Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin

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.

Inclusion Criteria:

- T2DM according to ADA criteria-HbA1C < 8.0%

- BMI = 25-35 kg/m2

- Subjects must be in good general health as determined by physical exam, medical
history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis

- Body weight has been stable (± 3 lbs) over the preceding three months

- Do not participate in an excessively heavy exercise program

- Taking stable dose (more than 3 months) of monotherapy or combination therapy with
metformin and/or a sulfonylurea

Exclusion Criteria:

- Subjects taking drugs known to affect glucose metabolism (other than metformin and
sulfonylurea) will be excluded

- Individuals with evidence of proliferative diabetic retinopathy, plasma creatinine
>1.4 females or >1.5 males, or 24-hour urine albumin excretion > 300 mg will be
excluded