Effect of Dapagliflozin on Hepatic and Renal Glucose Metabolism Subjects

Researchers will measure the rate of hepatic and renal glucose production following
dapagliflozin administration to determine the site of increase in EGP, liver versus kidney.
Researchers will measure the rate of whole body glucose production with 3-3H-glucose (a form
of radioactive glucose) and renal glucose production by renal vein catheterization in T2DM
(type 2 diabetes mellitus) and in lean healthy NGT (normal glucose tolerance) individuals.
Because the increase in EGP is associated with an increase in plasma glucagon concentration
and renal glucose production is stated to be unresponsive to glucagon, the investigators
anticipate that the liver will be responsible, in part, for the increase in EGP.

Inclusion Criteria:

- 25-35 kg/m^2

- Normal Glucose Tolerance subjects (24)

- Type 2 Diabetic Subjects (24)

- Diabetic subjects must be on a stable dose (more than 3 months) of monotherapy or
combination therapy with metformin and/or a sulfonylurea

- Diabetic subjects must have HbA1c <8.0%

- Other than diabetes, subjects must be in good general health as determined by physical
exam, medical history, blood chemistries, CBC (complete blood count), TSH
(thyroid-stimulating hormone), T4 (thyroxine), EKG (electrocardiogram) and
urinanalysis.

- Only subjects whose body weight has been stable (± 3 lbs) over the preceding three
months and who do not participate in an excessively heavy exercise program will be
included.

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.