Regulation of Insulin Secretion by the GLP-1 Receptor

NCT02844907 | Terminated Phase 4 Results DMC FDA Drug

• 3 other identifiers: ENDA-006-15SPro0007032501992
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Insulin Secretion

Keywords

Incretins; GLP-1; Exendin-9; Insulin Resistance; Diabetes; Pre-diabetes

Outcome Measures

Primary Outcomes (2)

• 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)

Study Arms (2)

Hyperglycemic clamp + Exendin (9-39)

EXPERIMENTAL

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); Other: Hyperglycemic Clamp

Dexamethasone

EXPERIMENTAL

Subjects will be asked to take 4 mg once daily between Visit-2 and Visit-3.

Drug: Dexamethasone

Interventions

Exendin (9-39) DRUG

Upon establishing a hyperglycemic clamp (target blood glucose at basal +3 mM) Exendin (9-39) will be infused.

Also known as: GLP-1 receptor antagonist

Hyperglycemic clamp + Exendin (9-39)

Dexamethasone DRUG

Between Visit-2 and Visit-3, Dexamethasone (4 mg tablet) once daily for 5-7 days.

Dexamethasone

Hyperglycemic Clamp OTHER

A variable infusion of 20% dextrose will begin to clamp the blood glucose at basal +3 mM.

Hyperglycemic clamp + Exendin (9-39)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• VA Office of Research and Development: lead
• Durham VA Medical Center: collaborator

Study Sites (1)

Durham VA Medical Center, Durham, NC

Durham, North Carolina, 27705, United States

Location

MeSH Terms

Conditions

Insulin Resistance; Diabetes Mellitus; Glucose Intolerance

Interventions

exendin (9-39); Dexamethasone

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperglycemia

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Limitations and Caveats

Difficulty recruiting healthy veterans who were established at the Durham VA for this study. Healthy subjects were not frequently enrolled with VA healthcare and veterans enrolled with the VA did not often meet the inclusion/exclusion criteria. Enrollment was also limited by the COVID-19 pandemic. Due to the small sample with collected data statistical analysis was not performed.

Results Point of Contact

• Title: David D'Alessio, MD
• Organization: Durham VAMC

david.dalessio2@va.gov

919-684-5778

Study Officials

• David D'Alessio, MD

  Durham VA Medical Center, Durham, NC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 22, 2016
• First Posted: July 26, 2016
• Study Start: July 1, 2018
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2021
• Last Updated: December 12, 2024
• Results First Posted: December 12, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)