Molecular mechanisms of the impaired incretin effect in type 2 diabetes

2型糖尿病肠促胰岛素作用受损的分子机制

• 批准号: 239913634
• 负责人: Professor Dr. Juris Jendrik Meier
• 金额: --
• 依托单位: Klinik für Allgemein- und Viszeralchirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/239913634?language=en
• 关键词: Molecular; mechanisms; impaired; incretin; effect

The incretin effect, i.e. the postprandial augmentation of insulin secretion by the incretin hormones GIP and GLP-1, is markedly disturbed in patients with type 2 diabetes. The underlying causes of this defect are largely unknown. In the studies proposed we will compare the expression of GIP and GLP-1 in human gut samples from patients with and without type 2 diabetes using immunohistochemical and molecular biology techniques. Furthermore, alterations in entero-endocrine cell turnover (apoptosis and replication) and the molecular regulation of incretin hormone secretion will be studied. By comparing postprandial concentrations of GIP and GLP-1 with the intestinal expression of these hormones, we will examine, whether circulating levels of GIP and GLP-1 are primarily determined by the respective intestinal cell content or the functional regulation of incretin hormone secretion. To test the alternative hypothesis that the diminished incretin effect in type 2 diabetes is secondary to a general decline in beta-cell mass, we will compare the incretin effect immediately before and after partial pancreatectomy in patients with a clinical indication for pancreatic surgery using the isoglycaemic clamp technique. These studies will help to understand the underlying causes of the impaired incretin effect in type 2 diabetes and will broaden our knowledge on the mechanisms controlling incretin secretion in humans.

肠促胰岛素效应，即由肠促胰岛素激素GIP和GLP-1引起的餐后胰岛素分泌增加，在2型糖尿病患者中受到显著干扰。这种缺陷的根本原因在很大程度上是未知的。在这项研究中，我们将使用免疫组织化学和分子生物学技术比较GIP和GLP-1在2型糖尿病患者和非2型糖尿病患者的人肠道样本中的表达。此外，将研究肠内分泌细胞周转（细胞凋亡和复制）和肠促胰岛素激素分泌的分子调节的变化。通过比较GIP和GLP-1的餐后浓度与这些激素的肠表达，我们将检查GIP和GLP-1的循环水平主要是由各自的肠细胞内容物还是肠促胰岛素激素分泌的功能调节决定的。为了检验2型糖尿病中肠促胰岛素作用减弱继发于β细胞量普遍下降的备择假设，我们将使用等血糖钳夹技术比较具有胰腺手术临床指征的患者在部分胰腺切除术前后即刻的肠促胰岛素作用。这些研究将有助于了解2型糖尿病肠促胰岛素作用受损的根本原因，并将扩大我们对人类肠促胰岛素分泌控制机制的认识。