Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Institute of Experimental Pediatric Endocrinology, Berlin, Germany.
University Heart Center Freiburg-Bad Krozingen, Department of Congenital Heart Disease and Pediatric Cardiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Diabetes Obes Metab. 2019 May;21(5):1168-1176. doi: 10.1111/dom.13634. Epub 2019 Feb 19.
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that augments insulin secretion in pancreatic β-cells via its glucose-dependent insulinotropic polypeptide receptor (GIPR). Recent genome-wide association studies identified a single nucleotide variant (SNV) in the GIPR encoding gene (GIPR), rs1800437, that is associated with obesity and insulin resistance. In the present study, we tested whether GIPR variants contribute to obesity and disturb glucose homeostasis or diabetes in specific patient populations.
Exon sequencing of GIPR was performed in 164 children with obesity and insulin resistance and in 80 children with paediatric-onset diabetes of unknown origin. The Study of Health in Pomerania (SHIP) cohort, comprising 8320 adults, was screened for the GIPR variant 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.
A heterozygous missense GIPR variant Arg217Leu (rs200485112) was identified in a patient of Asian ancestry. Functional characterization of Arg217Leu revealed reduced surface expression and signalling after GIP challenge. The homology model of the GIPR structure supports the observed functional relevance of Arg217Leu.
In vitro functional studies and protein homology modelling indicate a potential relevance of the GIPR variant Arg217Leu in receptor function. The heterozygous variant displayed partial co-segregation with diabetes. Based on these findings, we suggest that GIPR variants may play a role in disturbed glucose homeostasis and may be of clinical relevance in homozygous patients.
葡萄糖依赖性胰岛素释放多肽（GIP）是一种肠促胰岛素激素，通过其葡萄糖依赖性胰岛素释放多肽受体（GIPR）增强胰腺β细胞中的胰岛素分泌。最近的全基因组关联研究鉴定出 GIPR 编码基因（GIPR）中的一个单核苷酸变异（SNV），即 rs1800437，与肥胖和胰岛素抵抗有关。在本研究中，我们测试了 GIPR 变体是否有助于肥胖和扰乱特定患者群体的葡萄糖稳态或糖尿病。
对 164 名肥胖和胰岛素抵抗的儿童和 80 名患有未知病因的儿科发病糖尿病的儿童进行 GIPR 外显子测序。对包含 8320 名成年人的波罗的海健康研究（SHIP）队列进行 GIPR 变体 Arg217Leu 的筛查。在 COS-7 细胞中表达 GIPR 变体，并在 GIP 刺激后测量 cAMP 产生。通过 ELISA 测定细胞表面表达。对 GIPR 变体进行蛋白质同源建模，以提取受体的三维信息。
在一名亚洲血统的患者中发现了一种杂合错义 GIPR 变体 Arg217Leu（rs200485112）。Arg217Leu 的功能特征表明，在 GIP 挑战后，表面表达和信号转导减少。GIPR 结构的同源模型支持观察到的 Arg217Leu 的功能相关性。
体外功能研究和蛋白质同源建模表明，GIPR 变体 Arg217Leu 在受体功能中具有潜在的相关性。杂合变体显示与糖尿病部分共分离。基于这些发现，我们建议 GIPR 变体可能在葡萄糖稳态紊乱中起作用，并可能对纯合患者具有临床意义。
