Mechanisms by which variants in the TCF7L2 gene increase the risk of developing Type 2 diabetes
Abstract: Type 2 diabetes mellitus (T2DM) is a heterogeneous disease with a multifactorial aetiology comprising of genetic and environmental factors. The common variant most highly associated with T2DM known to date is a SNP rs7903146 in the TCF7L2 gene. However, the role TCF7L2 plays in the development of T2DM was unclear. Clinical, animal and in vitro studies have revealed an association of the risk T-allele of rs7903146 with impaired β cell function including glucose- and incretin-stimulated insulin secretion and β cell survival. The aim of this thesis is to elucidate the function of TCF7L2 in the β cells and explain the mechanisms by which genetic variants in TCF7L2 confer the increased risk of developing T2DM. TCF7L2 is a transcription factor of the WNT signalling pathway. Risk genotype carriers of rs7903146 displayed higher TCF7L2 mRNA expression in islets of Langerhans, reduced insulin content and perturbed glucose stimulated insulin secretion. We have identified a large number of target genes (study I) and target networks (study II) of TCF7L2 that regulate β cell survival, proinsulin expression and insulin maturation. The expression of many of these TCF7L2 target genes, including T2DM associated genes/loci, correlated with TCF7L2 mRNA expression in CC, but not in CT/TT genotype carriers in human pancreatic islets. These data indicate that TCF7L2 has a central role in insulin synthesis and secretion, as well as in the regulation of other T2DM associated genes. We provided a possible explanation for the large impact TCF7L2 has on the risk of T2DM. The molecular link between the T-risk allele and the diabetogenic action of TCF7L2 in β cells is still unclear. In vitro and animal experiments have indicated that the 92kb around rs7903146 locus is an enhancer region, and that the T-allele has a higher activity compared to the C-allele. In study III, we identified a protein (HMGB1) that binds the rs7903146 locus, which potentially influence this enhancer activity. At last, we have also investigated the function of different TCF7L2 splice variants and their influence on β cell function using Antisense Oligo Nucleotides (study IV). These results indicated that exon 4 of TCF7L2 has an inhibitory function, influencing both insulin synthesis and β cell survival.
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