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

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.

Bioactivity and mechanisms of flavonoids in decreasing insulin resistance

“…Sithandiwe et al. 41 found that orientin (10 μM) treatment of insulin-resistant liver cells can combat dyslipidemia or IR. This may be related to orientin improving gene expression of GLUT2, insulin signal transduction (IRS1 and PI3k), and energy regulation (AMPK and Cpt1).…”

Hypoglycemic and hypolipidemic effects of Lippia origanoides Kunth in diabetic rats

“…When phosphorylated (p‐AMPK‐α), this protein improves the use of glucose (Rena et al., 2013 ), contributing to the reduction of hyperglycemia. In in vitro models, Orientin demonstrated the ability to increase glucose uptake and effectively modulate the expression of genes that encode glucose transport (GLUT2 and GLUT4) (Choi et al., 2020 ; Mazibuko‐Mbeje et al., 2021 ).…”

“…Another possible mechanism of action of Elo in cardiac dysfunction associated with diabetes is through the modulation of genes that encode insulin signaling. Elo compounds (Orientin and Vitexin) capable of activating insulin receptor substrate‐1 (IRS‐1), in addition to increasing glucose uptake, play an important role in the activation of phosphatidylinositide‐dependent kinase‐3 (PI‐3K) by increasing the phosphorylation of IR, IRS‐1, and IRS‐2 (Choi et al., 2020 ; Ganesan et al., 2020 ; Inamdar et al., 2019 ; Mazibuko‐Mbeje et al., 2021 ). PI‐3K controls the signaling cascade that regulates mitochondrial function, cardiac energy metabolism, and the renin–angiotensin system (Guo & Guo, 2017 ).…”

Identification of Novel Cannabinoid CB2 Receptor Agonists from Botanical Compounds and Preliminary Evaluation of Their Anti-Osteoporotic Effects

“…Mangiferin is a xanthone present in significant levels in higher plants and possesses a variety of pharmacological actions, including anticancer, antidiabetic, antioxidative, immunomodulatory, hepatoprotective, analgesic, and neuroprotective effects [ 69 , 70 ]. Orientin is a water-soluble flavonoid C-glycoside with antioxidant, antiaging, antiviral, antibacterial, anti-inflammation, vasodilatation and cardioprotective, antiadipogenesis, antinociceptive, radiation-protective, neuroprotective, and antidepressant-like effects [ 71 , 72 , 73 , 74 ]. CB2R was also reported to be involved in the regulation of inflammation, anti-cancer, anti-fibrotic, and nerve system disease [ 10 , 13 ].…”