Can Exenatide Prevent Increase in EGP in Response to Dapagliflozin-induced Increase in Glucosuria
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      Research Design/Plan: After screening, each subject will receive 1 measurements of Endogenous
      Glucose Production [EGP] with prime-continuous Infusion of 3-3H-glucose. After completing the
      EGP measurement each subject will receive a Double Tracer Oral Glucose Tolerance Test [OGTT].

      Methods: Visit 1: Screening. Medical history will be obtained, physical exam performed, and
      pregnancy test performed.

      Visit 2: Endogenous Glucose Production Measurement: The rate of EGP will be measured with
      3-3H-glucose.

      Visit 3: Double Tracer OGTT
    

Detailed description: 
      Eligible subjects will receive a measurement of endogenous glucose production (EGP) with a
      prime-continuous infusion of 3-3H-glucose. The EGP measurement will be performed in the
      morning after a 10-12 hour overnight fast and will last 8 hours (from 6 AM to 2 PM). After a
      3-hour tracer equilibration period, subjects (20 per group) will receive one of the following
      medications: (i) placebo; (ii) exenatide 5 ug subcutaneously; (iii) dapagliflozin (10 mg);
      and (iv) dapagliflozin 10 mg plus exenatide 5 ug. Following the test medication at 9 AM,
      blood samples will be drawn every 15 minutes for an additional 5 hours and plasma glucose,
      insulin, C-peptide, glucagon, cortisol, growth hormone, and catecholamine concentrations and
      glucose specific activity will be measured.

      Visit 1: Screening. Medical history & physical exam will be performed. Blood will be drawn
      for fasting plasma glucose [FPG], routine blood chemistries, complete blood count [CBC],
      lipid profile, HbA1c, and thyroid function [TSH], Urinalysis, electrocardiogram [EKG],
      albumin/creatinine ratio and pregnancy test will be performed.

      Visit 2: EGP Measurement: The rate of endogenous glucose production will be measured with
      3-3H-glucose infusion. [3-3H]-glucose infusion will be started at 6 in the morning [AM] and
      continued until 2:30 afternoon [PM](5 hours after drug administration). At 6 AM a catheter
      will be placed into an anticubital vein and a prime (40 uCi x FPG/100)- continuous (0.4 uCi)
      infusion of [3-3H]- glucose will be started and continued until 2:30 PM. (5 hours after drug
      administration). Participant's hand will be placed in a box heated to 50-60°C (122-140°F).
      Baseline blood samples will be obtained at-210, -60, -50, -45, -40, -35, -30, -20, -10, and 0
      . After 3.5 hours of tracer equilibration blood samples will be obtained every 10-20 minutes
      from 9 AM to 2 PM. Plasma glucose, insulin, C-peptide, glucagon, cortisol, growth hormone,
      and catecholamine concentrations, and [3-3H]-glucose specific activity will be measured.
      Urine will be collected from 6 to 9 AM and from 9 AM to 2 PM. Urinary volume and glucose
      concentration will be measured and urinary glucose excretion rate calculated. The study will
      end at 2:30 PM.

      Visit 3: Double Tracer Oral Glucose Tolerance Test [OGTT]: Within the week after the
      measurement of EGP, all subjects will have a 5-hour OGTT with measurement of plasma glucose,
      insulin (I), C-peptide (CP), and glucagon concentrations at -180, -6-, -5-, -45, -40, -35,
      -30, -20, -10, 0 and every 15-30 minutes thereafter to obtain a measure of overall glucose
      tolerance, insulin secretion (CP0-120/G0-120), insulin sensitivity ([Matsuda Index=MI]), beta
      cell function, (CP0-120/G0-120 x MI), and suppression of plasma glucagon concentration (64).
      At 7 AM a catheter will be placed into an antecubital vein and a prime (25 uCi x FPG/100)-
      continuous (0.25 uCi) infusion of [3-3H]- glucose will be started and continued until 3 PM.
      Urinary volume and glucose concentration will be measured and urinary glucose excretion rate
      calculated.

      HbA1c will be measured 2x, 1 on the day of the OGTT & 1 on the day of the EGP measurement.
    

Intervention name(s): Placebo; Exenatide; Dapagliflozin; Exenatide and Dapagliflozin
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Placebo will be administered to 20 subjects after a 3 hour tracer equilibration period; Exenatide will be administered to 20 subjects after a 3 hour tracer equilibration period; Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period; Exenatide and Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period
Other intervention name(s): Placebo drug; Byetta, Bydureon; Farxiga; Byetta plus Dapagliflozin
Intervention MeSH terms: Dapagliflozin; Exenatide
Allocation: Randomized
Intervention model: Single Group Assignment
Intervention model description: Participants will be randomized to one of four groups (20 per group): i) placebo; (ii) exenatide 5 ug subcutaneously; (iii) dapagliflozin (10 mg); and (iv) dapagliflozin 10 mg plus exenatide 5 ug
Masking: None (Open Label)
Primary purpose: Basic Science