Research Article: Aspalathin, a natural product with the potential to reverse hepatic insulin resistance by improving energy metabolism and mitochondrial respiration

Date Published: May 2, 2019

Publisher: Public Library of Science

Author(s): Sithandiwe E. Mazibuko-Mbeje, Phiwayinkosi V. Dludla, Rabia Johnson, Elizabeth Joubert, Johan Louw, Khanyisani Ziqubu, Luca Tiano, Sonia Silvestri, Patrick Orlando, Andy R. Opoku, Christo J. F. Muller, Michael Bader.


Aspalathin is a rooibos flavonoid with established blood glucose lowering properties, however, its efficacy to moderate complications associated with hepatic insulin resistance is unknown. To study such effects, C3A liver cells exposed to palmitate were used as a model of hepatic insulin resistance. These hepatocytes displayed impaired substrate metabolism, including reduced glucose transport and free fatty acid uptake. These defects included impaired insulin signaling, evident through reduced phosphatidylinositol-4,5-bisphosphate 3-kinase/ protein kinase B (PI3K/AKT) protein expression, and mitochondrial dysfunction, depicted by a lower mitochondrial respiration rate. Aspalathin was able to ameliorate these defects by correcting altered substrate metabolism, improving insulin signaling and mitochondrial bioenergetics. Activation of 5ʹ-adenosine monophosphate-activated protein kinase (AMPK) may be a plausible mechanism by which aspalathin increases hepatic energy expenditure. Overall, these results encourage further studies assessing the potential use of aspalathin as a nutraceutical to improve hepatocellular energy expenditure, and reverse metabolic disease-associated complications.

Partial Text

Obesity and dysglycemia, the major characteristic features of the metabolic syndrome, have become prevalent in the general population and are associated with a rapid rise in morbidity and mortality [1, 2]. Insulin resistance, mostly driven by an imbalance between intake and utilization of metabolic substrates such as carbohydrates and lipids remains a prominent hallmark of the metabolic syndrome [3]. Since described by Randle in 1963 as an important biochemical mechanism in the development of insulin resistance [4], increasingly research has focused on effective regulation of glucose and free fatty acid (FFA) metabolism to control diabetes and its associated complications [5–9]. Based on these studies, it is now well-accepted that impaired glucose and FFA metabolism affects optimal functioning of major organs in the human body, including adipose tissue, skeletal muscle, myocardium and liver. In fact, abnormal substrate metabolism has been correlated with reduced insulin sensitivity and glucose transport in the liver [10]. The liver plays an essential role in the physiological regulation of whole-body energy homeostasis and in the pathogenesis of the epidemiologically relevant metabolic disorders [11]. Diets rich in saturated fat and sugar content that are increasingly consumed in industrialized and developing societies, together with lack of physical activity contribute greatly to the development of pathological conditions, such as obesity, hypertension, insulin resistance, and liver diseases [12]. Through various experimental models, for example, high fat diet-fed rodents or palmitate exposed hepatocytes, abnormal FFA metabolism has also been linked with defective insulin signaling, mainly through the impairment of the phosphatidylinositol-4,5-bisphosphate 3-kinase/ protein kinase B (PI3K/AKT) pathway [10, 13, 14].

The rapid rise in deaths due to noncommunicable diseases warrants further investigation into novel drugs that can act broadly to alter energy metabolism or influence pathways that contribute to metabolic disease-associated complications. Hepatocytes play a major role in regulating energy metabolism, in addition to their established function in the detoxification of metabolites and synthesis of proteins. Abnormal hepatic energy metabolism has been associated with the development of various metabolic complications, including NAFLD, insulin resistance, and diabetes mellitus [7, 14, 35]. C3A cells are known to exhibit many liver-specific features, including gluconeogenesis and glycogen synthesis in response to insulin stimulation. These cells also express GLUT2 and produce lipid intermediates such as cholesterol [35]. On the other hand, exposure to high palmitate concentrations has been successfully used to set up models of insulin resistance in many cell types, including C3A liver cells [8, 14, 31]. To date, studies reporting on the therapeutic potential of aspalathin against liver associated metabolic complications are lacking. The current study tested the beneficial effects of aspalathin against palmitate-induced hepatic insulin resistance using C3A cells.

This study showed that aspalathin can target the liver cells to regulate hepatic cellular metabolism and increase energy expenditure likely by modulating PI3K/AKT and AMPK signaling pathways. However, before proposals presented in this study are accepted, several issues need to be resolved first. This includes confirming these results in an established in vivo model of insulin resistance. Such information would not only improve our current understanding on the mechanisms involved in metabolic disease associated liver dysfunction, but would also highlight the potential use of aspalathin as a nutraceutical to protect against metabolic disease-related complications.




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