Reduced expression of receptors for the incretin hormones GIP and GLP-1 as a potential cause of an impaired GIP- or GLP-1-mediated augmentation of insulin secretion in type 2-diabetes

在拟制的研究项目中，将解决以下问题：与代谢健康的对照组相比，2型糖尿病患者内分泌胰腺β细胞上肠促胰岛素激素GIP（葡萄糖依赖性胰岛素肽）和GLP-1（胰高血糖素样肽-1）受体的表达是否减少？这个问题源于研究结果，记录了两种肠促胰岛素激素（即GIP）在2型糖尿病患者中的胰岛素治疗效果大大降低。动物实验已经为糖尿病啮齿动物模型中促肠促胰岛素激素受体的表达减少提供了线索。在糖尿病患者和非糖尿病患者中，对GIP-和/或GLP-1受体的检测完全缺乏。研究结果的任务是回答项目的核心问题，需要来自患者的胰腺组织库，其关于葡萄糖代谢的临床数据已经被仔细记录，并使用/优化具有挑战性的技术，如显微解剖，以检查GIP和GLP-1受体在mRNA和蛋白质水平上的表达，以及放射性配体测定。由于内分泌胰腺只占胰腺总组织质量的1- 2%。手术胰腺组织标本来自26例2型糖尿病患者和95例非糖尿病患者。在这个项目中使用的技术已经发展到可以成功使用的程度。

In the proposed research project the following question will be addressed: Is the Expression of receptors for the incretin hormones GIP (Glucose-dependent Insulinotropic Peptide) and GLP-1 (Glucagon-Like Peptide-1) on beta cells in the endocrine pancreas reduced in subjects with type 2 diabetes mellitus compared to metabolically healthy control subjects?This question is derived from findings documenting a much reduced insulinotropic effectiveness of both incretin hormones, namely GIP, in subjects with type 2 diabetes. Animal experiments have already provided hints towards a reduced expression of incretin hormone receptors in diabetic rodent models. Examinations of GIP- and/or GLP-1 receptors in human subjects with and without diabetes mellitus are completely lacking. The task of findings anwers to the central question of the project requires a bank of pancreatic tissue from patients, whose clinical data concerning glucose metabolism have been meticulously documented and the employment/optimization of challenging techniques like microdissection for the examination of the expression of GIP and GLP-1 receptors at the mRNA and protein level as well as with a radio-ligand assay, since the endocrine pancreas makes up only 1-2 % of the total pancreatic tissue mass. Surgical pancreatic tissue specimens are available from 26 type 2-diabetic subjects and 95 patients without diabetes mellitus. The techniques to be employed in the project have been developed to the degree, that they can be used successfully.