Recently, several types of foods and drinks, including
coffee, cream, and cake, have been found to result in high
methylglyoxal (MG) levels in the plasma, thus causing both nutritional and health concerns. MG can be metabolized by phase-II
enzymes in liver through the positive regulation of nuclear factor-erythroid 2-related factor 2 (Nrf2). In this study, we investigated the ability of
scopoletin (SP) to protect against MG-induced
hyperglycemia and
insulin resistance. Recently, SP was shown to be a
peroxisome proliferator-activated receptor-γ activator to elevate
insulin sensitivity. We investigated the effects of
oral administration of SP on the metabolic, biochemical, and molecular abnormalities characteristic of
type 2 diabetes in MG-treated Wistar rats to understand the potential mechanism of
scopoletin for diabetes protection. Our results suggested that SP activated Nrf2 by Ser40 phosphorylation, resulting in the metabolism of MG into
d-lactic acid and the inhibition of AGEs generation, which reduced the accumulation of AGEs in the livers of MG-induced rats. In this manner, SP improved the results of the oral
glucose tolerance test and
dyslipidemia. Moreover, SP also increased the plasma translocation of
glucose transporter-2 and promoted Akt phosphorylation caused by
insulin treatment in MG-treated FL83B hepatocytes. In contrast, SP effectively suppressed
protein tyrosine phosphatase 1B (PTP1B) expression, thereby alleviating
insulin resistance. These findings suggest that SP acts as an anti-glycation and anti-diabetic agent, and thus has therapeutic potential for the prevention of diabetes.