Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin
Condition: Type II; Diabetes
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

Summary: 
      To determine the role of plasma glucagon and insulin in the rise of endogenous glucose
      production (EGP) following the SGLT2 inhibition.
    

Detailed description: 
      The increase in plasma glucagon conc and/or decrease in plasma insulin conc in response to
      glucosuria is (are) important signal(s) responsible, at least in part, for the increase in
      EGP, which the investigators anticipate will be derived primarily from the liver. Insulin and
      glucagon are powerful regulators of HGP. Therefore, the investigators anticipate that, at
      least in part, an increase in HGP secondary to the rise in plasma glucagon concentration and
      decrease in plasma insulin concentration in response to dapagliflozin-induced glucosuria will
      account for the majority of increase in EGP in both NGT and T2DM subjects. This study will
      define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the
      trigger to stimulate EGP. Eligible subjects will receive three 5-hour measurements of
      endogenous glucose production (EGP), which is the biosynthesis of new glucose, with
      administration of study drug after a 3-hour tracer equilibration period. Hepatic glucose
      production (HGP), which is the net release of glucose from the liver, will be measured for 5
      hours after drug administration to allow sufficient time for a significant increase in HGP
      above baseline after dapagliflozin administration (10). In study 1, HGP will be measured for
      5 hours after dapagliflozin (10 mg) or placebo administration. This is the control study. The
      investigators expect to observe the "paradoxical" rise in EGP following dapagliflozin. Study
      2 will be performed under glucose clamp conditions (i.e. maintaining the plasma glucose
      concentration stable at each subject's fasting level). This study will define whether the
      decline in plasma glucose concentration is the trigger to stimulate EGP. Study 3 will be
      performed under pancreatic clamp conditions (maintaining the plasma glucagon and insulin
      concentrations constant at the basal level). This study will define whether the increase in
      plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP.
      Subjects will be randomized in a 2:1 ratio; 32 subjects will receive dapagliflozin and 16
      subjects will receive placebo. Each study will be performed on a separate day, after a 10-12
      hour overnight fast within 1-2 week period. Following studies 1-3, subjects will return for a
      renal (kidney) MRI-measurement to record kidney size.
    

Intervention name(s): Dapagliflozin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.; Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.
Other intervention name(s): Farxiga; Placebo for Dapagliflozin
Intervention MeSH terms: Dapagliflozin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment