Generally, canonical Wnt cascades such as Wnt3a can stimulate insulin secretion and enhance the proliferation of β cell by activating β-catenin/TCF/LEF-mediated Cyclin D1 transcription.50 However, in T2D, most non-classical Wnt ligands such as Wnt4 and Wnt2a are highly upregulated,159 inhibiting Wnt3a and promoting β cell dysfunction.160 In addition, Wnt2b and TCF7L2, encoding an important transcription factor TCF4, are associated with the susceptibility of T2D among individuals with impaired glucose tolerance161 (Fig. 2g). This evidence concerns the gene WNT4 and type 2 diabetes mellitus.