Transcription factor 7-like 2 was first implicated when a signal associated with Type 2 diabetes on chromosome 10q was shown in Icelandic populations to host a microsatellite DG10748, containing single nucleotide polymorphisms rs7903146 and rs12255372 in intron 3 of the TCF7L2 gene, associated with a ~ 45% increase in Type 2 diabetes risk per allele. As such, the TCF7L2 locus presently repre- sents the strongest known genetic determinant of Type 2 diabetes. Risk allele carriers show impaired insulin production and b-cell dysfunction in vitro.’TCF7L2 (previously referred to as TCF-4) is a high-mobility group box-containing transcription factor involved in Wingless-type MMTV integration site (Wnt) signalling, cell growth and survival. As such, alterations (decreases) in expression may be predicted to lower b-cell mass, whilst having little effect on function. Surprisingly, however, studies in mice have shown that b-cell function is just as dependent as b-cell mass on TCF7L2 (see below). Important recent controversies have revolved around whether: (1) the TCF7L2 risk allele leads to increased or decreased TCF7L2 function in the islet b cell and (2) the actions on the liver are equally or more important than those on the b cell.
An early report  indicated that Type 2 diabetes patient-derived islets and risk (T-) allele carriers had elevated TCF7L2 mRNA levels compared with healthy islets, consis- tent with the observation that the at-risk allele is associated with a more open chromatin conformation and enhanced promoter activity ; however, the identity of the splice variants was not confirmed, leaving the possibility that the upregulated variants may, in fact, be enriched for dominant negative-acting isoforms, or that the measurements may mask a decrease in expression of the most potent variants . Consistent with the latter view, subsequent studies  found lower TCF7L2 protein levels in Type 2 diabetes patient-derived islets. Moreover, Osmark et al.  reported an unusual preponderance of variants containing exon 4 in human islets vs other tissues, although no association was evident between variant level and number of rs7903146 risk alleles. By contrast, Prokunina-Olsson et al.  did not detect an effect of risk allele number on TCF7L2 mRNA levels, as measured using the assay of the splice variant ‘Ex7-8’ previously deployed ; however, a weak associa- tion was found with variants at the splice boundaries of exon 13, 13b and 14. The consequent loss of a ‘CRARF’ domain, formed by splicing exons 13 and 14, may be of particular
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