1520-P: Pyridylnidulin, a Semisynthesized Fungal Metabolite, Exerts the Insulin-Mimicking Effect and Improves Glucose Homeostasis in Mice

Fungal metabolites have contributed significantly to medication development. However, there are few reports of the fungal metabolites beneficial for type 2 diabetes (T2D) treatment. This study performed a semi-synthesis converting nornidulin, a secondary metabolite of Aspergillus unguis ATCC10032, to pyridylnidulin. We aimed to investigate the stimulatory effect of pyridylnidulin on glucose uptake and the mechanism of action, and determine an improvement in glucose homeostasis in mice fed high-fat diet. Our results showed that pyridylnidulin stimulated 2-[³H]-deoxy-glucose greater than nornidulin in 3T3-L1 adipocytes and L6 myotubes. Pyridylnidulin-stimulated glucose uptake was found in a dose- and time-dependent manner. Our study also provided evidence that pyridylnidulin enhanced upregulation of GLUT4, and phosphorylation of IRS1, AKT, and AMPK. Importantly, the levels of GLUT4 in the plasma membrane were increased in response to nidulin treatment. The presence of the PI3K/AKT inhibitor, wortmannin, but not AMPK inhibitor, compound C, largely lowered pyridylnidulin-stimulated glucose uptake. In addition, pyridylnidulin triggered p42/p44 MAPK phosphorylation of which inhibition by PD98059 limited pyridylnidulin-stimulated glucose uptake. In palmitic acid-induced insulin resistance in myotubes, pyridylnidulin-stimulated glucose uptake remained significant. In C57BL/6 mice fed high-fat diet for 10 weeks, oral administration of 120 mg/kg pyridylnidulin for 4 weeks not only improved glucose homeostasis in IPGTT, but also ameliorated hepatic steatosis. Taken together, pyridylnidulin exerts the insulin-mimicking effect stimulating glucose uptake mainly through PI3K/AKT-dependent GLUT4 translocation, and improved T2D pathogenesis in a mouse model.