Molecular mechanisms of the impaired incretin effect in type 2 diabetes

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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.