Diabetes Mellitus, Type 2
Conditions
Brief summary
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
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.
Interventions
DRUGPlacebo
Placebo will be administered to 20 subjects after a 3 hour tracer equilibration period
DRUGExenatide
Exenatide will be administered to 20 subjects after a 3 hour tracer equilibration period
DRUGDapagliflozin
Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period
DRUGExenatide and Dapagliflozin
Exenatide and Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention 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
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in EGP From Baseline to Post-oral Glucose Load. | From baseline [-35 to 0min] to the last hour post-glucose load [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 acute drug treatments (exenatide; dapagliflozin; exenatide plus dapagliflozin this data includes change in EGP above baseline following dapagliflozin alone vs dapagliflozin/exenatide) with ANOVA. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Placebo: Placebo will be administered to 20 subjects after a 3 hour tracer equilibration period | 15 |
| 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.
Exenatide: Exenatide will be administered to 20 subjects after a 3 hour tracer equilibration period | 25 |
| 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.
Dapagliflozin: Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period | 25 |
| 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.
Exenatide and Dapagliflozin: Exenatide and Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period | 25 |
| Total | 90 |
Baseline characteristics
| Characteristic | Exenatide and Dapagliflozin | Total | Placebo | Exenatide | Dapagliflozin |
|---|---|---|---|---|---|
| Age, Continuous | 49 years STANDARD_DEVIATION 2 | 51 years STANDARD_DEVIATION 3 | 54 years STANDARD_DEVIATION 3 | 52 years STANDARD_DEVIATION 3 | 51 years STANDARD_DEVIATION 2 |
| ENDOGENOUS GLUCOSE PRODUCTION [EGP] | 2.41 mg/kg.min STANDARD_DEVIATION 0.1 | 2.33 mg/kg.min STANDARD_DEVIATION 0.25 | 2.30 mg/kg.min STANDARD_DEVIATION 0.05 | 2.33 mg/kg.min STANDARD_DEVIATION 0.13 | 2.27 mg/kg.min STANDARD_DEVIATION 0.04 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 56 Participants | 11 Participants | 15 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 32 Participants | 2 Participants | 10 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 28 Participants | 4 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 60 Participants | 9 Participants | 18 Participants | 16 Participants |
| Sex: Female, Male Female | 16 Participants | 58 Participants | 10 Participants | 17 Participants | 15 Participants |
| Sex: Female, Male Male | 9 Participants | 32 Participants | 5 Participants | 8 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 25 | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 0 / 15 | 4 / 25 | 7 / 25 | 6 / 25 |
| serious Total, serious adverse events | 0 / 15 | 0 / 25 | 0 / 25 | 0 / 25 |
Outcome results
Primary
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.
Time frame: From baseline [-35 to 0min] to the last hour post-glucose load [240-300 minutes]
Population: Type 2 diabetes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in EGP From Baseline to Post-oral Glucose Load. | -0.03 mg/kg.min | Standard Error 0.02 |
| Exenatide | Change in EGP From Baseline to Post-oral Glucose Load. | -0.18 mg/kg.min | Standard Error 0.02 |
| Dapagliflozin | Change in EGP From Baseline to Post-oral Glucose Load. | 0.14 mg/kg.min | Standard Error 0.03 |
| Exenatide and Dapagliflozin | Change in EGP From Baseline to Post-oral Glucose Load. | -0.08 mg/kg.min | Standard Error 0.03 |