The study investigations include evaluation of the acute effects of a single dose of dapagliflozin (10mg), exenatide (5µg), a combination of exenatide and dapagliflozin or placebo under insulinopenic condition and the long term effect under basal conditions before and after 12 weeks treatment with dapagliflozin, Exenatide extended release, a combination of Exenatide extended release and dapagliflozin or placebo on ketogenesis, glucagon and lipolysis.~In the acute effects study, qualified patients will come fasting to the research center. Review of study procedures and vitals will be performed. Insulin infusion (pump) will be stopped and basal blood, urine and adipose tissue biopsy samples will be obtained. Placebos, exenatide (5µg) or dapagliflozin (10mg) (with appropriate placebos) or combination of exenatide and dapagliflozin will be administered, according to a randomized fashion, and blood samples will be collected every 30 min for up to 8 hours after starting the treatment. Urine will be collected every hour up to 8 hours and a second adipose tissue biopsy will be collected at 6 hours after the start of the treatment. Additional blood samples will be collected at 1, 2, 4 and 6 and 8 hour marks for MNC isolation. Plasma and mononuclear cell (MNC) fractions will be prepared from the blood samples. The patient will then come back at the 24 hour mark for a fasting blood and urine collection. The long term study will then commence. Exenatide extended release or dapagliflozin (along with appropriate placebos) or a combination of both drugs will be started and continued for 12 weeks according to original randomization of day 0. In the long term study, dapagliflozin (or the appropriate placebo) will be started at 5mg dose and will be titrated to 10mg/day after 5 days. Fasting blood and 24hr urine samples will be collected at 1, 4 and 8 weeks. At 12 weeks, the 2nd acute effects testing study will be repeated as described above.~Measurements of beta-hydroxybutyrate, acetoacetic acid, glucose, FFA and glucagon, will be measured from all blood samples collected. HSL, GLP-1, glycerol, electrolytes, serum bicarbonate, cortisol and catecholamines will be measured at 0, 60, 120, 240, 360, 480 min and at 24hr following single dose studies at 0 and 12 weeks visits and at baseline on the 1, 4 and 8 weeks visits. Ketone bodies will be measured in all urine samples. All MNC and adipose tissue samples will be tested for HSL and SGLT2 expression.
The study investigations include evaluation of the acute effects of a single dose of dapagliflozin (10mg), exenatide (5µg), a combination of exenatide and dapagliflozin or placebo under insulinopenic condition and the long term effect under basal conditions before and after 12 weeks treatment with dapagliflozin, Exenatide extended release, a combination of Exenatide extended release and dapagliflozin or placebo on ketogenesis, glucagon and lipolysis.