| Summary: | Prolonged exposure to hyperglycaemia may contribute to the development of microvascular complications and loss of ~-cell viability in diabetes. In the past decade it has become clear that glucose itself acts as a signalling molecule via the induction of candidate genes which contribute to the disease process. ChREBP is a glucose responsive transcription factor with a response element in the promoter region of various genes, and is one of the targets through which glucose exerts its effect on gene expression. Both aldose reductase and thioredoxin interacting protein are under ChREBP mediated, glucose dependent regulation. Aldose reductase has been indicated in the process of diabetic complications, whereas the TXNIP protein is described as a central proapoptotic factor in the loss of ~-cell viability and is also emerging as a candidate gene for microvascular complication of diabetes. The current study has investigated the role of ChREBP, AR and TXNIP in these disease processes by collecting PBMCs from blood samples from different patient populations, and by using HEK293 and INS-1 cell lines to establish in vitro models in which the underlying mechanisms of pathogenesis could be investigated further. It was found that the binding of ChREBP to both genes of interest was significantly higher in the PBMCs of patients with diabetic nephropathy compared to other patient groups, which may be due to the upregulation of the ChREBP protein itself. A β-cell model overexpressing the TXNIP protein was also established and revealed a time dependent effect of increased TXNIP expression on β-cell apoptosis. The endogenous TXNIP protein was found to be rapidly induced upon addition of glucose and this may contribute to the process of glucolipotoxicity. The novel finding was also made that TXNIP protein was upregulated by melatonin. Finally, previously established single nucleotide polymorph isms associated with blood glucose levels in the TXNIP and MTNR1 B genes of patients with diabetic complications were studied, but no association was found between these loci and disease state in our cohort. The current study suggests that the ChREBP may be an influential factor in the genetic basis of diabetic complications and confirms TXNIP's role as a proapoptotic factor in the ~-cell; it also reports for the first time a link between melatonin and TXNIP
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