TCF7L2 and Glucose Metabolism: Time to Look Beyond the Pancreas

Noncoding genetic variation in the locus encod-ing for the Wnt signaling effector TCF7L2remains the strongest genetic determinant oftype 2 diabetes (T2D) risk in humans. This as-sociation raises the hypothesis that disease variants alter the quantitative, spatial, and/or temporal expression pat-terns of this gene. Understanding the mechanisms by which TCF7L2 and Wnt signaling regulate glucose metab-olism may reveal novel insights into the pathogenesis of T2D, as well as highlight cellular and genetic pathways amenable to becoming novel therapeutic targets. Therefore, a large body of work has emerged over the past 4 years describing previously unknown glucose metabolism roles of TCF7L2. Curiously, most of this work has focused on TCF7L2 actions in pancreatic b-cells, despite evidence that ca-nonical Wnt signaling is not active in adult b-cells (1). The extensive evaluation of TCF7L2 actions or Wnt signalin