297-OR: ß-Catenin Facilitates Skeletal Muscle Insulin-Stimulated Glucose Transport through the Regulation of Actin Remodeling

Abstract

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. Disclosure S.W. Masson: None. T.L. Merry: None. Funding Rutherford Discovery Fellowship (RDF-15-UOA-020)