A Dose-response Study Examining the Contribution of GLP-1 Receptor Signaling to Glucagon-stimulated Insulin Secretion

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Other: Saline; Biological: Exendin-9,39

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Saline, Then Exendin-9,39; A week or two after screening, participants were admitted to the CRTU and Saline was infused during a hyperglycemic clamp during which escalating doses of glucagon were infused. After completion of this study participants underwent a washout period of 2 weeks after which they were readmitted to the CRTU and Exendin-9,39 was infused at 300pmol/kg/min was infused during a hyperglycemic clamp during which escalating doses of glucagon were infused.	Other: Saline; Placebo comparator; Biological: Exendin-9,39; Exendin-9,39 is a competitive antagonist of GLP-1 actions at the GLP-1 receptor
Experimental: Exendin-9,39, Then Saline; A week or two after screening, participants were admitted to the CRTU and Exendin-9,39 was infused at 300pmol/kg/min during a hyperglycemic clamp during which escalating doses of glucagon were infused. After completion of this study participants underwent a washout period of 2 weeks after which they were readmitted to the CRTU and Saline was infused during a hyperglycemic clamp during which escalating doses of glucagon were infused.	Other: Saline; Placebo comparator; Biological: Exendin-9,39; Exendin-9,39 is a competitive antagonist of GLP-1 actions at the GLP-1 receptor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Area under the curve was quantified at the end of the Saline Study and at the end of the Exendin-9,39 study

Collaborators and Investigators

• Sponsor: Adrian Vella
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Adrian Vella, MD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2021
• Primary Completion (Actual): June 14, 2022
• Study Completion (Actual): June 14, 2022

Study Registration Dates

• First Submitted: June 30, 2020
• First Submitted That Met QC Criteria: July 1, 2020
• First Posted (Actual): July 7, 2020

Study Record Updates

• Last Update Posted (Actual): June 9, 2023
• Last Update Submitted That Met QC Criteria: June 8, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Other Study ID Numbers: 20-003995; 5R01DK126206-03 (U.S. NIH Grant/Contract)

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