SGLT2 Inhibition and Stimulation of Endogenous Glucose Production: Protocol 2

Protocol 2: Elucidation of Mechanisms Responsible for the Increase in EGP Following SGLT2 Inhibition: Decrease in Plasma Glucose Conc or Change in Islet Hormone (Glucagon/Insulin) Secretion

In Protocol 2, the investigators will determine the role of pancreatic hormones (increase in plasma glucagon and decrease in plasma insulin concentration) in the stimulation of EGP following SGLT2 inhibition.

The inhibition of the renal (kidney) SGLT2 transporter has proven to be an effective therapeutic intervention to reduce plasma glucose levels (amount of glucose found in the liquid part of blood) and HbA1c.

In this study, the investigators hope to define the role of increased plasma glucagon, decline in plasma insulin, and fall in plasma glucose concentration. The investigators will examine whether the signal for the increase in EGP (endogenous glucose production) caused by glucosuria (an excess of sugar in the urine, typically associated with diabetes) is mediated via the decrease in plasma glucose and insulin concentrations, or by the increase in plasma glucagon concentration.

Inclusion Criteria:

• T2DM subjects
• 18 - 70 yrs old
• BMI = 25-45 kg/m2
• Must be on a stable dose (more than 3 months) of monotherapy or combination therapy with metformin and/or a sulfonylurea
• HbA1c <10.0%
• Stable body weight (± 3 lbs) over preceding 3 months
• Do not participate in excessively heavy exercise

Exclusion Criteria:

• Subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea)
• Individuals with evidence of proliferative diabetic retinopathy, plasma creatinine >1.4 females or >1.5 males, or 24-hour urine albumin excretion > 300 mg