Skeletal muscle metabolic dysfunction with circulating carboxymethyl‐lysine in dietary food additive‐induced leaky gut

Abstract Impaired intestinal permeability induces systemic inflammation and metabolic disturbance. The effect of a leaky gut on metabolism in skeletal muscle, a major nutrient consumer, remains unclear. In this study, we aimed to investigate the glucose metabolic function of the whole body and skeletal muscles in a mouse model of diet‐induced intestinal barrier dysfunction. At Week 2, we observed higher intestinal permeability in mice fed a titanium dioxide (TiO 2 )‐containing diet than that of mice fed a normal control diet. Subsequently, systemic glucose and insulin tolerance were found to be impaired. In the skeletal muscle, glucose uptake and phosphorylation levels in insulin signaling were lower in the TiO 2 group than those in the control group. Additionally, the levels of pro‐inflammatory factors were higher in TiO 2 ‐fed mice than those in the control group. We observed higher carboxymethyl‐lysin (CML) levels in the plasma and intestines of TiO 2 ‐fed mice and lower insulin‐dependent glucose uptake in CML‐treated cultured myotubes than those in the controls. Finally, soluble dietary fiber supplementation improved glucose and insulin intolerance, suppressed plasma CML, and improved intestinal barrier function. These results suggest that an impaired intestinal barrier leads to systemic glucose intolerance, which is associated with glucose metabolism dysfunction in the skeletal muscles due to circulating CML derived from the intestine. This study highlights that the intestinal condition regulates muscle and systemic metabolic health.