The Role of Islet GLP-1 in the Pathogenesis of Prediabetes

Phase 2

Not yet recruiting

• Conditions: PreDiabetes
• Interventions: Biological: Exendin 9-39; Biological: Saline

• Registration Number: NCT06967558
• Lead Sponsor: Mayo Clinic

Brief Summary

We recently demonstrated that blockade of Glucagon-Like Peptide-1's (GLP-1) receptor (GLP1R) results in changes in islet function without changes in circulating GLP-1. These effects are more pronounced in people with early type 2 diabetes (T2DM) in keeping with increased expression of PC-1/3 and GLP-1 that is observed in diabetic islets. However, its regulation is at present unknown. At present it is unknown if these abnormalities develop in prediabetes and whether they contribute to the phenotypes observed. In this experiment we will use blockade of GLP1R to probe the contribution of endogenous GLP-1 secretion to the regulation of fasting glucose and islet function in prediabetes.

Detailed Description

We recently demonstrated that blockade of Glucagon-Like Peptide-1's (GLP-1) receptor (GLP1R) results in changes in islet function without changes in circulating GLP-1. This supports other evidence (rodents and humans) that through the (inducible) expression of a prohormone convertase (PC-1/3), the α-cell can process proglucagon to intact GLP-1. 'Islet' or 'pancreatic' GLP-1 acts in a paracrine fashion to regulate insulin and glucagon secretion. These effects are more pronounced in people with early type 2 diabetes (T2DM). Although pancreatic GLP-1 adapts to support islet function in T2DM, it is unclear if this mechanism is upregulated in prediabetes and whether it contributes to the phenotype(s) observed. Abnormal α-cell responsivity to glucose, measured using G50, is associated with Impaired Fasting Glucose (IFG); β-cell dysfunction is associated with Impaired Glucose Tolerance (IGT). Does IGT (or IFG) represent selective failure of intra-islet GLP-1 to support islet function? In this experiment we will use blockade of GLP1R to probe the contribution of endogenous GLP-1 secretion to the regulation of fasting glucose and islet function in prediabetes

Study Timeline

• Status Verified: 2025-05
• Study First Submitted: 2025-05-05
• Study First Submitted QC: 2025-05-12
• Last Update Submitted: 2025-05-12
• Study First Posted: 2025-05-13
• Last Update Posted: 2025-05-13
• Study Start: 2025-09-01
• Primary Completion: 2027-10-30
• Study Completion: 2028-03-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• People with stable weight and no history of diabetes.
• Fasting glucose < 126 mg/dL
• 2hr glucose after 75g OGTT < 200 mg/dL

Exclusion Criteria

• Age < 25 or > 70 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 any glucose-lowering agents including metformin or sulfonylureas.
• 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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Exendin 9-39	Exendin 9-39	Subjects will receive exendin 9-39 during the study
Saline	Saline	Subjects will receive saline during the study

Primary Outcome Measures

Name	Time	Method
Alpha-cell responsivity to glucose as measured by G50	0-240 minutes	The change in glucose necessary to suppress glucagon secretion by 50%
Beta-cell responsivity to glucose	0-240 minutes	This is measured as the gradient of the increase in insulin secretion rate per unit increase in glucose concentration

Trial Locations

Locations (1)

Mayo Clinic in Rochester; 🇺🇸 Rochester, Minnesota, United States