The Effect of rs7903146 Genotype on Islet GLP-1 Production in Humans
Mayo Clinic
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.
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…
Eligibility
- Age range
- 25–70 years
- Sex
- All
- Healthy volunteers
- Yes
Inclusion Criteria: * Subjects with the TT or CC genotype at rs7903146 Exclusion Criteria: 1. 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). 2. CT genotype at rs7903146 3. HbA1c \> 6.5% 4. Use of any glucose-lowering agents including metformin or sulfonylureas. 5. For female subjects: positive pregnancy test at the time of enrollment or study. 6. History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy. 7. Active syst…
Interventions
- BiologicalExendin 9-39
A competitive antagonist of the GLP-1 receptor
- OtherSaline
Saline infusion will serve as an inactive comparator
Location
- Mayo Clinic in RochesterRochester, Minnesota