The Effect of rs7903146 Genotype on Islet GLP-1 Production in Humans

NCT06972407 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 24-007701
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators 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. Common genetic variation in the TCF7L2 locus (T-allele at rs7903146) arguably confers the greatest genetic risk of T2DM. It is associated with α- and β-cell dysfunction. TCF7L2 (the product of TCF7L2) was first described as the transcription factor necessary for proglucagon expression in intestinal L-cells (which secrete GLP-1). This led to speculation that TCF7L2 confers risk of diabetes via changes in circulating GLP-1. This has turned out to not be the case. This raises the possibility that these diabetogenic effects are mediated via an inability of islet GLP-1 to adapt to rising glycemia. Therefore, this experiment will determine the contribution of islet GLP-1 to the functional abnormalities of the islet associated with the TCF7L2 locus.

Conditions

Genetic Predisposition; Type2diabetes

Keywords

TCF7L2

Outcome Measures

Primary Outcomes (2)

• Change in fasting glucose

  comparison of fasting glucose during saline vs. exendin 9-39 infusion

  Change in average glucose concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day)

• Change in fasting glucagon

  comparison of fasting glucagon during saline vs. exendin 9-39 infusion

  Change in average glucagon concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day)

Secondary Outcomes (2)

• Change in fasting insulin

  Change in average insulin concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day)

• Change in first phase insulin secretion

  Change in integrated insulin concentrations (area above baseline) between 0 min and 30 min of each study day (saline day vs. exendin 9-39 day)

Study Arms (2)

Exendin 9-39

ACTIVE COMPARATOR

Exendin 9-39 will be infused during fasting and during a hyperglycemic clamp

Biological: Exendin 9-39

Saline

PLACEBO COMPARATOR

Saline will be infused during fasting and during a hyperglycemic clamp

Other: Saline

Interventions

Exendin 9-39 BIOLOGICAL

A competitive antagonist of the GLP-1 receptor

Exendin 9-39

Saline OTHER

Saline infusion will serve as an inactive comparator

Saline

Eligibility Criteria

• Age: 25 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects with the TT or CC genotype at rs7903146

You may not qualify if:

• 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).
• CT genotype at rs7903146
• 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.

Sponsors & Collaborators

• Mayo Clinic: lead

Study Sites (1)

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

MeSH Terms

Conditions

Genetic Predisposition to Disease

Interventions

exendin (9-39); Sodium Chloride

Condition Hierarchy (Ancestors)

Disease Susceptibility; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Adrian Vella, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Adrian Vella, MD

CONTACT

507-255-6515; vella.adrian@mayo.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Subjects will be studied in the presence and absence of exendin 9-39 a competitive antagonist of the GLp-1 receptor

Study Record Dates

• First Submitted: May 5, 2025
• First Posted: May 15, 2025
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): March 1, 2029
• Last Updated: January 30, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)