Stevioside Attenuates Insulin Resistance in Skeletal Muscle by Facilitating IR/IRS-1/Akt/GLUT 4 Signaling Pathways: An In Vivo and In Silico Approach.

Abilasha Deenadayalan,Selvaraj Jayaraman,Vijayalakshmi Subramanian,Ponnulakshmi Rajagopal,Gayathri Rengasamy,Janaki Coiambatore Sadagopan,Vishnu Priya Veeraraghavan,Vijayalakshmi Paramasivan

doi:10.3390/molecules26247689

Abstract

Type-2 diabetes mellitus (T2DM), the leading global health burden of this century majorly develops due to obesity and hyperglycemia-induced oxidative stress in skeletal muscles. Hence, developing novel drugs that ameliorate these pathological events is an immediate priority. The study was designed to analyze the possible role of Stevioside, a characteristic sugar from leaves of Stevia rebaudiana (Bertoni) on insulin signaling molecules in gastrocnemius muscle of obesity and hyperglycemia-induced T2DM rats. Adult male Wistar rats rendered diabetic by administration of high fat diet (HFD) and sucrose for 60 days were orally administered with SIT (20 mg/kg/day) for 45 days. Various parameters were estimated including fasting blood glucose (FBG), serum lipid profile, oxidative stress markers, antioxidant enzymes and expression of insulin signaling molecules in diabetic gastrocnemius muscle. Stevioside treatment improved glucose and insulin tolerances in diabetic rats and restored their elevated levels of FBG, serum insulin and lipid profile to normalcy. In diabetic gastrocnemius muscles, Setvioside normalized the altered levels of lipid peroxidase (LPO), hydrogen peroxide (H2O2) and hydroxyl radical (OH*), antioxidant enzymes (CAT, SOD, GPx and GSH) and molecules of insulin signaling including insulin receptor (IR), insulin receptor substrate-1 (IRS-1) and Akt mRNA levels. Furthermore, Stevioside enhanced glucose uptake (GU) and oxidation in diabetic muscles by augmenting glucose transporter 4 (GLUT 4) synthesis very effectively in a similar way to metformin. Results of molecular docking analysis evidenced the higher binding affinity with IRS-1 and GLUT 4. Stevioside effectively inhibits oxidative stress and promotes glucose uptake in diabetic gastrocnemius muscles by activating IR/IRS-1/Akt/GLUT 4 pathway. The results of the in silico investigation matched those of the in vivo study. Hence, Stevioside could be considered as a promising phytomedicine to treat T2DM.

Highlights

The Diabetes Mellitus Association predicted that 578 million people will have diabetes in 2030 and the number will increase by 51% (700 million) in 2045 [1]
We investigated if Stevioside possess the potential to reverse oxidative stress mediated downregulation of insulin signaling and augment glucose transporter 4 (GLUT 4) dependent glucose uptake (GU) in gastrocnemius muscles of high fat diet (HFD) and sucrose induced type 2 diabetes mellitus (T2DM) rats
We studied whether Stevioside may activate insulin signaling pathways, upregulate GLUT 4 expression and eventually improve GU in diabetic gastrocnemius muscles that are insulin resistant

Summary

Introduction

The Diabetes Mellitus Association predicted that 578 million people will have diabetes in 2030 and the number will increase by 51% (700 million) in 2045 [1]. To maintain a constant blood glucose level, the body relies on two hormones produced in the pancreas that have opposite actions: insulin and glucagon [6] Over the years, it has become more and more evident that the development of type 2 diabetes mellitus (T2DM) is fueled by bad diets and unhealthy lifestyles which majorly contain high fat or the sugar [7]. Podolin et al [10] reported that high-fat diet feeding increased fat mass or obesity, the absolute rate of lipolysis and the contribution of estimated nonglycerol gluconeogenesis to hyperglycemia These diabetic environments trigger oxidative stress, resulting from the production of free radicals via glucose auto-oxidation, increase ROS and autophagy and have a great role in the initiation and progression of diabetic complications [11]. The modern lifestyle, genetics and nutritional overload [12] attributed to prevalence and outcomes of T2D with various complications develop including both macro and micro-vascular dysfunctions [13,14]

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