Molecular mechanisms of the impaired incretin effect in type 2 diabetes

肠促胰岛素效应，即肠促胰岛素激素GIP和GLP-1在餐后增加胰岛素分泌，在2型糖尿病患者中明显受到干扰。这种缺陷的潜在原因在很大程度上是未知的。在我们提出的研究中，我们将使用免疫组织化学和分子生物学技术比较2型糖尿病患者和非2型糖尿病患者肠道样本中GIP和GLP-1的表达。此外，肠内分泌细胞更新（凋亡和复制）的改变和肠促胰岛素激素分泌的分子调控将被研究。通过比较餐后GIP和GLP-1的浓度与肠道中这些激素的表达，我们将研究循环中GIP和GLP-1的水平主要是由各自的肠道细胞含量还是肠促胰岛素激素分泌的功能调节决定的。为了验证另一种假设，即2型糖尿病中肠促胰岛素作用的减弱是继发于β细胞质量的普遍下降，我们将比较有临床指证的患者在使用异糖钳技术进行胰腺手术之前和之后的肠促胰岛素效果。这些研究将有助于了解2型糖尿病中肠促胰岛素作用受损的潜在原因，并将拓宽我们对控制人类肠促胰岛素分泌机制的认识。

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.