured by GCMS. The isotopic data for 3-hydroxybutyrate will be used to calculate the relative partitioning of systemic plasma NEFA into \[13C\] 3-hydroxybutyrate as the ratio of \[13C\] 3-hydroxybutyrate to \[13C\] palmitate (in NEFA and TAG pool) in the plasma, where \[13C\] is expressed in micromol/L. The ratio of \[13C\] 3-hydroxybutyrate to \[13C\] palmitate (in TAG pool) in the plasma will be calculated, where \[13C\] is expressed in micromol/l measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480 minutes) and mean of last three points 420, 450 and 480 minutes., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Glucagon, insulin and cortisol concentrations, At visit 4 and visit 6, the concentration of Glucagon, insulin and cortisol will be measured by RIA. Ratio of glucagon to insulin concentration will be measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480) and mean of last three points 420, 450 and 480 minutes. The data will be compared following 4-weeks dapagliflozin versus placebo treatment., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Cardiac output via Transthoracic Echocardiogram, At visit 4 and visit 6, the cardiac output responses investigated using Echocardiogram will be compared following 4-weeks dapagliflozin versus placebo treatment., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Pulse wave velocity, At visit 4 and visit 6, aortic pulse wave velocity (m/s) will be measured by Vicorder between a cuff placed on the leg and around the neck. The data will be compared following 4-weeks dapagliflozin versus placebo treatment., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years|Plasma acylcarnitines measured by targeted metabolomics, At visit 4 and visit 6, targeted metabolomics will be used to measure 188 species from the metabolome including 40 species of acyl carnitines at 480 minutes. The data will be compared following 4-weeks dapagliflozin versus placebo treatment., The main analysis will be conducted once all participants have completed the metabolic studies within 2 years
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