Type 2 diabetes (T2D) is characterized by insulin resistance in skeletal muscle. GWAS studies have shown a link between T2D and Wnt signalling, and there is evidence that mutations in LRP5, a co-receptor in the canonical Wnt signaling pathway, may alter insulin sensitivity. Here, we investigated whether a gain-of-function (GoF) LRP5 mutation causing high bone mass is accompanied by changes in insulin sensitivity and abnormalities in the insulin signalling pathway in skeletal muscle. Skeletal muscle biopsies were obtained before and after a euglycemic-hyperinsulinemic clamp (3-h, 40 mU/min/m2) from 13 patients with GoF LRP5 mutation (T253I) and 14 age, and weight-matched controls. Protein abundance/phosphorylation of key mediators of insulin signalling to glucose transport and glycogen synthesis, such as Akt, TBC1D4, glycogen synthase kinase 3 (GSK3α and ß) and Erk1/2 were investigated. Insulin sensitivity measured as insulin-stimulated glucose disposal (Rd) was reduced (25%) in GoF LRP5 mutation carriers (p<0.05). However, the insulin-stimulated phosphorylation of Akt at Ser473 and Thr308, TBC1D4 at Thr642 and Erk1/2 was fully intact in skeletal muscle of GoF LRP5 mutation carriers. Moreover, both the basal and the insulin-mediated inhibitory phosphorylation of GSK3 (α and ß) were unaltered in muscle of LRP5 mutation carriers compared with controls. To further investigate the molecular consequences of this GoF LRP5 mutation, we are currently investigating key regulators of Wnt signalling (activity of ß-catenin and CaMKII) and performing RNA-sequencing in muscle.
In conclusion, our data demonstrate that reduced insulin sensitivity in GoF LRP5 mutation carriers is not explained by abnormalities in the classical components of the insulin signalling cascade in skeletal muscle. This suggests that the GOF LRP5 mutation negatively affects insulin sensitivity by other mechanisms possible involving over-activation in Wnt signalling.
R. Sabaratnam: None. J. Lauterlein: None. M.F. Nielsen: None. K. Hojlund: None.