Orientin Improves Substrate Utilization and the Expression of Major Genes Involved in Insulin Signaling and Energy Regulation in Cultured Insulin-Resistant Liver Cells.

Sithandiwe E Mazibuko-Mbeje,Phiwayinkosi V Dludla,Khanyisani Ziqubu,Andani Tshiitamune,Ndivhuwo Muvhulawa,Christo J F Muller,Fikile T Mthiyane,Sinenhlanhla X H Mthembu

doi:10.3390/molecules26206154

Abstract

Our group has progressively reported on the impact of bioactive compounds found in rooibos (Aspalathus linearis) and their capacity to modulate glucose homeostasis to improve metabolic function in experimental models of type 2 diabetes. In the current study, we investigated how the dietary flavone, orientin, modulates the essential genes involved in energy regulation to enhance substrate metabolism. We used a well-established hepatic insulin resistance model of exposing C3A liver cells to a high concentration of palmitate (0.75 mM) for 16 hrs. These insulin-resistant liver cells were treated with orientin (10 µM) for 3 h to assess the therapeutic effect of orientin. In addition to assessing the rate of metabolic activity, end point measurements assessed include the uptake or utilization of glucose and palmitate, as well as the expression of genes involved in insulin signaling and regulating cellular energy homeostasis. Our results showed that orientin effectively improved metabolic activity, mainly by maintaining substrate utilization which was marked by enhanced glucose and palmitate uptake by liver cells subjected to insulin resistance. Interestingly, these effects can be explained by the improvement in the expression of genes involved in glucose transport (Glut2), insulin signaling (Irs1 and Pi3k), and energy regulation (Ampk and Cpt1). These preliminary findings lay an important foundation for future research to determine the bioactive properties of orientin against dyslipidemia or insulin resistance in reliable and well-established models of type 2 diabetes.

Highlights

According to global health surveillance organizations, such as the World Health Organization (WHO) [1] and International Diabetes Federation (IDF) [2], metabolic diseases such as diabetes mellitus consistently rank among the leading causes of death each year, especially over the last decade
Effect of Orientin on Metabolic Activity in Palmitate-Exposed Liver Cells. Metabolic assays, such as MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and adenosine triphosphate (ATP) assays are widely used to measure the metabolic activity of cells in response to different types of treatments after induction of insulin resistance
This is consistent with the classical features of type 2 diabetes (T2D) which represent abnormal insulin signaling paralleled by severely reduced hepatic glucose production and enhanced liver lipid synthesis, i.e., consequences that aggravate the state of hyperglycemia and hyperlipidemia [18,19]

Summary

Introduction

According to global health surveillance organizations, such as the World Health Organization (WHO) [1] and International Diabetes Federation (IDF) [2], metabolic diseases such as diabetes mellitus consistently rank among the leading causes of death each year, especially over the last decade. Due to its envisaged health benefits against metabolic disease, the major focus has been placed on unraveling the therapeutic mechanisms of bioactive compounds found in rooibos (Aspalathus linearis) against T2D-related complications [9]. Predominantly from our group, has reported on the impact of these rooibos bioactive compounds in modulating prime mechanisms involved in the development of insulin resistance and T2D, such as the regulation of phosphoinositide 3-kinase and protein kinase B (Pi3k/Akt) as well as the activation of AMP-activated protein kinase (AMPK) to improve cellular metabolism, through the use of experimental models of metabolic disease [7,9,11,12]

Methods

Results

Conclusion