Can Exenatide Prevent Increase in EGP in Response to Dapagliflozin-induced Increase in Glucosuria

Study Overview
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Brief Summary
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Research Design/Plan: After screening, each subject will receive 1 measurements of Endogenous Glucose Production [EGP] with prime-continuous Infusion of 3-3H-glucose. After completing the EGP measurement each subject will receive a Double Tracer Oral Glucose Tolerance Test [OGTT]. Methods: Visit 1: Screening. Medical history will be obtained, physical exam performed, and pregnancy test performed. Visit 2: Endogenous Glucose Production Measurement: The rate of EGP will be measured with 3-3H-glucose. Visit 3: Double Tracer OGTT

Detailed Description
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Eligible subjects will receive a measurement of endogenous glucose production (EGP) with a prime-continuous infusion of 3-3H-glucose. The EGP measurement will be performed in the morning after a 10-12 hour overnight fast and will last 8 hours (from 6 AM to 2 PM). After a 3-hour tracer equilibration period, subjects (20 per group) will receive one of the following medications: (i) placebo; (ii) exenatide 5 ug subcutaneously; (iii) dapagliflozin (10 mg); and (iv) dapagliflozin 10 mg plus exenatide 5 ug. Following the test medication at 9 AM, blood samples will be drawn every 15 minutes for an additional 5 hours and plasma glucose, insulin, C-peptide, glucagon, cortisol, growth hormone, and catecholamine concentrations and glucose specific activity will be measured. Visit 1: Screening. Medical history & physical exam will be performed. Blood will be drawn for fasting plasma glucose [FPG], routine blood chemistries, complete blood count [CBC], lipid profile, HbA1c, and thyroid function [TSH], Urinalysis, electrocardiogram [EKG], albumin/creatinine ratio and pregnancy test will be performed. Visit 2: EGP Measurement: The rate of endogenous glucose production will be measured with 3-3H-glucose infusion. [3-3H]-glucose infusion will be started at 6 in the morning [AM] and continued until 2:30 afternoon [PM](5 hours after drug administration). At 6 AM a catheter will be placed into an anticubital vein and a prime (40 uCi x FPG/100)- continuous (0.4 uCi) infusion of [3-3H]- glucose will be started and continued until 2:30 PM. (5 hours after drug administration). Participant's hand will be placed in a box heated to 50-60°C (122-140°F). Baseline blood samples will be obtained at-210, -60, -50, -45, -40, -35, -30, -20, -10, and 0 . After 3.5 hours of tracer equilibration blood samples will be obtained every 10-20 minutes from 9 AM to 2 PM. Plasma glucose, insulin, C-peptide, glucagon, cortisol, growth hormone, and catecholamine concentrations, and [3-3H]-glucose specific activity will be measured. Urine will be collected from 6 to 9 AM and from 9 AM to 2 PM. Urinary volume and glucose concentration will be measured and urinary glucose excretion rate calculated. The study will end at 2:30 PM. Visit 3: Double Tracer Oral Glucose Tolerance Test [OGTT]: Within the week after the measurement of EGP, all subjects will have a 5-hour OGTT with measurement of plasma glucose, insulin (I), C-peptide (CP), and glucagon concentrations at -180, -6-, -5-, -45, -40, -35, -30, -20, -10, 0 and every 15-30 minutes thereafter to obtain a measure of overall glucose tolerance, insulin secretion (CP0-120/G0-120), insulin sensitivity ([Matsuda Index=MI]), beta cell function, (CP0-120/G0-120 x MI), and suppression of plasma glucagon concentration (64). At 7 AM a catheter will be placed into an antecubital vein and a prime (25 uCi x FPG/100)- continuous (0.25 uCi) infusion of [3-3H]- glucose will be started and continued until 3 PM. Urinary volume and glucose concentration will be measured and urinary glucose excretion rate calculated. HbA1c will be measured 2x, 1 on the day of the OGTT & 1 on the day of the EGP measurement.

Official Title
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SGLT2 INHIBITION AND STIMULATION OF ENDOGENOUS GLUCOSE PRODUCTION [EGP]: Can the Glucagon-like Peptide-1 [GLP-1] Receptor Agonist, Exenatide, Prevent the Increase in EGP in Response to Dapagliflozin-induced Increase in Glucosuria

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Placebo
* Drug: Exenatide
* Drug: Dapagliflozin
* Drug: Exenatide and Dapagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Health Status: Type 2 Diabetes Mellitus according to ADA criteria (subjects must be in good general health as determined by physical exam, medical history, blood chemistry-CBC, TSH, T4, EKG and urinalysis) BMI: 21-45kg/m HbA1C>7.0% and <10.5% Medication: Drug naïve and/or on a stable dose of metformin and/or sulfonylurea (more than 3 months) Exclusion Criteria: Health Status: Type 1 Diabetics Proliferative diabetic retinopathy Plasma Creatinine greater than 1.4mg/dL in females or greater than 1.5mg/dL in males, or 24 hour urine albumin excretion greater than 300mg/dL Medication: Subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea)

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Participants will be randomized to one of four groups (20 per group): i) placebo; (ii) exenatide 5 ug subcutaneously; (iii) dapagliflozin (10 mg); and (iv) dapagliflozin 10 mg plus exenatide 5 ug
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>we will examine whether the coadministration of exenatide plus dapagliflozin will prevent the increase in EGP and result in an additive or even synergistic decrease in plasma glucose conc compared to each agent alone. | Drug: Placebo<br>* Placebo will be administered to 20 subjects after a 3 hour tracer equilibration period<br>* Other names: Placebo drug;|
| Active Comparator: Exenatide<br>we will examine whether the coadministration of exenatide plus dapagliflozin will prevent the increase in EGP and result in an additive or even synergistic decrease in plasma glucose conc compared to each agent alone. | Drug: Exenatide<br>* Exenatide will be administered to 20 subjects after a 3 hour tracer equilibration period<br>* Other names: Byetta, Bydureon;|
| Active Comparator: Dapagliflozin<br>we will examine whether the coadministration of exenatide plus dapagliflozin will prevent the increase in EGP and result in an additive or even synergistic decrease in plasma glucose conc compared to each agent alone. | Drug: Dapagliflozin<br>* Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period<br>* Other names: Farxiga;|
| Active Comparator: Exenatide and Dapagliflozin<br>we will examine whether the coadministration of exenatide plus dapagliflozin will prevent the increase in EGP and result in an additive or even synergistic decrease in plasma glucose conc compared to each agent alone. | Drug: Exenatide and Dapagliflozin<br>* Exenatide and Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period<br>* Other names: Byetta plus Dapagliflozin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in EGP From Baseline to Post-oral Glucose Load. | The difference in rate of EGP during the last hour of the study (from 240-300 minutes) between drug-treatment and placebo treatment studies represents the effect of drug treatment on EGP, which will be compared among the 3 acute drug treatments (exenatide; dapagliflozin; exenatide plus dapagliflozin this data includes change in EGP above baseline following dapagliflozin alone vs dapagliflozin/exenatide) with ANOVA. | From baseline [-35 to 0min] to the last hour post-glucose load [240-300 minutes] |