Regulation of Insulin Secretion by the GLP-1 Receptor

AIM2: The purpose of Aim-2 of this study is to determine the role of basal GLP-1 action on the beta-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. The investigators hypothesize that fasting GLP-1 action will increase to compensate for experimental insulin resistance.

AIM3: The purpose of Aim-3 of this study is to determine the role of basal GLP-1 action on fasting glucose regulation in lean, obese, pre-diabetic and type 2 diabetic (T2DM) subjects. A cross sectional study of age-matched subjects across the spectrum of glucose tolerance will be used to test the hypothesis that fasting GLP-1 action increases as beta-cell function declines.

Study Overview

• Status: Terminated
• Conditions: Insulin Secretion
• Intervention / Treatment: Drug: Exendin (9-39); Other: Hyperglycemic Clamp; Drug: Dexamethasone

Detailed Description

AIM2: The purpose of this study is to determine the role of basal GLP-1 action on the beta-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. The investigators hypothesize that fasting GLP-1 action will increase to compensate for experimental insulin resistance.

The study will enroll up to 20-25 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.

The investigators 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 the investigators' previous studies the investigators expect a significant time effect due to Ex-9. If there is an interaction with treatment the investigators would conclude that experimental insulin resistance influences the fasting GLP-1 effect. Data from control subjects will be analyzed identically; here the investigators expect no interaction, indicating that the fasting GLP-1 is a stable measure. In the investigators' 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.

AIM3: The purpose of Aim-3 of this study is to determine the role of basal GLP-1 action on fasting glucose regulation in lean, obese, pre-diabetic and type 2 diabetic (T2DM) subjects. Approximately 15-20 subjects will complete this cross sectional study of age-matched subjects across the spectrum of glucose tolerance will be used to test the hypothesis that fasting GLP-1 action increases as beta-cell function declines.

Enrolled participants for Aim-3 will be asked to complete two study visits including the consent visit and one infusion visit that will include a hyperglycemic clamp and an infusion of the antagonist Exendin (9-39). The infusion procedure will last approximately 2 hours.

The primary outcome measure for Aim-3 will be the fasting GLP-1 effect. This will be defined as the difference in steady state glucose-stimulated insulin secretion with and without Ex-9. The difference will be expressed as a percentage of glucose stimulated insulin secretion without Ex-9, and serve as the primary variable for comparison among the lean, obese and diabetic cohorts.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Durham VA Medical Center, Durham, NC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

AIM2: SELECTION OF HEALTHY SUBJECTS

• Healthy adults age 20-45 years
• Body Mass Index (BMI) less than or equal to 35.0 kg/m2
• HbA1c less than or equal to 5.7% as measured at screening visit
• Ability to speak and understand English

AIM3: NON-DIABETIC SUBJECTS

• Adults age 18-65 years
• Body Mass Index (BMI) 25-40.0 kg/m2
• HbA1c less than or equal to 6.5% as measured at screening visit
• No Diabetes or use of diabetes medications such as insulin or metformin
• Ability to speak and understand English

AIM3: DIABETIC Type II SUBJECTS

• Adults age 18-65 years
• Body Mass Index (BMI) 25-40.0 kg/m2
• HbA1c less than or equal to 7.5% plus a diagnosis of Type II diabetes managed by either Metformin, Sulfonylurea, or diet and exercise
• Ability to speak and understand English

Exclusion Criteria:

AIM2:

• Uncontrolled high blood pressure
• Diabetes or use of diabetes medications such as insulin or metformin
• Evidence of active heart disease, unstable angina or heart failure
• Lung disease or COPD
• Malabsorptive GI disease, such as celiac disease, or gastric bypass
• Significant hepatic disease
• Kidney disease or renal insufficiency (eGFR < 60 mL/kg/min)
• Untreated anemia (hematocrit < 34%) as measured at screening visit
• Pregnant females
• Active substance abuse
• Chronic use of oral steroid medications such as prednisone and hydrocortisone
• Apparent sensitivity to any study peptides as determined by the skin test
• Diagnosis or h/o PTSD
• Active mental health disorders such as depression, or as a result of Traumatic Brain Injury (TBI)

AIM3: ALL SUBJECTS

• Uncontrolled high blood pressure
• Evidence of active heart disease, unstable angina or heart failure
• Lung disease or COPD
• Malabsorptive GI disease, such as celiac disease, or gastric bypass
• Significant hepatic disease
• Kidney disease or renal insufficiency (eGFR < 60 mL/kg/min)
• Untreated anemia (hematocrit < 34%) as measured at screening visit
• Pregnant females
• Active substance abuse
• Chronic use of oral steroid medications such as prednisone and hydrocortisone
• Apparent sensitivity to any study peptides as determined by the skin test
• Diagnosis or h/o PTSD
• Active mental health disorders such as depression, or as a result of Traumatic Brain Injury (TBI)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: GLP-1 receptor antagonist; Other: Hyperglycemic Clamp; A variable infusion of 20% dextrose will begin to clamp the blood glucose at basal +3 mM.
Experimental: Dexamethasone; Subjects will be asked to take 4 mg once daily between Visit-2 and Visit-3.	Drug: Dexamethasone; Between Visit-2 and Visit-3, Dexamethasone (4 mg tablet) once daily for 5-7 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AIM2: C-peptide Levels.	Primary variable for analysis will be C-peptide during the clamp. Mean values will be compared between the control and dexamethasone studies for C-peptide levels during the hyperglycemia plus exendin-(9-39) period of the clamps. For each subject the mean C-peptide during the 60-90 minute period of the initial study (with no dexamethasone) will be compared to the 60-120 period with dexamethasone.	Minute infusion periods (0-60 vs 60-120) baseline and treatment (Dex vs no Dex)
AIM3: To Determine the Fasting GLP-1 Effect.	The fasting GLP-1 effect will be defined as the difference in steady state glucose stimulated insulin secretion with and without Ex-9.	Minute infusion periods (0-60 vs 60-120)

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: Durham VA Medical Center
• Investigators: Principal Investigator: David D'Alessio, MD, Durham VA Medical Center, Durham, NC

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2018
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: July 22, 2016
• First Submitted That Met QC Criteria: July 22, 2016
• First Posted (Estimated): July 26, 2016

Study Record Updates

• Last Update Posted (Actual): December 12, 2024
• Last Update Submitted That Met QC Criteria: November 19, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Diabetes; GLP-1; Insulin Resistance; Pre-diabetes; Incretins; Exendin-9
• Additional Relevant MeSH Terms: Antineoplastic Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: ENDA-006-15S; Pro00070325 (Other Identifier: Duke University); 01992 (Other Identifier: Durham VA Medical Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No