The Effect of rs7903146 Genotype on Islet GLP-1 Production in Humans
Official 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.
Study Design
- Study Type: INTERVENTIONAL
- Allocation: RANDOMIZED
- Model: CROSSOVER
- Masking: NONE
- Enrollment: 80 participants
Interventions
- BIOLOGICAL: Exendin 9-39 — A competitive antagonist of the GLP-1 receptor
- OTHER: Saline — Saline infusion will serve as an inactive comparator
Primary Outcomes
- Change in fasting glucose (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 (Change in average glucagon concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day))
Secondary Outcomes
- 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))
Trial Locations
- Mayo Clinic in Rochester, Rochester, Minnesota, United States
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