Studies of the Pancreas: Implications for Type 1 Diabetes Aetiology

Abstract: Type 1 diabetes (T1D) is a disease of severe insulin deficiency through loss of β cells in the endocrine pancreas. The T1D dogma maintains that a precipitating event unleashes autoimmunity in at-risk individuals, often measured through autoantibodies against β cell antigens. This is followed by the death of β cells at the hands of autoreactive cytotoxic T cells. However, several findings have not found their place within this dogma; first, the immune cell infiltrate in islets is usually located outside the islets, and second, there is a pronounced impact on the exocrine pancreas with lower pancreatic weight and fibrosis surrounding the ducts. In this thesis, pancreata from human subjects without diabetes (ND) as well as with T1D or type 2 diabetes (T2D) have been examined in an attempt to clarify the aetiology of T1D.The consensus definition of insulitis (≥15 CD45+ cells per islet in ≥3 islets) was validated against ND pancreata. In paper I we show that this definition cannot sufficiently discriminate between the findings in T1D and T2D pancreata, due to an increase in exocrine infiltration in T2D, predominantly made up by macrophages. As exocrine infiltration is also a common finding in T1D, we propose a new definition. In paper II we found tissue resident memory T (TRM) cells in association to islets in both ND and T1D pancreata, and they made up a significant proportion of the insulitic lesion in T1D. Islets contain on average 60% β cells. In paper III we found that despite the seeming loss of this predominant cell type in the T1D islets, islet size remained the same. Instead, islet density was markedly reduced. The islets contained mainly α cells, some of which expressed PDX1, a transcription factor marker of β cells. In paper IV we examined pancreata from ND organ donors aged 1-81 years. For the first time, the islet transcriptome was analysed without prior enzymatic digestion of the tissue. We corroborate earlier findings of reduced cell cycle activity and increased senescence with increasing age, as well as present a hypothesis of how islet age might affect T1D.The findings in this thesis sprout an alternative hypothesis that disturbed establishment of β cells in early life, due to lower islet density and lower pancreatic weight, would lead to β cell stress as insulin demand increases with physical growth. However, as islets do not decrease in size, we suggest that the disappearance of β cells could be explained by transdifferentiation into glucagon-producing cells.