Diabetes
Conditions
Keywords
GLP-1, Insulin Secretion
Brief summary
Glucagon-like Peptide-1 (GLP-1) is an important incretin hormone which acts as a powerful insulin secretagogue. Defects in GLP-1 synthesis and secretion are thought to be part of the pathogenesis of type 2 diabetes. Furthermore GLP-1 based therapy is an important part of the therapeutic armamentarium for the treatment of type 2 diabetes. The GLP-1 receptor (GLP1R) is the principal site of action of GLP-1 and GLP-1 receptor agonists like exenatide and liraglutide. The gene coding for this receptor, GLP1R, is highly polymorphic and contains numerous non-synonymous Single Nucleotide Polymorphisms (nsSNPs) which could potentially alter response to endogenous or exogenous GLP-1 or GLP-1R agonists. Indeed there is some in vitro data to support this concept. We propose to utilize a hyperglycemic clamp to test the insulin secretory response to infused GLP-1 in healthy volunteers to determine the effect of genetic variation in GLP1R on response to GLP-1.
Interventions
DRUGGLP-1
GLP-1 infused at 0.75 pmol/kg/min from 121-180 minutes, GLP-1 infused at 1.55 pmol/kg/min from 181-240 minutes,
Sponsors
Merck Sharp & Dohme LLC
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Aged 18-40 * fasting glucose concentration of less than 95 mg/dl.
Exclusion criteria
* Individuals with a BMI \< 19 or \> 40 kg/m\^2 * active systemic illness * medication that can alter gastric emptying, insulin secretion & action * history of abdominal surgery (other than appendectomy or tubal ligation).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Secretion at 150-180 Minutes. | 150 - 180 minutes after GLP-1 infusion | The 180 minute value represents the mean of the values obtained at 150, 160, 170, and 180 minutes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Secretion at 210-240 Minutes | 210 - 240 minutes after GLP-1 infusion | The 240 minute value represents the mean of values obtained at 210, 220, 230, and 240 minutes. |
Countries
United States
Participant flow
Recruitment details
Healthy volunteers recruited from Olmsted County, MN.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study All participants recieved glucose for 2 hours then Glucagon Like Peptide-1 (GLP-1) intravenously at a rate of 0.75 pmol/kg/min for 1 hour followed by 1.5 pmol/kg/min for the subsequent hour. The study lasted for 240 minutes. | 88 |
| Total | 88 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age Continuous | 26.3 years STANDARD_DEVIATION 5.6 |
| Region of Enrollment United States | 88 participants |
| Sex: Female, Male Female | 52 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 88 |
| serious Total, serious adverse events | 0 / 88 |
Outcome results
Primary
Insulin Secretion at 150-180 Minutes.
The 180 minute value represents the mean of the values obtained at 150, 160, 170, and 180 minutes.
Time frame: 150 - 180 minutes after GLP-1 infusion
Population: all participants completed the study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Insulin Secretion at 150-180 Minutes. | rs6923761 (1,1) genotype | 104 10^-9 min^-1 | Standard Error 9 |
| All Participants | Insulin Secretion at 150-180 Minutes. | rs6923761 (1, 2) genotype | 94 10^-9 min^-1 | Standard Error 11 |
| All Participants | Insulin Secretion at 150-180 Minutes. | rs6923761 (2, 2) genotype | 81 10^-9 min^-1 | Standard Error 8 |
| All Participants | Insulin Secretion at 150-180 Minutes. | rs3765467 (1,2) genotype | 92 10^-9 min^-1 | Standard Error 6 |
| All Participants | Insulin Secretion at 150-180 Minutes. | rs3765467 (2,2) genotype | 219 10^-9 min^-1 | Standard Error 35 |
Comparison: Using the Kruskal-Wallis test (general allelic model), we assessed univariate associations of rs6923761 genotype with Phi Total in the presence of either glucose alone, glucose and 0.75 pmol/kg/min GLP-1 or glucose and 1.5 pmol/kg/min GLP-1 If the p-value for the overall univariate test of association was \<0.1, then the associations for specific genotype pairs (e.g.: 1,1 vs. 1,2 or 2,2 vs. 1,1) were also examined using a Mann-Whitney Rank Sum test.p-value: 0.11Kruskal-Wallis
Secondary
Insulin Secretion at 210-240 Minutes
The 240 minute value represents the mean of values obtained at 210, 220, 230, and 240 minutes.
Time frame: 210 - 240 minutes after GLP-1 infusion
Population: All participants completing the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Insulin Secretion at 210-240 Minutes | rs6923761 (1,1) genotype | 152 10^-9 min^-1 | Standard Error 12 |
| All Participants | Insulin Secretion at 210-240 Minutes | rs6923761 (1,2) genotype | 133 10^-9 min^-1 | Standard Error 15 |
| All Participants | Insulin Secretion at 210-240 Minutes | rs6923761 (2,2) genotype | 112 10^-9 min^-1 | Standard Error 10 |
| All Participants | Insulin Secretion at 210-240 Minutes | rs3765467 (1,2) genotype | 132 10^-9 min^-1 | Standard Error 7 |
| All Participants | Insulin Secretion at 210-240 Minutes | rs3765467 (2,2) genotype | 325 10^-9 min^-1 | Standard Error 44 |
Comparison: All data are presented as means ± SEM. Using the Kruskal-Wallis test (general allelic model), we assessed univariate associations of genotype with ΦTotalp-value: 0.09Kruskal-Wallis