Total Sesquiterpene Glycosides from Loquat Leaves Ameliorate HFD-Induced Insulin Resistance by Modulating IRS-1/GLUT4, TRPV1, and SIRT6/Nrf2 Signaling Pathways.

Ruoyun Wu,Xiaoqin Ding,Jing Li,Jian Chen,Han Lv,Bingru Ren,Tunyu Jian,Xiuhua Meng,Weilin Li,Anderson J Teodoro

doi:10.1155/2021/4706410

Abstract

Loquat (Eriobotrya japonica Lindl.), a subtropical fruit tree native to Asia, is not only known to be nutritive but also beneficial for the treatment of diabetes in the south of China. To expand its development, this study was undertaken concerning the potential therapeutic role of total sesquiterpene glycosides (TSGs) from loquat leaves in insulin resistance (IR), the major causative factor of type 2 diabetes mellitus (T2DM). Male C57BL/6 mice were fed on high-fat diet (HFD) to induce IR and then were given TSG by oral administration at 25 and 100 mg/kg/day, respectively. TSG notably improved metabolic parameters including body weight, serum glucose, and insulin levels and prevented hepatic injury. Moreover, inflammatory response and oxidative stress were found to be remarkably alleviated in IR mice with TSG supplement. Further research in liver of IR mice demonstrated that TSG repaired the signalings of insulin receptor substrate-1 (IRS-1)/glucose transporter member 4 (GLUT4) and AMP-activated protein kinase (AMPK), which improved glucose and lipid metabolism and prevented lipid accumulation in liver. It was also observed that TSG suppressed the expression of transient receptor potential vanilloid 1 (TRPV1), whereas the signaling pathway of sirtuin-6 (SIRT6)/nuclear factor erythroid 2-related factor 2 (Nrf2) was significantly promoted. Based on the results, the current study demonstrated that TSG from loquat leaves potentially ameliorated IR in vivo by enhancing IRS-1/GLUT4 signaling and AMPK activation and modulating TRPV1 and SIRT6/Nrf2 signaling pathways.

Highlights

Owing to the popularity of fast food and takeout, dietary habits in the form of high fat are so common that metabolic disorders are prevalently increasing worldwide
The molecular mechanism of Insulin resistance (IR) is not fully understood, but it is confirmed that imbalanced glucose and lipid metabolism, inflammation, and oxidative stress are major factors associated with the development of IR [1–3]
Total sesquiterpene glycosides from loquat leaves were prepared in our lab following the method that we reported earlier [36, 37]

Summary

Introduction

Owing to the popularity of fast food and takeout, dietary habits in the form of high fat are so common that metabolic disorders are prevalently increasing worldwide. Insulin resistance (IR) is regarded as a main pathological feature of metabolic disorders, such as obesity, type 2 diabetes mellitus (T2DM), and nonalcoholic fatty liver disease (NAFLD). Insulin binds to the insulin receptor, and insulin receptor substrate-1 (IRS-1) is phosphorylated. It activates its downstream targets including glucose transporter member 4 (GLUT4) and regulates blood glucose balance [4]. AMP-activated protein kinase (AMPK) is a vital regulator in the metabolism of glucose and lipid [5]. AMPK has been believed to be a therapeutic target for many metabolic disorders including IR [6, 7]. A few earlier studies have revealed that the activated AMPK could positively regulate the expression of GLUT4 [8, 9]

Methods

Results

Conclusion