Clinical trial NCT06967558: The Role of Islet GLP-1 in the Pathogenesis of Prediabetes
Official title: The Role of Islet GLP-1 in the Pathogenesis of Prediabetes
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: PreDiabetes
Keywords: Impaired Fasting Glucose
Impaired Glucose Tolerance
GLP-1
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
First posted: 2025-05-13
Enrollment: 60
Sex: ALL
Minimum age (years): 25
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: we will study people with normal glucose tolerance with or without impaired fasting glucose together with people with impaired fasting glucose with or without impaired glucose tolerance. All subjects will be studied on 2 occasions - on one they will receive exendin 9-39 and on the other saline
Primary purpose: BASIC_SCIENCE

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

Eligibility criteria: 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.

Primary outcomes:
measure: Alpha-cell responsivity to glucose as measured by G50
timeFrame: 0-240 minutes
measure: Beta-cell responsivity to glucose
timeFrame: 0-240 minutes
Secondary outcomes:
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Adrian Vella, MD
role: PRINCIPAL_INVESTIGATOR
References: