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- Fred, Rikard G.
(författare)
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The Role of RNA Binding Proteins in Insulin Messenger Stability and Translation
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Although the reason for insufficient release of insulin in diabetes mellitus may vary depending on the type and stage of the disease, it is of vital importance that an amplified insulin biosynthesis can meet the increased need during periods of hyperglycemia. The insulin mRNA is highly abundant in beta cells and changes in insulin mRNA levels are, at least in part, controlled by altered rates of mRNA degradation. Since the mechanisms behind the control of insulin messenger stability and translation are still largely obscure, the work presented in this thesis therefore aimed to further investigate the role of insulin mRNA binding proteins in the control of insulin mRNA break-down and utilization for insulin biosynthesis. To clarify how glucose regulates insulin mRNA stability and translation we studied the correlation between polypyrimidine tract binding protein (PTB) gene expression and insulin mRNA levels. It was found that an increase in PTB mRNA and protein levels is paralleled by an increase in insulin mRNA levels. It was also found that PTB binds to the 5’-untranslated region of the insulin mRNA and that insulin mRNA can be translated through a cap-independent mechanism in human islets of Langerhans, possibly due to the interaction with PTB. Further it was discovered that the suppressed insulin biosynthesis in human islets during glucotoxicity is partly due to an induction of the microRNA miR-133a. This induction leads to decreased levels of PTB and insulin biosynthesis rates in human islets. Finally, we were able to identify two proteins, hnRNP U and TIAR, that bind specifically to the insulin mRNA in vitro, and show that the stability and translation of insulin mRNA is oppositely affected by these proteins. In conclusion, insulin producing cells seem to be able to regulate insulin messenger stability and translation by a control mechanism in which the binding of specific proteins to the insulin messenger dictates the outcome. A better understanding of the events leading to insulin production may in the future aid in optimal diagnosis and treatment of type 2 diabetes.
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| 2. |
- Seiron, Peter, 1990-
(författare)
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Studies of the Pancreas: Implications for Type 1 Diabetes Aetiology
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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