Transcriptional and morphological analysis of organ donor pancreata

Abstract: The diabetes disease panorama affects more than 400 million people world wide – a number projected to rise above 640 million in the next 20 years. Type 1 and type 2 diabetes are associated with adverse complications, resulting in severe morbidity and high healthcare costs exerting substantial strain on society. Type 1 diabetes results from the destruction of the insulin producing beta-cells, while type 2 diabetes is a multifactorial combination of a decreased ability of the beta cells to secrete sufficient insulin and a peripheral resistance to insulin-mediated glucose uptake. The cause of diabetes is unknown, as are the possibly sequential cellular events resulting in overt disease. In this thesis, organ-donor pancreata from donors with or without diabetes are analysed in order to deepen our understanding of the Islets of Langerhans, the beta cells and the pancreas. In Paper I, islets from a donor that died at onset of type 1 diabetes, showing morphological signs of hydropic degeneration are analyzed on a gene-expression level, and the results are compared to islets from a donor without diabetes. We find no signs of ongoing inflammation, apoptosis or ER stress. In Paper IIwe compare the expression levels of genes related to cellular stress, in islets from donors with type 2 diabetes and from donors with high pre-mortal HbA1c levels but without a diabetes diagnosis, to the expression levels in islets from donors with normal HbA1c levels. We report that islets from donors with type 2 diabetes show signs of cellular stress on a transcriptional level compared with islets from donors without diabetes. In Paper III we performed a transcriptional analysis of the islets from organ donors aged between 1 and 81 years in order to elucidate whether age induces specific changes in the islet transcriptome. We found 20 genes that co-varied with increasing age. In Paper IV,the pancreatic expression of host-defense molecules is characterized, and we report the expression of several host-defense molecules not previously described in the human pancreas. Together, these results deepen our understanding of the effects of ageing and prolonged exposure to high blood sugar levels on the islets, as well as our knowledge about the innate immunity of the human pancreas.