After two decades of limited success, the genetic architecture of type 2 diabetes (T2D) is finally being revealed. Within only 2 years, an avalanche of studies identified several genes expressed in pancreatic beta cells and involved in the control of insulin secretion, such as transcription factor 7-like 2 (TCF7L2), a key element of the Wnt signaling pathway. In Europeans, genome-wide association scans showed that TCF7L2 has been the most important locus predisposing to T2D so far. For the first time, a gene is consistently involved in T2D susceptibility in all major ethnic groups. At the individual level, carrying the TCF7L2 risk allele increases T2D risk 50%. However, at the population level, the attributable risk is lower than 25% and varies with the allele frequency. The presence of the TCF7L2 rs7903146 risk allele increases TCF7L2 gene expression in beta cells, possibly impairing glucagon-like peptide-1-induced insulin secretion and/or the production of new mature beta cells. The tremendous association of TCF7L2 polymorphisms with T2D provides new insights into future genetic predisposition tests but remains the tip of the T2D genetic iceberg.
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