Bulu, Mahfuja Jannat (2018) The effects of metabolic conditions relevant to Type 2 Diabetes on alternative splicing. (MSc(R) thesis), Kingston University, .
Abstract
Type 2 diabetes is a metabolic disorder associated with chronic hyperglycaemia and hyperlipidaemia, with consequent insulin resistance and a progressive deterioration of pancreatic β cell mass and function. The combined deleterious effects of these metabolic changes on β cell are known as glucolipotoxicity (GLT). Alternative splicing is a post-transcriptional process that allows a single gene to encode multiple transcripts and is a crucial mechanism for generating proteomic diversity. However, little is known about the role of alternative splicing in diabetes. The aim of this study was to test whether metabolic conditions relevant to type 2 diabetes affect alternative splicing in β cells. INS1 β cells were treated under GLT or control conditions and the expression of a panel of genes important for the regulation of alternative splicing was examined by quantitative reverse transcriptase PCR (RT-qPCR). These experiments showed that GLT conditions significantly increase expression of the stress-associated mRNA processing and stability gene Elavl1 in β cells (p=0.04, n=4 independent experiments). The role of Elavl1 in β cells is not known, but it has been shown previously that siRNA knockdown of the related family member, Elavl4, increases β cell apoptosis, suggesting that this family of genes regulates β cell survival. Using a combination of exon arrays and a candidate gene approach, we have further shown that the increased Elavl1 expression in β cells by GLT conditions is associated with alternative splicing of apoptosis genes, including a variant of the TCF7L2 gene thought to induce β cell apoptosis. This suggests that the metabolic conditions existing in many people with type 2 diabetes may cause aberrant alternative splicing in β cells increasing susceptibility to apoptosis and subsequent β cell loss.
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