Molecular Function of TCF7L2: Consequences of TCF7L2 Splicing for Molecular Function and Risk for Type 2 Diabetes

TCF7L2 harbors the variant with the strongest effect on type 2 diabetes (T2D) identified to date, yet the molecular mechanism as to how variation in the gene increases the risk for developing T2D remains elusive. The phenotypic changes associated with the risk genotype suggest that T2D arises as a consequence of reduced islet mass and/or impaired function, and it has become clear that TCF7L2 plays an important role for several vital functions in the pancreatic islet. TCF7L2 comprises 17 exons, five of which are alternative (ie, exons 4 and 13-16). In pancreatic islets four splice variants of TCF7L2 are predominantly expressed. The regulation of these variants and the functional consequences at the protein level are still poorly understood. A clear picture of the molecular mechanism will be necessary to understand how an intronic variation in TCF7L2 can influence islet function.