Regulation of Insulin Secretion by the GLP-1 Receptor
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02844907|
Recruitment Status : Recruiting
First Posted : July 26, 2016
Last Update Posted : October 17, 2018
The purpose of this study is to determine the role of basal GLP-1 action on the β-cell response to insulin resistance. Healthy subjects will have fasting GLP-1 action determined with GLP-1r blockade before and after induction of experimental insulin resistance. We hypothesize that fasting GLP-1 action will increase to compensate for experimental insulin resistance.
The study will enroll up to 40 healthy participants and while it is anticipated that the screening blood draw will yield a number of screen failures, it is estimated that 10-15 subjects will complete the entire study protocol. Enrolled participants will be asked to complete three study visits including the consent visit and two infusion study visits that will include hyperglycemic clamp procedures with the addition of the GLP-1 receptor antagonist Exendin (9-39) to determine the fasting GLP-1 effect. Each infusion procedure will last 2 hours. Subjects will be asked to take dexamethasone daily for approximately one week between Visit-2 and Visit-3 to induce insulin resistance.
We will enroll 6-10 additional subjects as controls for effects of time and repeat testing. These individuals will have identical clamps with no dexamethasone at approximately 1 week intervals and will be determined at random by study staff.
The primary outcome for visits 2-3 will be to measure the effects of Ex-9 on fasting glucose-stimulated insulin secretion before and after experimentally induced insulin resistance. The primary experimental variable for analysis will be C-peptide during the clamp. Mean values will be compared between the period of glucose only stimulation and glucose with Ex-9. For each subject in the active treatment arm data will be analyzed using 2-way ANOVA for repeated measures using time (0-60 vs 60-120 min) and treatment (Dex vs no Dex) as the two factors. Based on our previous studies we expect a significant time effect due to Ex-9. If there is an interaction with treatment we would conclude that experimental insulin resistance influences the fasting GLP-1 effect. Data from control subjects will be analyzed identically; here we expect no interaction, indicating that the fasting GLP-1 is a stable measure. In our previous study using Ex-9 during a glucose clamp, the average coefficient of variation in insulin concentrations at the conclusion of each step in the ramp was 30%. Using this estimate of between subject variation, detecting a 20% difference between subsequent steps in the GLP-1 ramp with a power of 80% and significance level of 0.05 will require 8 subjects.
|Condition or disease||Intervention/treatment||Phase|
|Insulin Secretion||Drug: Exendin (9-39) Drug: Dexamethasone Other: Hyperglycemic Clamp||Phase 4|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||40 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Regulation of Insulin Secretion by the GLP-1 Receptor|
|Actual Study Start Date :||July 1, 2018|
|Estimated Primary Completion Date :||December 2020|
|Estimated Study Completion Date :||December 2020|
Experimental: Hyperglycemic clamp
During the 2-hour procedure, a variable infusion of 20% dextrose and blood glucose will be clamped at basal + 3mM.
Other: Hyperglycemic Clamp
A variable infusion of 20% dextrose will begin to clamp the blood glucose at basal +3 mM.
Experimental: Hyperglycemic clamp + Exendin (9-39)
During the 2-hour procedure, a variable infusion of 20% dextrose and blood glucose will be clamped at basal + 3mM. Participants will receive an infusion of the GLP-1 receptor antagonist Exendin (9-39) between the 60-120 minute time-points of the clamp. The amount of Ex-9 infused will be 750 pmol/kg/min for 60 minutes.
Drug: Exendin (9-39)
Upon establishing a hyperglycemic clamp (target blood glucose at basal +3 mM) Exendin (9-39) will be infused.
Other Name: Dextrose
Subjects will be asked to take 4 mg once daily between Visit-2 and Visit-3.
Between Visit-2 and Visit-3, Dexamethasone (4 mg tablet) once daily for 5-7 days.
- Beta-cell sensitivity [ Time Frame: 20-30 minute infusion periods ]Beta-cell sensitivity for each incretin will equal the slope of the insulin secretion
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02844907
|Contact: Lucy W Piner, MSfirstname.lastname@example.org|
|Contact: Leslie Kellyemail@example.com|
|United States, North Carolina|
|VA Health Care System||Recruiting|
|Durham, North Carolina, United States, 27705|
|Contact: Leslie S Kelly 910-782-9771 firstname.lastname@example.org|
|Contact: Lucy W Piner, MS 919-660-6781 email@example.com|
|Principal Investigator: David D'Alessio, MD|
|Principal Investigator:||David D'Alessio, MD||Durham VA Medical Center|