Studies of the human pancreas to understand the pathologic events leading to type 1 diabetes

Abstract: Type 1 diabetes (T1D) is classically described as a disease emanating from beta-cell loss, and as such, the beta cells have been the main target of investigation. However, recent years have witnessed a shift in perspective, with T1D being increasingly recognized as a condition that affects the entire pancreas. This shift in focus emphasizes the importance of investigating not only the islets but also the exocrine pancreas and endocrine cells beyond the islet perimeters. In this thesis, pancreases from individuals with and without T1D have been investigated with regard to the exocrine tissue, islets, and other endocrine cells in an endeavour to shed light on the aetiology of the disease.In Paper I, the exocrine part of the pancreas was investigated in donors with and without longstanding T1D. While no histological evidence of acinar atrophy in T1D was found, transcriptional alterations were identified. The absence of atrophy supports the idea of a reduced number of acinar cells as an explanation of the reduced pancreas volume, and the transcriptome analysis demonstrated the impact on the exocrine pancreas in T1D. In Paper II, islets from control and T1D subjects were examined. Islets from T1D subjects showed upregulation of transcriptional pathways related to vasculature and angiogenesis, along with increased vascular density. As endothelial cells are important for proper beta-cell function, the changes in vasculature might be a reaction to the loss of beta-cells. Paper III aimed to characterize extra-islet endocrine cells in healthy donors aged 1-25. Similar frequencies of these cells were observed in all age groups, indicating that new cells are continually formed as the pancreas grows, in part likely through replication as mitotic cells were found. Notably, many of the insulin- and glucagon-positive extra-islet cells lacked the expression of their corresponding transcription factors, PDX1 and ARX, suggesting they may be newly formed or plastic. The focus of Paper IV was to examine endocrine extra-islet cells in T1D donors compared with matched controls. The density of extra-islet insulin cells was decreased, whereas the density of extra-islet glucagon cells was increased. The latter might be due to a compensatory response to impaired alpha-cell function or beta-to-alpha-cell conversion. These findings contribute to our understanding of the entire pancreas's function in both health and disease, enhancing our knowledge of T1D development and progression.