Endogenous GLP-1 Secretion on Islet Function in People With and Without Type 2 Diabetes

To Determine the Effect of Endogenous GLP-1 Secretion on Islet Function in People With and Without Type 2 Diabetes

GLP-1 is a hormone made by the body that promotes the production of insulin in response to GLP-1 is produced within the islets expressing prohormone convertase 1/3eating. However, there is increasing evidence that this hormone might help support the body's ability to produce insulin when diabetes develops. The purpose of this study is to determine the effect of endogenous GLP-1 secretion on insulin secretion in people with and without type 2 diabetes.

Study Overview

• Status: Completed
• Conditions: Healthy; Type 2 Diabetes
• Intervention / Treatment: Biological: Saline; Biological: Exendin-9,39; Biological: Saline + Intralipid/Heparin; Biological: Exendin-9,39 + Intralipid/Heparin

Detailed Description

Accumulating evidence suggests that in rodents and humans GLP-1 is synthesized within islets and may act locally in a paracrine fashion. Indeed, mice with genetic loss of intra-islet GLP-1 exhibit decreased insulin secretion and impaired response to metabolic stressors. 'Pancreatic' GLP-1 may contribute to the effects of DPP-4 inhibitors in rodents and humans. Antagonism of GLP1R with exendin-9,39 during fasting impairs the islet cell response to an I.V. glucose challenge. Islet GLP-1 content is increased in T2DM and in islets from non-diabetic humans exposed to hyperglycemia and Free Fatty Acids. These observations imply that paracrine GLP-1 secretion supports islet function in the presence of glucolipotoxicity. In this experiment we will examine the role of endogenous GLP-1 secretion in people with and without T2DM and during β-cell stress induced by FFA elevation.

• Study Type: Interventional
• Enrollment (Actual): 23
• 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 - non-diabetic subjects:

• Weight-stable, non-diabetic subjects

Exclusion Criteria - non-diabetic subjects:

• 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 ≥ 6.5%
• 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.

Inclusion criteria - diabetic subjects:

• Weight-stable, diabetic subjects treated with diet and lifestyle alone or with metformin monotherapy

Exclusion Criteria - diabetic subjects:

• 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).
• Use of any glucose-lowering agent other than metformin.
• 2 or more fasting glucose values > 250mg/dl on medication or after medication withdrawal.
• Unwillingness or inability to withdraw medication for three weeks prior to, and for the duration of the study.
• 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: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Saline; Saline infusion	Biological: Saline; Saline infused during the study
Active Comparator: Exendin-9,39; Exendin-9,39 infusion	Biological: Exendin-9,39; Exendin-9,39 infused during the study
Active Comparator: Saline + Intralipid/Heparin; Induction of acute insulin resistance during Saline infusion	Biological: Saline + Intralipid/Heparin; Saline infused during acute insulin resistance
Active Comparator: Exendin-9,39 + Intralipid/Heparin; Induction of acute insulin resistance during Exendin-9,39 infusion	Biological: Exendin-9,39 + Intralipid/Heparin; Exendin-9,39 infused during acute insulin resistance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Fasting Glucagon in the Presence or Absence of Exendin-9,39	Concentrations of glucagon Measured by immunoassay over the -30 to 0 minutes of study. On one study day subjects received saline, on the other exendin-9,39. The infusion commenced at -120 minutes.	Average concentration over the -30 to 0 minutes of study

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2021
• Primary Completion (Actual): December 15, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: June 30, 2020
• First Submitted That Met QC Criteria: July 7, 2020
• First Posted (Actual): July 10, 2020

Study Record Updates

• Last Update Posted (Actual): December 26, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Heparin; Calcium heparin; Soybean oil, phospholipid emulsion
• Other Study ID Numbers: 20-003993; R01DK126206 (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