Skeletal muscle insulin-resistance is a major risk factor for type 2 diabetes. During the early stages of insulin-resistance the proximal insulin-signalling proteins are activated by insulin despite GLUT4 vesicle translocation and glucose transport being impaired. There is growing evidence that the dual function protein β-catenin can support vesicle trafficking, and is dysregulated in insulin resistance. Here we investigate the potential role of β-catenin in facilitating skeletal muscle glucose transport. We report that novel adult-induced skeletal muscle-specific β-catenin knockout mice are insulin resistant and have impaired skeletal muscle glucose transport. Furthermore, the mutation of β-cateninS552 in muscle cells impairs insulin-stimulated GLUT4 translocation and glucose uptake, an effect that appears to be independent of β-catenin’s WNT-signalling transcriptional role. Using immunoprecipitation coupled to proteomics we identify M-cadherin as an insulin-sensitive binding partner of β-catenin, which we confirmed to be required for normal insulin-stimulated glucose transport. Consistent with the role of cadherins in regulating actin filament organization, β-cateninS552 mutant muscle cells have impaired insulin-stimulated actin remodelling. This suggests that insulin-mediated phosphorylation of β-cateninS552 promotes the binding of β-catenin to M-cadherin which then provides support for actin polymerisation at the plasma membrane, a critical step for GLUT4 trafficking. We therefore propose that the dysregulation of β-catenin may play a role insulin resistance independent of proximal insulin signalling.


S.W. Masson: None. T.L. Merry: None.


Rutherford Discovery Fellowship (RDF-15-UOA-020)

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at