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

ConditionsGenetic PredispositionType2diabetes
Trial statusNot yet recruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age25-70
SponsorMayo Clinic

About this trial

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.

Eligibility criteria

This trial accepts healthy volunteers

Qualifiers

Subjects with the TT or CC genotype at rs7903146

Disqualifiers

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.

Trial design

Design model

Crossover

Treatments tested in this trial

  • Exendin 9-39

    Biological/Vaccine

    A competitive antagonist of the GLP-1 receptor

  • Saline

    Other intervention

    Saline infusion will serve as an inactive comparator

Treatment groups

80 Participants
are divided into 2 treatment groups
Group A: Exendin 9-39Active comparator 1 intervention
Group B: SalinePlacebo comparator 1 intervention

Trial outcomes

Primary outcomes

1

Change in fasting glucose

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

Time frame
Change in average glucose concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day)
2

Change in fasting glucagon

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

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

Secondary outcomes

1

Change in fasting insulin

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

Time frame
Change in average insulin concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day)
2

Change in first phase insulin secretion

comparison of first phase insulin secretion during saline vs. exendin 9-39 infusion

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)

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Mayo Clinic

Lead sponsor

Source ClinicalTrials.gov

This trial is not recruiting at the moment. You can still explore other options: