Type 2 Diabetes
Conditions
Keywords
GLP1, insulin, glucose, exenatide, GLP1 receptor agonist, insulin secretion, glucagon receptor, GIP receptor
Brief summary
Healthy volunteers were recruited from the Old Order Amish population in Lancaster County, Pennsylvania. After providing informed consent, research participants were screened for eligibility. The clinical trial was designed as a randomized crossover study in which participants underwent two frequently sampled intravenous glucose tolerance tests - one after receiving a subcutaneous injection of saline and one after receiving a subcutaneous injection of rapid-acting exenatide (BYETTA). The study sought to determine whether genetic variants are associated with the magnitude of the effect of exenatide. However, because the study fell far short of its recruitment targets, it was under-powered to evaluate genetic association. Thus, the data analysis focused on testing the hypothesis that the order of testing (whether the placebo FSIGT was conducted before the exenatide-stimulated FSIGT or whether the FSIGTs were conducted in the reverse order) does not alter the magnitude impact of exenatide on responses to a frequently sampled iv glucose tolerance test.
Detailed description
Healthy volunteers were recruited from the Old Order Amish population in Lancaster County, Pennsylvania. After providing informed consent, research participants were screened for eligibility. The clinical trial was designed as a randomized crossover study in which participants underwent two frequently sampled intravenous glucose tolerance tests (FSIGT) - one after receiving a subcutaneous injection of saline and one after receiving a subcutaneous injection of rapid-acting exenatide (BYETTA). Based on data obtained from the FSIGT, participants' response to exenatide was assessed -- specifically, the effect of exenatide to enhance insulin secretion and accelerate metabolism of glucose. The study sought to determine whether genetic variants are associated with the magnitude of the effect of exenatide. However, because the study fell far short of its recruitment targets, it was under-powered to evaluate genetic association. Thus, the data analysis focused on testing the hypothesis that the order of testing (whether the placebo FSIGT was conducted before the exenatide-stimulated FSIGT or whether the FSIGTs were conducted in the reverse order) does not alter the magnitude impact of exenatide on responses to a frequently sampled iv glucose tolerance test.
Interventions
DRUGExenatide Injection (before the first FSIGT)
Nurses administered exenatide (5 mcg) subcutaneously 15 minutes prior to conducting the first frequently sampled intravenous glucose tolerance test. In this crossover study, participants will also be crossed over to receive saline rather than exenatide: Nurses administered saline (0.2 mL) subcutaneously 15 minutes prior to conducting a frequently sampled intravenous glucose tolerance test.
DRUGExenatide injection before the second FSIGT)
Nurses administered exenatide (5 mcg) subcutaneously 15 minutes prior to conducting the second frequently sampled intravenous glucose tolerance test.
Sponsors
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Masking description
Participants were not informed whether the nurse was administering saline or exenatide injections.
Intervention model description
Research participants all received the same two interventions (saline or exenatide) but the order of the interventions was randomized.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Member of the Old Order Amish community in Lancaster County, Pennsylvania * BMI: 18-40 kg/sq.m.
Exclusion criteria
* Known allergy to exenatide * History of diabetes, random glucose \>200 mg/dL, or HbA1c \> 6.5% * Significant debilitating chronic cardiac, hepatic, pulmonary, or renal disease or other diseases that the investigator judges will make interpretation of the results difficult or increase the risk of participation * Seizure disorder * Pregnant by self-report or known pregnancy within 3 months of the start of study * Currently breast feeding or breast feeding within 3 months of the start of the study * Estimated glomerular filtration rate \<60 mL/min/1.73m2 * Hematocrit \<35% * Liver function tests greater than 2 times the upper limit of normal * Abnormal thyroid stimulating hormone * History of pancreatitis or pancreatic cancer. Personal or family history of medullary carcinoma of the thyroid.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exenatide Effect on First Phase Insulin Secretion | 0-10 minutes | The ratio of the area-under-the-curve (AUC) for 1st phase insulin secretion in the exenatide-stimulated FSIGT divided by the AUC for 1st phase insulin secretion in the saline FSIGT. |
| Exenatide Effect on Glucose Disappearance Rate | 25-50 minutes | The ratio of the glucose disappearance rate (exenatide) divided by the glucose disappearance rate (placebo). Glucose disappearance rates were calculated as the slope of the plot of the logarithm of the glucose concentration as a function of time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| First Phase Insulin Secretion (Exenatide) | 0-10 minutes | The area under the curve for plasma insulin levels during a frequently sampled intravenous glucose tolerance test after participants received exenatide |
| First Phase Insulin Secretion (Placebo) | 0-10 minutes | The area under the curve for plasma insulin levels during a frequently sampled intravenous glucose tolerance test after participants received saline |
| Glucose Disappearance Rate (Exenatide) | 25-50 minutes | The slope of the line plotting the logarithm of glucose concentrations as a function of time during the exenatide frequently sampled intravenous glucose tolerance test. The slope of the line was estimated as the slope of the least-squares fit to the data points between 25-50 minutes. |
| Exenatide's Effect on the Rate of Glucose-disappearance (Genotype Specific) | 25-50 min during the FSIGT | The rate of glucose disappearance was calculated as the slope of a least-squared line fitted to the logarithms of glucose concentrations during time 25-50 min of FSIGTs |
| Drug Effect on First-Phase Insulin Secretion (Genotype-specific) | 0 - 10 min during the FSIGT | The effect of exenatide to increase first-phase insulin secretion was defined as the ratio of area-under-the-curve (AUC) for insulin levels during the first 10 minutes of the exenatide-stimulated FSIGT divided by the AUC for first phase insulin secretion during the saline FSIGT.. |
| Glucose Disappearance Rate (Placebo) | 25-50 minutes | The slope of the line plotting the logarithm of glucose concentrations as a function of time during the placebo frequently sampled intravenous glucose tolerance test. The slope of the line was estimated as the slope of the least-squares fit to the data points between 25-50 minutes. |
Countries
United States
Participant flow
Recruitment details
Dates: June 2016 - November 2018 Site: Community-based recruitment at Amish Research Clinic, Lancaster Pennsylvania (Univ. of Maryland School of Medicine)
Pre-assignment details
Participants were assigned to specific arms of the study based on the order in which they were randomized to a subcutaneous injection of either exenatide or normal saline solution: Arm 1: Exenatide followed by Normal Saline Arm 2: Normal Saline followed by Exenatide Frequently sampled intravenous glucose tolerance tests (FSIGT) were initiated 15 minutes after the subcutaneous injections of exenatide or normal saline. The second FSIGT was performed 5-28 days after the first FSIGT.
Participants by arm
| Arm | Count |
|---|---|
| Exenatide First Followed by Normal Saline Exenatide (5 mcg, sc) was injected 15 minutes before the first frequently sampled iv glucose tolerance test (FSIGT). After a washout period of 5-28 days, participants underwent a second FSIGT with saline (0.20 mL) being injected 15 min before the 2nd FSIGT. | 26 |
| Normal Saline Followed by Exenatide Saline (0.2 mL) was injected 15 minutes before the first frequently sampled iv glucose tolerance test (FSIGT). After a washout period of 5-28 days, participants underwent a second FSIGT with exenatide (5 mcg) being injected 15 min before the 2nd FSIGT. | 26 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 1st iv Glucose Tolerance Test | Some critical blood samples not collecte | 5 | 5 |
| 1st iv Glucose Tolerance Test | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Normal Saline Followed by Exenatide | Total | Exenatide First Followed by Normal Saline |
|---|---|---|---|
| Age, Continuous | 44.6 Years | 47.3 Years | 50.2 Years |
| Body Mass Index | 27.8 kg/m^2 STANDARD_DEVIATION 3.7 | 28.1 kg/m^2 STANDARD_DEVIATION 3.7 | 28.3 kg/m^2 STANDARD_DEVIATION 3.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 52 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hemoglobin A1c | 5.5 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.3 | 5.5 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.3 | 5.6 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.4 |
| Number of participants homozygous for major alleles of both GCGR and GIPR | 10 Participants | 19 Participants | 9 Participants |
| Number of participants homozygous for p.E354Q allele of GIPR | 8 Participants | 13 Participants | 5 Participants |
| Number of participants homozygous for p.G40S allele of GCGR | 8 Participants | 20 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 52 Participants | 26 Participants |
| Region of Enrollment United States | 26 participants | 52 participants | 26 participants |
| Sex: Female, Male Female | 13 Participants | 21 Participants | 8 Participants |
| Sex: Female, Male Male | 13 Participants | 31 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 62 | 0 / 62 |
| other Total, other adverse events | 3 / 62 | 7 / 62 |
| serious Total, serious adverse events | 0 / 62 | 0 / 62 |
Outcome results
Primary
Exenatide Effect on First Phase Insulin Secretion
The ratio of the area-under-the-curve (AUC) for 1st phase insulin secretion in the exenatide-stimulated FSIGT divided by the AUC for 1st phase insulin secretion in the saline FSIGT.
Time frame: 0-10 minutes
Population: The analysis population included 52 patients who completed the study and for whom the necessary blood samples were collected and available for assays of insulin and glucose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide First Followed by Saline | Exenatide Effect on First Phase Insulin Secretion | 1.90 Ratio (no units) | Standard Error 0.17 |
| Saline First Followed by Exenatide | Exenatide Effect on First Phase Insulin Secretion | 2.18 Ratio (no units) | Standard Error 0.25 |
Comparison: Null hypothesis: the order of FSIGTs (saline or exenatide-stimulated) does not affect the response during an FSIGTp-value: 0.37t-test, 2 sided
Primary
Exenatide Effect on Glucose Disappearance Rate
The ratio of the glucose disappearance rate (exenatide) divided by the glucose disappearance rate (placebo). Glucose disappearance rates were calculated as the slope of the plot of the logarithm of the glucose concentration as a function of time.
Time frame: 25-50 minutes
Population: The analysis population included 52 patients who completed the study and for whom the necessary blood samples were collected and available for assays of insulin and glucose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide First Followed by Saline | Exenatide Effect on Glucose Disappearance Rate | 2.16 Ratio (no units) | Standard Error 0.19 |
| Saline First Followed by Exenatide | Exenatide Effect on Glucose Disappearance Rate | 2.28 Ratio (no units) | Standard Error 0.2 |
Comparison: Null hypothesis: The order of FSIGT (exenatide-stimulated or saline) does not affect the response to an FSIGT.p-value: 0.66t-test, 2 sided
Secondary
Drug Effect on First-Phase Insulin Secretion (Genotype-specific)
The effect of exenatide to increase first-phase insulin secretion was defined as the ratio of area-under-the-curve (AUC) for insulin levels during the first 10 minutes of the exenatide-stimulated FSIGT divided by the AUC for first phase insulin secretion during the saline FSIGT..
Time frame: 0 - 10 min during the FSIGT
Population: Participants with the specified genotypes. Based on the observation that the order of FSIGT (exenatide-first versus saline-first) did not affect the data obtained in the FSIGT, we have pooled data from the two arms of the study (exenatide-first and saline-first).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide First Followed by Saline | Drug Effect on First-Phase Insulin Secretion (Genotype-specific) | 2.25 Ratio: no units | Standard Error 0.31 |
| Saline First Followed by Exenatide | Drug Effect on First-Phase Insulin Secretion (Genotype-specific) | 1.94 Ratio: no units | Standard Error 0.21 |
| Homozygotes for the p.E354Q Allele of GIPR | Drug Effect on First-Phase Insulin Secretion (Genotype-specific) | 1.87 Ratio: no units | Standard Error 0.27 |
Comparison: Null hypothesis: no differences between the two groups with respect to exenatide's effect on first-phase insulin secretion.~t-test conducted on logarithms of the valuesp-value: 0.41t-test, 2 sided
Comparison: Null hypothesis: no difference between two groups with respect to exenatide's effect on first phase insulin secretionp-value: 0.38t-test, 2 sided
Secondary
Exenatide's Effect on the Rate of Glucose-disappearance (Genotype Specific)
The rate of glucose disappearance was calculated as the slope of a least-squared line fitted to the logarithms of glucose concentrations during time 25-50 min of FSIGTs
Time frame: 25-50 min during the FSIGT
Population: Same as for effect of exenatide on first phase insulin secretion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide First Followed by Saline | Exenatide's Effect on the Rate of Glucose-disappearance (Genotype Specific) | 2.19 Log(mg/dL) per min | Standard Error 0.24 |
| Saline First Followed by Exenatide | Exenatide's Effect on the Rate of Glucose-disappearance (Genotype Specific) | 2.28 Log(mg/dL) per min | Standard Error 0.24 |
| Homozygotes for the p.E354Q Allele of GIPR | Exenatide's Effect on the Rate of Glucose-disappearance (Genotype Specific) | 2.18 Log(mg/dL) per min | Standard Error 0.19 |
Comparison: Null hypothesis: the two genotype groups do not differ with respect to the effect of exenatide on the rate of glucose disappearancep-value: 0.8t-test, 2 sided
Comparison: Null hypothesis: the two genotype groups do not differ with respect to the effect of exenatide on the rate of glucose disappearance during an FSIGTp-value: 0.98t-test, 2 sided
Secondary
First Phase Insulin Secretion (Exenatide)
The area under the curve for plasma insulin levels during a frequently sampled intravenous glucose tolerance test after participants received exenatide
Time frame: 0-10 minutes
Population: The analysis population included 52 patients who completed the study and for whom the necessary blood samples were collected and available for assays of insulin and glucose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide First Followed by Saline | First Phase Insulin Secretion (Exenatide) | 561 microunits/mL*min | Standard Error 94 |
| Saline First Followed by Exenatide | First Phase Insulin Secretion (Exenatide) | 494 microunits/mL*min | Standard Error 50 |
Comparison: Null hypothesis: the order of FSIGT (exenatide or saline) does not affect the response during an FSIGTp-value: 0.86t-test, 2 sided
Secondary
First Phase Insulin Secretion (Placebo)
The area under the curve for plasma insulin levels during a frequently sampled intravenous glucose tolerance test after participants received saline
Time frame: 0-10 minutes
Population: The analysis population included 52 patients who completed the study and for whom the necessary blood samples were collected and available for assays of insulin and glucose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide First Followed by Saline | First Phase Insulin Secretion (Placebo) | 305 microunits/mL*min | Standard Error 38 |
| Saline First Followed by Exenatide | First Phase Insulin Secretion (Placebo) | 254 microunits/mL*min | Standard Error 23 |
Comparison: Null hypothesis: The order of FSIGTs (exenatide-stimulated or saline) does not affect the response to an FSIGTp-value: 0.44t-test, 2 sided
Secondary
Glucose Disappearance Rate (Exenatide)
The slope of the line plotting the logarithm of glucose concentrations as a function of time during the exenatide frequently sampled intravenous glucose tolerance test. The slope of the line was estimated as the slope of the least-squares fit to the data points between 25-50 minutes.
Time frame: 25-50 minutes
Population: The analysis population included 52 patients who completed the study and for whom the necessary blood samples were collected and available for assays of insulin and glucose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide First Followed by Saline | Glucose Disappearance Rate (Exenatide) | 1056 Log(mg/dL) per min | Standard Error 94 |
| Saline First Followed by Exenatide | Glucose Disappearance Rate (Exenatide) | 1131 Log(mg/dL) per min | Standard Error 81 |
Comparison: Null hypothesis: the order of testing (exenatide-stimulated or saline FSIGT) does not affect data obtained in the FSIGTs.p-value: 0.55t-test, 2 sided
Secondary
Glucose Disappearance Rate (Placebo)
The slope of the line plotting the logarithm of glucose concentrations as a function of time during the placebo frequently sampled intravenous glucose tolerance test. The slope of the line was estimated as the slope of the least-squares fit to the data points between 25-50 minutes.
Time frame: 25-50 minutes
Population: The analysis population included 52 patients who completed the study and for whom the necessary blood samples were collected and available for assays of insulin and glucose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide First Followed by Saline | Glucose Disappearance Rate (Placebo) | 500 Log(mg/dL) per min | Standard Error 37 |
| Saline First Followed by Exenatide | Glucose Disappearance Rate (Placebo) | 547 Log(mg/dL) per min | Standard Error 48 |
Comparison: The order of FSIGTs (exenatide-stimulated or saline) does not affect the response during an FSIGTp-value: 0.45t-test, 2 sided