Type II Diabetes Mellitus
Conditions
Brief summary
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
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.
Interventions
DRUGDapagliflozin
SGLT2 inhibitor (dapagliflozin)
DRUGPlacebo
Placebo Comparator
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
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Glucose Concentration | Baseline to 240-300 minutes | Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration |
| Change in Endogenous Glucose Production (EGP) | Baseline to 240-300 minutes | The change in endogenous glucose production is measured from baseline until the last hour of the study |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Insulin During Measurement of EGP | Baseline to 240-300 minutes | Measurement of change in plasma insulin concentration during measurement of of EGP from baseline to last hour of the study |
| Change in Glucagon During EGP Measurement | Baseline to 240-300 minutes | Measurement of change in glucagon during EGP measurement from baseline to the last hour of the study |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin Subjects will receive dapagliflozin 10mg
Dapagliflozin: SGLT2 inhibitor (dapagliflozin) | 20 |
| Placebo Subjects will receive placebo
Placebo: Placebo Comparator | 10 |
| Total | 30 |
Baseline characteristics
| Characteristic | Dapagliflozin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 54 Years STANDARD_DEVIATION 2 | 53 Years STANDARD_DEVIATION 2 | 53.5 Years STANDARD_DEVIATION 2 |
| Body Mass Index (BMI) | 32.6 kg/m^2 STANDARD_DEVIATION 0.7 | 31.4 kg/m^2 STANDARD_DEVIATION 1.3 | 32 kg/m^2 STANDARD_DEVIATION 2.85 |
| Diabetes Duration | 6.9 years STANDARD_DEVIATION 1.3 | 5.9 years STANDARD_DEVIATION 1.5 | 6.4 years STANDARD_DEVIATION 1.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 4 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 6 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Free Plasma Glucose (FPG) | 148 mg/dL STANDARD_DEVIATION 8 | 127 mg/dL STANDARD_DEVIATION 8 | 137 mg/dL STANDARD_DEVIATION 8 |
| Glomerular Filtration Rate (eGFR) | 97 ml/min STANDARD_DEVIATION 3 | 97 ml/min STANDARD_DEVIATION 3 | 97 ml/min STANDARD_DEVIATION 3 |
| HBA1c (3 month blood glucose level measure) | 7.5 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.2 | 7.5 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.1 | 7.5 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.15 |
| Region of Enrollment United States | 20 participants | 10 participants | 30 participants |
| Sex: Female, Male Female | 8 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Male | 12 Participants | 7 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 10 |
| other Total, other adverse events | 4 / 20 | 0 / 10 |
| serious Total, serious adverse events | 0 / 20 | 0 / 10 |
Outcome results
Primary
Change in Endogenous Glucose Production (EGP)
The change in endogenous glucose production is measured from baseline until the last hour of the study
Time frame: Baseline to 240-300 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Change in Endogenous Glucose Production (EGP) | Study 1 | 0.1 mg/kg.min | Standard Deviation 0.1 |
| Dapagliflozin | Change in Endogenous Glucose Production (EGP) | Study 2 with glucose clamp | -0.57 mg/kg.min | Standard Deviation 0.12 |
| Dapagliflozin | Change in Endogenous Glucose Production (EGP) | Study 3 with pancreatic clamp | -0.23 mg/kg.min | Standard Deviation 0.09 |
| Placebo | Change in Endogenous Glucose Production (EGP) | Study 1 | -0.56 mg/kg.min | Standard Deviation 0.1 |
| Placebo | Change in Endogenous Glucose Production (EGP) | Study 2 with glucose clamp | -1.28 mg/kg.min | Standard Deviation 0.17 |
| Placebo | Change in Endogenous Glucose Production (EGP) | Study 3 with pancreatic clamp | -0.48 mg/kg.min | Standard Deviation 0.05 |
Primary
Change in Plasma Glucose Concentration
Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration
Time frame: Baseline to 240-300 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Change in Plasma Glucose Concentration | Study 1 | -29.7 mg/dl | Standard Deviation 3 |
| Dapagliflozin | Change in Plasma Glucose Concentration | Study 2 with glucose clamp | 3.1 mg/dl | Standard Deviation 0.9 |
| Dapagliflozin | Change in Plasma Glucose Concentration | Study 3 with pancreatic clamp | -30.3 mg/dl | Standard Deviation 3.5 |
| Placebo | Change in Plasma Glucose Concentration | Study 1 | -17.2 mg/dl | Standard Deviation 2.9 |
| Placebo | Change in Plasma Glucose Concentration | Study 2 with glucose clamp | 0.9 mg/dl | Standard Deviation 1.1 |
| Placebo | Change in Plasma Glucose Concentration | Study 3 with pancreatic clamp | -2.3 mg/dl | Standard Deviation 6.1 |
Secondary
Change in Glucagon During EGP Measurement
Measurement of change in glucagon during EGP measurement from baseline to the last hour of the study
Time frame: Baseline to 240-300 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Change in Glucagon During EGP Measurement | Study 2 with glucose clamp | -6 ng/ml | Standard Deviation 2 |
| Dapagliflozin | Change in Glucagon During EGP Measurement | Study 1 | 5 ng/ml | Standard Deviation 2 |
| Dapagliflozin | Change in Glucagon During EGP Measurement | Study 3 with pancreatic clamp | -1 ng/ml | Standard Deviation 1 |
| Placebo | Change in Glucagon During EGP Measurement | Study 1 | -1 ng/ml | Standard Deviation 2 |
| Placebo | Change in Glucagon During EGP Measurement | Study 2 with glucose clamp | -7 ng/ml | Standard Deviation 3 |
| Placebo | Change in Glucagon During EGP Measurement | Study 3 with pancreatic clamp | -2 ng/ml | Standard Deviation 2 |
Secondary
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
Time frame: Baseline to 240-300 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Change in Plasma Insulin During Measurement of EGP | Study 1 | 5 microUnits/mL | Standard Deviation 1 |
| Dapagliflozin | Change in Plasma Insulin During Measurement of EGP | Study 2 with glucose clamp | 0 microUnits/mL | Standard Deviation 1 |
| Dapagliflozin | Change in Plasma Insulin During Measurement of EGP | Study 3 with pancreatic clamp | 2 microUnits/mL | Standard Deviation 1 |
| Placebo | Change in Plasma Insulin During Measurement of EGP | Study 1 | 3 microUnits/mL | Standard Deviation 1 |
| Placebo | Change in Plasma Insulin During Measurement of EGP | Study 2 with glucose clamp | 0 microUnits/mL | Standard Deviation 1 |
| Placebo | Change in Plasma Insulin During Measurement of EGP | Study 3 with pancreatic clamp | 0 microUnits/mL | Standard Deviation 1 |