Scopoletin Protects against Methylglyoxal-Induced Hyperglycemia and Insulin Resistance Mediated by Suppression of Advanced Glycation Endproducts (AGEs) Generation and Anti-Glycation

Abstract

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.

Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway

“…The ability of scopoletin to upregulate Nrf2/HO-1 signaling has been supported by few studies. Given the antidiabetic efficacy of scopoletin, Chang et al have investigated its insulin sensitizing and antiglycation effects in diabetic rats, pointing to the role of Nrf2 signaling [121]. Scopoletin suppressed the formation of advanced glycation end products (AGEs), hyperglycemia, and insulin resistance and enhanced Nrf2, Akt, and GLUT2 in hepatocytes [121].…”

“…Given the antidiabetic efficacy of scopoletin, Chang et al have investigated its insulin sensitizing and antiglycation effects in diabetic rats, pointing to the role of Nrf2 signaling [121]. Scopoletin suppressed the formation of advanced glycation end products (AGEs), hyperglycemia, and insulin resistance and enhanced Nrf2, Akt, and GLUT2 in hepatocytes [121]. Very recently, Narasimhan et al reported that scopoletin protected against oxidative stress and apoptosis induced by rotenone via Nrf2 activation and investigated its neuroprotective effects for Parkinson's disease in a rat model and in vitro using SH-SY5Y cells [122].…”

Coumarins as potential antidiabetic agents

“…Scopoletin (3) reactivates insulin‐stimulated Akt phosphorylation in insulin‐resistant hepatocytes and upregulates PPARγ expression in adipocytes . A recent study reported that scopoletin inhibit advanced glycation endproducts (AGEs) production by activating Nrf2(Ser40) phosphorylation and PTP1B expression, reducing accumulation of AGEs in the livers and promoting Akt phosphorylation . Fraxetin, subjected to cortex fraxini coumarins (5) , shows antihyperglycaemic effect by altering the activity of key enzymes of carbohydrate metabolism .…”

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises

“…Many natural compounds have been described to have therapeutic effects in preventing MG‐induced glycation, mainly due to MG‐scavenging and antioxidant properties, also increasing GLO1 activity. There are immense studies addressing this issue and a myriad of compounds including soy isoflavones, δ‐tocopherol, several flavonoids, phenols, xantonoids, and diterpenes and triterpenes from fruit and vegetables, phlorotannins, olive oil, polyunsaturated free fatty acids, and diverse plant, root and algae‐extracted compounds have been previously tested in in vitro and in vivo models of hyperglycemia and in presence of MG‐derived AGE. Such compounds were found to prevent from protein glycation by scavenging MG and, some of them, by activating GLO1.…”