Healthy
Conditions
Brief summary
The GLP-1 receptor (GLP1R) gene is found on the beta cells of the pancreas. Its role is in the control of blood sugar level by enhancing insulin secretion from the pancreas after eating a meal. The purpose of this research study is to evaluate the role of GLP1R in the response to elevated glucagon concentrations.
Detailed description
Glucagon within the islet can signal the β-cell through GLP1R, and acts as an insulin secretagogue. This signaling is blocked by exendin-9,39. The relative importance of glucagon signaling through its cognate receptor or through GLP1R is unknown. Despite the lower affinity of GLP1R for glucagon, intra-islet concentrations of glucagon are sufficiently high to stimulate GLP1R. The other situation where this may occur is in response to pharmacologic doses of glucagon as used for β-cell function testing or raising peripheral glucagon concentrations above fasting values. The experiments proposed will characterize the role of GLP1R in glucagon's actions on the β-cell and the potential therapeutic role of dual (GLP-1R and glucagon receptor) agonists for the treatment of T2DM and obesity.
Interventions
BIOLOGICALExendin-9,39
Exendin-9,39 is a competitive antagonist of GLP-1 actions at the GLP-1 receptor
OTHERSaline
Placebo comparator
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Adrian Vella
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
25 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* 20 weight-stable, non-diabetic subjects
Exclusion criteria
* Age \< 25 or \> 65 years (to avoid studying subjects who could have latent type 1 diabetes, or the effects of age extremes in subjects with normal or impaired fasting glucose). * HbA1c ≥5.9% * Use of glucose-lowering agents. * For female subjects: positive pregnancy test at the time of enrollment or study * History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy. * Active systemic illness or malignancy. * Symptomatic macrovascular or microvascular disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Secretion Rate During Exendin-9,39 Infusion vs. Insulin Secretion Rate During Saline Infusion | Area under the curve was quantified at the end of the Saline Study and at the end of the Exendin-9,39 study | This is the area under the curve for insulin secretion over the duration of the hyperglycemic clamp (0 to 300 minutes during the study in the Clinical Research Unit). |
Countries
United States
Participant flow
Recruitment details
Healthy volunteers responded to intramural advertising at the Mayo Clinic between March 2021 and September 2021
Pre-assignment details
None of the enrolled subjects were excluded and all were randomized
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants were randomized to receive all interventions | 11 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Loss of IV during study | 1 | 0 |
Baseline characteristics
| Characteristic | All Participants | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 11 Participants | — |
| Age, Continuous | 26 years STANDARD_DEVIATION 3 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 11 participants | — |
| Sex: Female, Male Female | 9 Participants | — |
| Sex: Female, Male Male | 2 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 2 / 11 | 0 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
Insulin Secretion Rate During Exendin-9,39 Infusion vs. Insulin Secretion Rate During Saline Infusion
This is the area under the curve for insulin secretion over the duration of the hyperglycemic clamp (0 to 300 minutes during the study in the Clinical Research Unit).
Time frame: Area under the curve was quantified at the end of the Saline Study and at the end of the Exendin-9,39 study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Secretion During the Saline Study | Insulin Secretion Rate During Exendin-9,39 Infusion vs. Insulin Secretion Rate During Saline Infusion | 191 nmol/min per 300 min | Standard Error 23 |
| Insulin Secretion During the Exendin-9,39 Study | Insulin Secretion Rate During Exendin-9,39 Infusion vs. Insulin Secretion Rate During Saline Infusion | 171 nmol/min per 300 min | Standard Error 19 |
Comparison: All continuous data are summarized as means ± SEM. Area Under the Curve (AUC) was calculated using the trapezoidal rule. A paired, two-way Student t-test (parametric) or a Wilcoxon matched-pairs signed rank test (non-parametric) was used to examine differences between study days. A p-value \<0.05 was considered statistically significant.p-value: 0.02t-test, 2 sided