Nidulin stimulates glucose uptake in myotubes through the IRS-AKT pathway and alters redox balance and intracellular calcium.

Nidulin is a secondary metabolite of the depsidone family produced by Aspergillus spp., and has shown promises in pharmacological applications. This study aimed to investigate the effect of nidulin on glucose metabolism in skeletal muscle, the primary site of physiological glucose disposal, and its underlying mechanisms. Using a 2-[H]-deoxy-glucose (2-DG) uptake assay, nidulin stimulated 2-DG in L6 myotubes in a dose- and time-dependent manner. This effect of nidulin was additive to insulin and metformin, and remained effective under palmitic acid-induced insulin resistance. At the molecular level, nidulin upregulated the mRNA expression and promoted membrane translocation of glucose transporters, GLUT4 and GLUT1. Although nidulin activated AMPK and p38 signaling, pharmacological inhibition of this pathway had minimal effect on nidulin-enhanced 2-DG uptake activity. Notably, nidulin activated key insulin signaling proteins, including IRS1, AKT, and p44/42, and its effect was attenuated by an AKT inhibitor. This study further compared the upstream mechanism of nidulin with that of insulin. While nidulin did not directly activate the insulin receptor β-subunit, it modulated redox homeostasis and intracellular calcium, evidenced by increased cytosolic H₂O₂ and Ca⁺ levels. The 2-DG uptake-enhancing effect of nidulin and its activation of AKT were suppressed by either an antioxidant or calcium chelator treatment. These findings position nidulin as a promising insulin-sensitizing agent, offering mechanistic insights and therapeutic potential for improving glucose homeostasis in type 2 diabetes.