Evaluation of a Rare Glucose-Dependent Insulinotropic Polypeptide Receptor Variant in a Patient with Diabetes [thesis]

Simon Friedrich Jacobi, Universitätsbibliothek Der FU Berlin
The glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone produced in the K cells of the gastrointestinal tract. In the target organs, GIP binds to its corresponding receptor (GIPR). The activation of GIPR in the β cells of the pancreas increases insulin secretion into the blood. Genome-wide association studies have recently identified the association of single nucleotide polymorphism (SNV) rs1800437 in the GIPR encoding gene (GIPR) with obesity and insulin resistance. In
more » ... present study we investigated whether GIPR variants occur more frequently in patient groups selected according to these criteria and whether a rare variant is functionally characterized in GIPR. Materials and methods: We screened two study populations with in total 244 pediatric patients for variants in GIPR. Study population 1 consisted of 164 children with obesity and insulin resistance and Study population 2 of 80 children with pediatric-onset diabetes of unknown origin. 8320 adults of the SHIP cohort (The Study of Health in Pomerania) were screened for the GIPR variant Arg217Leu. Arg217Leu, GIPR variants were expressed in COS-7 cells and cAMP production was measured upon stimulation with GIP. Cell surface expression was determined by ELISA. Protein homology modelling of the GIPR variants was performed to extract three-dimensional information of the receptor. Results: The missense variant Arg217Leu (rs200485112) was heterozygously identified in a child of Asian descent from patient group 2. In functional characterization Arg217Leu showed reduced surface expression and production of cAMP after stimulation with GIP. The homology model of the GIPR structure supports the functional findings of Arg217Leu for receptor function. Arg217Leu was not present in the SHIP cohort. The frequency of other SNV was the same in the investigated patient groups as in the normal population. Conclusion: The in vitro function studies and the modelling of protein homology indicate the relevance of the GIPR variant Arg217Leu for r [...]
doi:10.17169/refubium-29982 fatcat:g52m3nzmqnhtza77znvvebbfvm