Treatment of diabetes mellitus. Improvement of pancreatic beta-cell mass and function in clinical islet transplantation.

Diabetes mellitus is a rapidly increasing global problem leading to severe morbidity and early death. Insulin replacement is necessary for all patients with type-1 diabetes. Significant advances in human pancreatic islet transplantation have been achieved since the turn of the century and an 80% actual rate of insulin independence at 1 year after transplantation has recently been reported. However many obstacles still has to bee overcome. New research and development regarding the biochemistry and pathoph ysiology of the diabetes is providing exciting opportunities for drug development. Promising new therapeutic classes include glucagon-like peptide (GLP-1) and dipeptidyl peptidase IV (DPP-4) inhibitors. GLP-1 is an intestinal polypeptide hormone which sti mulates insulin secretion, upregulation of islet cell proliferation, and neogenesis and retardation of gastric emptying. GLP-1 has been shown to exert anti-diabetic effects in humans. In vivo, however, GLP-1 is cleaved by the enzyme DPP-4. Vildagliptin is a potent and highly selective, orally active DPP-4 inhibitor that has recently been used in combination with metformin in the treatment of type II diabetes. It has been shown to improve both meal-related β-cell function and insulin sensitivity in th e patients. This study evaluated improvement of long-term beta cell function and transplantation outcomes after GLP-1 derivates and DPP-4 inhibitors administration in pancreatic islet transplanted individuals. So far, no data from clinical trials covering this issue are available. In addition, we will develop a reliable method for in vivo targeting of human islet beta-cells by PET imaging technique. We will use this method to achieve a better understanding of the distribution of islets after transplantati on along with increased knowledge about the events leading to loss of pancreatic islets within the recipient