A role for beta-catenin in diet-induced skeletal muscle insulin resistance

A central characteristic of insulin resistance is the impaired ability for insulin to stimulate glucose uptake into skeletal muscle. While insulin resistance can occur distal to the canonical insulin receptor-PI3k-Akt signaling pathway, the signaling intermediates involved in the dysfunction are yet to be fully elucidated. beta-catenin is an emerging distal regulator of skeletal muscle and adipocyte insulin-stimulated GLUT4 trafficking. Here, we investigate its role in skeletal muscle insulin resistance. Short-term (5-week) high-fat diet (HFD) decreased skeletal muscle beta-catenin protein expression 27% (p = 0.03), and perturbed insulin-stimulated beta-catenin(S552) phosphorylation 21% (p = 0.009) without affecting insulin-stimulated Akt phosphorylation relative to chow-fed controls. Under chow conditions, mice with muscle-specific beta-catenin deletion had impaired insulin responsiveness, whereas under HFD, both mice exhibited similar levels of insulin resistance (interaction effect of genotype x diet p < 0.05). Treatment of L6-GLUT4-myc myocytes with palmitate lower beta-catenin protein expression by 75% (p = 0.02), and attenuated insulin-stimulated beta-catenin phosphorylation(S552) and actin remodeling (interaction effect of insulin x palmitate p < 0.05). Finally, beta-catenin(S552) phosphorylation was 45% lower in muscle biopsies from men with type 2 diabetes while total beta-catenin expression was unchanged. These findings suggest that beta-catenin dysfunction is associated with the development of insulin resistance.