the effect of rs7903146 genotype on islet glp-1 production in humans

Conditions: Genetic Predisposition; Type2diabetes

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.

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.

Eligibility criteria:
inclusion criteria: * subjects with the tt or cc genotype at rs7903146 exclusion criteria: 1. age \ 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 systemic illness or malignancy. 8. symptomatic macrovascular or microvascular disease.

Keywords: tcf7l2