Aspalathin-Enriched Green Rooibos Extract Reduces Hepatic Insulin Resistance by Modulating PI3K/AKT and AMPK Pathways.

Sithandiwe Mazibuko-Mbeje,Johan Louw,Phiwayinkosi Dludla,Christo Muller,Samira Ghoor,Andy Opoku,Rabia Johnson,Elizabeth Joubert,Candice Roux

doi:10.3390/ijms20030633

Abstract

We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor (Insr) and insulin receptor substrate 1 and 2 (Irs1 and Irs2), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways.

Highlights

Increased consumption of diets high in saturated fats such as palmitate, commonly found in processed and fast foods, contributes to the development of insulin resistance and related conditions, including obesity and type 2 diabetes [1]
We showed that green rooibos extract (GRE) dose dependently increased glucose uptake in normal C3A liver cells to the same level as insulin (Figure S1)
We evaluated the effects of GRE on palmitate-induced insulin resistance in C3A liver cells by measuring glucose and fatty acid uptake

Summary

Introduction

Increased consumption of diets high in saturated fats such as palmitate, commonly found in processed and fast foods, contributes to the development of insulin resistance and related conditions, including obesity and type 2 diabetes [1] In the literature, it is well-documented that obesity induced by a high-fat diet may lead to excessive lipid accumulation in insulin-sensitive tissues, such as skeletal muscle, adipose and the liver [2,3]. Activation of protein kinase C and subsequent inactivation of insulin receptor attenuate insulin-stimulated insulin receptor substrate 1 and 2 (IRS 1/2) tyrosine phosphorylation, a well-studied mechanism for accelerated hepatic insulin resistance [5,6] This process is normally initiated by increased lipogenesis, as well as intracellular accumulation of lipid metabolites such as diacylglycerol, and is associated with reduced mitochondrial fatty acid oxidation [7]. Hepatic insulin resistance suppresses phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT), an important cell survival signaling pathway, leading to reduced glycogen synthase kinase 3 (GSK3) and Forkhead box protein O1 (FOXO1) phosphorylation, which, in turn, results in lower insulin-stimulated liver glycogen synthesis and increased hepatic gluconeogenesis [8]

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Results

Discussion

Conclusion