Genetic PredispositionPhase 2NCT06972407
The Effect of rs7903146 Genotype on Islet GLP-1 Production in Humans
A Phase 2 study testing Exendin 9-39 and Saline in people with Genetic Predisposition and Type2diabetes, run by Mayo Clinic at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 25 to 70 yearsHealthy volunteers can take part
- Conditions the study is for
- Genetic Predisposition, Type2diabetes
- What is being tested?
- Exendin 9-39 and Saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 80 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Oct 2026to 1 Mar 2029
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 25 to 70 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Subjects with the TT or CC genotype at rs7903146
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site
Mayo Clinic in Rochester
Rochester, Minnesota, 55905
About this study
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.
Read the detailed description
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. 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 (basal and 1st phase) and glucagon secretion. 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.
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. There is evidence that α-cell proglucagon processing is subject to paracrine regulation by the β-cell. β-cell secretion of the signaling peptide 14-3-3-Zeta is decreased by GLP1R agonism, stimulating α-cell production of GLP-1. Common genetic variation in the TCF7L2 locus (T-allele at rs7903146) arguably confers the greatest genetic risk of T2DM4. 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). Does a relative absence or an inability of islet GLP-1 to adapt to rising glycemia explain the increased risk of T2DM associated with the T-allele at rs7903146? 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
- Being tested
- Exendin 9-39, Saline
- Keywords
- TCF7L2
- Medical subject headings
- Genetic Predisposition to Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Exendin 9-39Biological
A competitive antagonist of the GLP-1 receptor
SalineOther
Saline infusion will serve as an inactive comparator
| Study group | Role | What they receive |
|---|---|---|
| Exendin 9-39 | Active comparator | Exendin 9-39 will be infused during fasting and during a hyperglycemic clamp Receives: Biological: Exendin 9-39 |
| Saline | Placebo comparator | Saline will be infused during fasting and during a hyperglycemic clamp Receives: Other: Saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in fasting glucose
comparison of fasting glucose during saline vs. exendin 9-39 infusion
Measured: 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
Measured: 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
comparison of fasting insulin during saline vs. exendin 9-39 infusion
Measured: 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
comparison of first phase insulin secretion during saline vs. exendin 9-39 infusion
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 May 2025
- Study start1 Oct 2026 (estimated)
- Primary completion31 Dec 2028 (estimated)
- Study completion1 Mar 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Genetic PredispositionStudies of the same condition, open and under way.
- More trials run by Mayo ClinicThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Subjects will be studied in the presence and absence of exendin 9-39 a competitive antagonist of the GLp-1 receptor
- Masking
- None (open label)
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Mayo Clinic
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Adrian Vella, Mayo Clinic
- Investigators
- Adrian Vella, MD, Principal investigator, Mayo Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06972407
- Sponsor's protocol ID
- 24-007701
- Status last verified
- Jan 2026
- First submitted
- 5 May 2025
- Last updated
- 30 Jan 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 30 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of rs7903146 Genotype on Islet GLP-1 Production in Humans
- ClinicalTrials.gov ID
- NCT06972407
- Acronym / sponsor ID
- 24-007701
- Conditions
- Genetic Predisposition, Type2diabetes
- Keywords
- TCF7L2
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Mayo ClinicUniversity, hospital or other
- Study start
- 1 Oct 2026 (estimated)
- Primary completion
- 31 Dec 2028 (estimated)
- Study completion
- 1 Mar 2029 (estimated)
- First posted
- 15 May 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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. 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 (basal and 1st phase) and glucagon secretion. 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.
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. There is evidence that α-cell proglucagon processing is subject to paracrine regulation by the β-cell. β-cell secretion of the signaling peptide 14-3-3-Zeta is decreased by GLP1R agonism, stimulating α-cell production of GLP-1. Common genetic variation in the TCF7L2 locus (T-allele at rs7903146) arguably confers the greatest genetic risk of T2DM4. 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). Does a relative absence or an inability of islet GLP-1 to adapt to rising glycemia explain the increased risk of T2DM associated with the T-allele at rs7903146? This experiment will determine the contribution of islet GLP-1 to the functional abnormalities of the islet associated with the TCF7L2 locus.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Subjects will be studied in the presence and absence of exendin 9-39 a competitive antagonist of the GLp-1 receptor
| Arm | Type | Receives |
|---|---|---|
| Exendin 9-39 | Active comparator | Biological: Exendin 9-39Exendin 9-39 will be infused during fasting and during a hyperglycemic clamp |
| Saline | Placebo comparator | Other: SalineSaline will be infused during fasting and during a hyperglycemic clamp |
Who may qualify
- Ages
- 25 to 70 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Subjects with the TT or CC genotype at rs7903146
Key exclusion criteria (8 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Exendin 9-39A competitive antagonist of the GLP-1 receptor | Biological | Exendin 9-39 |
| SalineSaline infusion will serve as an inactive comparator | Other | Saline |
Primary outcome
Change in fasting glucose
Time frame: Change in average glucose concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day)
comparison of fasting glucose during saline vs. exendin 9-39 infusion
Change in fasting glucagon
Time frame: Change in average glucagon concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day)
comparison of fasting glucagon during saline vs. exendin 9-39 infusion
2 secondary outcomes
Change in fasting insulin
Time frame: 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
Time frame: 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)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jan 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Adrian Vella, MD principal investigator
Mayo Clinic
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Exendin 9-39 and Saline in people with Genetic Predisposition and Type2diabetes, run by Mayo Clinic at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 30 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Adrian Vella, MD (507-255-6515, vella.adrian@mayo.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in fasting glucose (time frame: Change in average glucose concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2026.