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Noncoding genetic variation in the locus encoding for the Wnt signaling effector TCF7L2 remains the strongest genetic determinant of type 2 diabetes (T2D) risk in humans. This association raises the hypothesis that disease variants alter the quantitative, spatial, and/or temporal expression patterns of this gene. Understanding the mechanisms by which TCF7L2 and Wnt signaling regulate glucose metabolism 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 β-cells, despite evidence that canonical Wnt signaling is not active in adult β-cells (1). The extensive evaluation of TCF7L2 actions or Wnt signaling effects in β-cells have resulted in contradictory findings at the molecular (2,3), cellular (1,4), and whole-animal physiology levels (5–7). Particularly difficult to reconcile is the incongruence of data showing that the presumed diabetogenic effects of TCF7L2 in β-cells, such as a blunted glucose-stimulated insulin secretion response, arises from reducing TCF7L2 expression (3,8). In contrast, evidence from human genetics and genomics studies suggests the risk alleles associated with T2D lead to increased expression of TCF7L2 (2,9–11), a notion recently confirmed by mouse models harboring germline null alleles …

TCF7L2 and Glucose Metabolism: Time to Look Beyond the Pancreas