Enhanced alleviation of insulin resistance via the IRS-1/Akt/FOXO1 pathway by combining quercetin and EGCG and involving miR-27a-3p and miR-96-5p

Quercetin and EGCG exhibit anti-diabetic and anti-obesity activities, however, their interactive effects in antidiabetic/anti-obesity actions and underlying mechanisms remain unclear. This study aimed to fill these knowledge gaps. Quercetin, EGCG or their combination attenuated insulin resistance and decreased hepatic gluconeogenesis in high-fat-high-fructose diet (HFFD)-fed C57BL/6 mice and in palmitic acid (PA)-treated HepG2 cells. In mice, supplementation with quercetin (0.05%w/w), EGCG (0.05%w/w) and their combination (quercetin 0.05%+EGCG 0.05%w/w) reduced weight gain and fasting blood glucose and improved serum biochemical parameters. Compare with quercetin/EGCG alone, the quercetin-EGCG combination reduced gluconeogenesis to a greater extent via IRS-1/Akt/FOXO1-mediated down-regulation of downstream PEPCK and G-6-pase. In HepG2 cells, the quercetin (5 mu M)-EGCG (5 mu M) co-treatment exerted greater suppression on PAinduced changes in glucose and glycogen contents and hexokinase and G-6-pase activities than quercetin/ EGCG alone (each 10 mu M). The quercetin-EGCG co-treatment reduced glucose production through targeting FOXO1 and inhibiting the transcription of gluconeogenic enzymes. MiR-27a-3p and miR-96-5p regulated directly FOXO1 expression and function, and co-inhibition of miR-27a-3p and miR-96-5p weakened greatly the protective effect of quercetin-EGCG combination. This is the first report on the contributions of miR-27a-3p and miR-96-5p to the synergistic and protective effect of the quercetin-EGCG co-treatment against PA-induced insulin resistance through inhibiting FOXO1 expression.

Automated summary

This study investigated the interactive effects of quercetin and EGCG in anti-diabetic/anti-obesity actions. The results showed that the combination of quercetin and EGCG had stronger effects in reducing insulin resistance and hepatic gluconeogenesis compared to individual treatments. The study also identified miR-27a-3p and miR-96-5p as key regulators in the protective effect of quercetin-EGCG combination against insulin resistance. This is the first report on the contributions of these microRNAs to the synergistic effect of quercetin and EGCG.