Endocrine Abstracts (2008) 16 P556

Screening for mutations in the glucose-dependent insulinotrophic polypeptide receptor gene (GIPR) in obese patients with disturbed glucose tolerance

Maria Behm1, Petra Ambrugger1, Jeannine Sauber1, Anke Hinney2, Johannes Hebebrand2, Susann Friedel2, Günter Brönner2, Susanna Wiegand1, Heiko Krude1, Annette Grüters1 & Heike Biebermann1

1Charité Universitätsmedizin Berlin; Institute for Experimental Pediatric Endocrinology, Berlin, Germany; 2Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, Essen, Germany.

Objective: The increasing incidence of obesity is a major health problem world-wide. So far, mutations were identified in genes encoding major contributors in energy homeostasis. With the exception of mutations in the melanocortin-4-receptor gene (MC4R) obesity-causing mutations are very rare. To date great efforts were undertaken to identify gene variants that contribute to polygenic obesity. The GIPR belongs to the large superfamily of G-protein coupled receptors. It is mainly expressed in pancreatic beta cells and is involved in glucose-mediated insulin secretion. Activation with GIP leads to signalling via the Gs/adenylylcyclase pathway. In mice target disruption of GIPR resulted only in modest alterations in glucose homeostasis. However, overexpression of a dominant-negative GIPR mutation in mice severely interfere with pancreatic beta cell development and resulted in a diabetic phenotype. Recent studies provide evidence that decreased insulin sensitivity and the risk for cardiovascular disease is enhanced when GIPR expression is reduced.

Patients/methods: We investigated 150 obese children including patients with disturbed glucose tolerance from our out-patients clinic for sequence variation in the GIPR. The 14 exons of the coding region including the exon/intron boundaries were PCR-amplified and directly sequenced.

Results/conclusion: We detected 5 known and two novel single nucleotide polymorphisms (SNP). Additionally, we identified 32 heterozygous and 3 homozygous carrier of the non-synonymous amino acid exchange Glu354Gln in exon 12 (transmembrane domain 6). Functional studies are ongoing to understand the functional role of identified sequence variations in the GIPR for obesity and glucose homeostasis.