The chronic effects of dietary (poly)phenols on mitochondrial dysfunction and glucose uptake in cellular models of the liver and skeletal muscle.

Background: Type 2 diabetes is characterised by chronic hyperglycaemia, insulin resistance and associated mitochondrial dysfunction. (Poly)phenols have been shown to attenuate cellular oxidative stress and restore glucose homeostasis, but the specific mechanisms and compounds responsible remain unknown. Methods: HepG2 cells were used as an in vitro hepatic model, on which the effects of quercetin on high glucose-induced oxidative stress and mitochondrial dysfunction were investigated. Mitochondria were assessed for complex I activity, cellular redox status, mitochondrial respiration and PGC-1α expression. LHCN-M2 human skeletal myocytes were differentiated in various glucose and insulin concentrations and characterised for their use as a model to explore the effects of relevant (poly)phenol metabolites on glucose uptake and metabolism. Metabolic phenotype and the effects of metabolites derived from ferulic acid, flavonols, resveratrol and berry (poly)phenols were evaluated by Western capillary protein assays, uptake of 2-[1-14C(U)]-deoxy-D-glucose and D-[14C(U)]-glucose; respirometry and the ROS assay were also used for initial metabolic characterisation. Results: Mitochondrial function was restored by quercetin in HepG2 cells exposed to high glucose, by reversing the increased cellular NADH, enhancing mitochondrial respiration and preventing proton leak, and upregulating PGC-1α, all of which led to restored complex I activity after 24 h. The LHCN-M2 model was established and cells differentiated in a normal or high glucose/insulin environment. Glucose transport was restored, and metabolism increased, in high glucose/insulin myotubes by various metabolites. Isovanillic acid 3-O-sulfate in particular elicited this effect by upregulating GLUT1, GLUT4 and PI3K protein expression, and acutely activating the insulin signalling pathway. Conclusions: Quercetin protects against hepatic mitochondrial dysfunction through pleiotropic effects involving improved redox status and enhanced mitochondrial respiration and function. (Poly)phenol metabolites, including the gut microbiome catabolite isovanillic acid 3-O-sulfate, restore glucose uptake and metabolism in human skeletal muscle exposed to high glucose and insulin, via insulin-dependent pathways.