SGLT2 Inhibition and Stimulation of Endogenous Glucose Production: Protocol 2

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Type II Diabetes Mellitus

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dapagliflozin<br>20 subjects will receive dapagliflozin 10mg | Drug: Dapagliflozin<br>* SGLT2 inhibitor (dapagliflozin)<br>* Other names: Farxiga;|
| Placebo Comparator: Placebo<br>10 subjects will receive placebo | Drug: Placebo<br>* Placebo Comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Plasma Glucose Concentration | Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration | Baseline to 240-300 minutes | 
| Change in Endogenous Glucose Production (EGP) | The change in endogenous glucose production is measured from baseline until the last hour of the study | Baseline to 240-300 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Plasma Insulin During Measurement of EGP | Measurement of change in plasma insulin concentration during measurement of of EGP from baseline to last hour of the study | Baseline to 240-300 minutes | 
| Change in Glucagon During EGP Measurement | Measurement of change in glucagon during EGP measurement from baseline to the last hour of the study | Baseline to 240-300 minutes |