Effect of Dapagliflozin on Hepatic and Renal Glucose Metabolism Subjects

Effect of Dapagliflozin on Hepatic and Renal Glucose Metabolism Subjects (11038)

Researchers hope to determine the organ (liver and/or kidney) responsible for the increase in endogenous glucose production (EGP) following the induction of glucosuria (when glucose is excreted in detectable amounts in the urine) with an SGLT2 inhibitor, dapagliflozin.

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.