Can Exenatide Prevent the Increase in EGP in Response to Dapagliflozin-induced Increase in Glucosuria

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 FPG, routine blood chemistries, CBC, lipid profile, HbA1c, and thyroid function.
Urinalysis, EKG, albumin/creatinine ratio and pregnancy test will be performed.

Visit 2: EPG Measurement: The rate of endogenous glucose production will be measured with
3-3H-glucose infusion. [3-3H]-glucose infusion will be started at 6 AM and continued until
2:30 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: 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 ([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 anticubital 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.

Inclusion Criteria:

- Health Status: Type 2 Diabetes Mellitus according to ADA criteria (subjects must be in
good general health as determined by physical exam, medical history, blood
chemistry-CBC, TSH, T4, EKG and urinalysis)

- BMI: 21-45kg/m

- HbA1C>7.0% and <10.0%

- Medication: Drug naïve and/or on a stable dose of metformin and/or sulfonylurea (more
than 3 months)

Exclusion Criteria:

- Health Status: Type 1 Diabetics

- Proliferative diabetic retinopathy

- Plasma Creatinine greater than 1.4mg/dL in females or greater than 1.5mg/dL in males,
or 24 hour urine albumin excretion greater than 300mg/dL

- Medication: Subjects taking drugs known to affect glucose metabolism (other than
metformin and sulfonylurea)