Can Exenatide Prevent the Increase in EGP in Response to Dapagliflozin-induced Increase in Glucosuria
Study Details
Study Description
Brief Summary
Research Design/Plan: After screening, each subject will receive 1 measurements of EGP with prime-continuous Infusion of 3-3H-glucose. After completing the EGP measurement each subject will receive a Double Tracer 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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Detailed Description
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 FPG, routine blood chemistries, CBC, lipid profile, HbA1c, and thyroid function. Urinalysis, EKG, albumin/creatinine ratio and pregnancy test will be performed.
Visit 2: EPG Measurement: The rate of endogenous glucose production will be measured with 3-3H-glucose infusion. [3-3H]-glucose infusion will be started at 6 AM and continued until 2:30 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: 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 ([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 anticubital 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Placebo 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
Placebo will be administered to 20 subjects after a 3 hour tracer equilibration period
|
| Active Comparator: Exenatide 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
Exenatide will be administered to 20 subjects after a 3 hour tracer equilibration period
Other Names:
|
| Active Comparator: Dapagliflozin 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
Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period
Other Names:
|
| Active Comparator: Exenatide and Dapagliflozin 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
Exenatide and Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period
|
Outcome Measures
Primary Outcome Measures
- Change in EGP [240-300 minutes]
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 drug treatments (exenatide; dapagliflozin; exenatide plus dapagliflozin) with ANOVA.
- change in EGP above baseline following dapagliflozin alone versus dapagliflozin/exenatide [-35 - 0 minutes]
The following primary comparison will be performed: (i) change in EGP above baseline following dapagliflozin alone versus dapagliflozin/exenatide.
Eligibility Criteria
Criteria
Inclusion Criteria:
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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)
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BMI: 21-45kg/m
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HbA1C>7.0% and <10.5%
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Medication: Drug naïve and/or on a stable dose of metformin and/or sulfonylurea (more than 3 months)
Exclusion Criteria:
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Health Status: Type 1 Diabetics
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Proliferative diabetic retinopathy
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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
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Medication: Subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University Health System Texas Diabetic Institute | San Antonio | Texas | United States | 78207 |
Sponsors and Collaborators
- The University of Texas Health Science Center at San Antonio
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HSC20170582H
- R01DK107680