Understanding the Elusive Mechanism of Action of TCF7L2 in Metabolism

Common intronic variation within the geneencoding transcription factor 7-like 2 (TCF7L2)is now considered to be definitively associatedwith type 2 diabetes (T2D). Since our first re-port of this association in 2006 (1), independent inves-tigators have readily replicated this finding in all the main ethnic groups; in addition, from the first genome-wide as-sociation study (GWAS) of T2D in Caucasians (2) on-wards, the strongest association has been consistently with the TCF7L2 locus. Indeed, a meta-analysis of pub-lished studies worldwide as early as 2007 estimated a pooled odds ratio of 1.46 (with an impressive P = 5.4 3 102140) (3), making it one of the most statistically signifi-cant genetic findings in T2D to date. Despite knowing that this association has been beyond doubt for over 6 years, the mechanism through which TCF7L2 exerts its effect on T2D is still very unclear, thus making the work by Kaminska et al. (4) in this curren