Exp Clin Endocrinol Diabetes 2014; 122 - P013
DOI: 10.1055/s-0034-1372030

Mutations in the coding region of GIPR gene are not frequent in obese children with insulin resistance

SF Jacobi 1, S Wiegand 1, A Ernert 1, P Kühnen 1, K Raile 1, H Krude 1, H Biebermann 1
  • 1Charité Universitätsmedizin Berlin, Institut für Experimentelle Pädiatrische Endokrinologie, Berlin, Germany

Pathogenesis of obesity and diabetes is besides environmental influences promoted by genetic factors. Recently, genome-wide associsation studies (GWAs) have shown that single nucleotide polymorphisms (SNPs) in the glucose-dependent insulinotropic polypeptide receptor (GIPR) gene are associated with obesity and impaired HOMA-IR, a measurement for insulin resistance. GIPR as a receptor for the incretin hormone GIP directly mediates glucose-dependent insulin secretion in pancreatic ß-cells and is therefore a potential candidate gene for mutations. So far mutation screening in a small cohort of obese children did not reveal any mutations.

We chose a preselected cohort of children with both associated traits increased BMI standard deviation score (BMI-SDS) indicating obesity and increased HOMA-IR in order to find contributing or causal mutations.

234 children with increased BMI-SDS (2.71 ± 5.1) indicating obesity and additionally increased insulin resistance (HOMA-IR 5.01 ± 3.17) were selected. Blood samples were taken and DNA extracted. We sequenced the 14 coding exons of GIPR by Sanger-Sequencing and analyzed it with the software SEQUENCE Pilot.

We did not detect new causal mutations in the coding regions of GIPR. The established associated SNP rs1800437 (E354Q) could be shown in a similar frequency as in overall population. Furthermore, several other known SNPs in the GIPR gene could be identified but none correlated with the phenotype of our patients.

Even though GWAs strongly suggest the GIPR gene as a potential target gene for genetic variations linked to obesity and insulin resistance, our screening revealed no causal mutations. This indicates that GIPR variations play a less important role in our selected cohort. Adjusting the phenotype, increasing the cohort size and adding intron sequencing could be future strategies to identify mutations. Further studies have to address the role of variations in GIPR for obesity, insulin resistance and glucose homeostasis.