Pterostilbene Improves Insulin Resistance Caused by Advanced Glycation End Products (AGEs) in Hepatocytes and Mice.

ABSTRACT

SCOPE Increased consumption of modern processed foods rich in AGEs is drawing worldwide concerns because they are related with rising diabetes prevalence. This study aimed to investigate if pterostilbene (PTE) regulates glucose metabolism and insulin signaling, as well as its potential mechanism in the context of AGEs exposure. METHODS AND RESULTS: In vitro, Lo2 and HepG2 cells are treated with vehicle, AGEs with or without PTE. AGEs exposure directly impair insulin action as evidenced by assays of insulin-stimulated glucose uptake, consumption, and output. However, PTE efficiently rescue the AGE-induced phenotypes in both cell lines, and enhance IRS-1/PI3K/AKT insulin signaling in a dose-dependent manner. In vivo, C57BL6 mice are fed with regular, high AGEs diet and high AGEs plus PTE. PTE administration effectively improves hyperglycemia, glucose tolerance, and impaired hepatic insulin signaling induced by AGEs, consistent with the in vitro experiments. Moreover, PTE reduce AGEs accumulation in liver and serum. RNA-seq data indicate that PTE counteracts several AGEs-induced dysfunctions including diabetes related process, glucose metabolic process, immune response, and so on. CONCLUSION: PTE treatment prominently reduced AGEs accumulation and alleviated AGEs-associated diabetes symptoms. PTE could be used as a promising glucose-sensitizing agent for nutritional intervention.