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

在拟议的研究项目中，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岛β细胞上的胰岛素激素受体GIP(葡萄糖依赖的促胰岛素多肽)和GLP-1(GLP-1)的表达是否减少？这个问题源于研究结果，这两种胰岛素激素，即GIP，在2型糖尿病患者中的促胰岛素效果大大降低。动物实验已经提供了糖尿病啮齿动物模型中胰岛素激素受体表达减少的线索。糖尿病患者和非糖尿病患者的GIP-和/或GLP-1受体检测完全缺乏。由于内分泌胰腺仅占总胰腺组织质量的1-2%，因此，针对该项目中心问题的研究结果需要患者的胰腺组织库，其有关糖代谢的临床数据已被仔细记录，并使用/优化具有挑战性的技术，如显微解剖，以在mRNA和蛋白水平上检测GIP和GLP-1受体的表达，以及使用放射配基分析。手术胰腺组织标本取自26例2型糖尿病患者和95例非糖尿病患者。项目中要采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.