Potential Molecular Targets of Oleanolic Acid in Insulin Resistance and Underlying Oxidative Stress: A Systematic Review

Abstract

Oleanolic acid (OA) is a natural triterpene widely found in olive leaves that possesses antioxidant, anti-inflammatory, and insulin-sensitizing properties, among others. These OA characteristics could be of special interest in the treatment and prevention of insulin resistance (IR), but greater in-depth knowledge on the pathways involved in these properties is still needed. We aimed to systematically review the effects of OA on the molecular mechanisms and signaling pathways involved in the development of IR and underlying oxidative stress in insulin-resistant animal models or cell lines. The bibliographic search was carried out on PubMed, Web of Science, Scopus, Cochrane, and CINHAL databases between January 2001 and May 2022. The electronic search produced 5034 articles but, after applying the inclusion criteria, 13 animal studies and 3 cell experiments were identified, using SYRCLE's Risk of Bias for assessing the risk of bias of the animal studies. OA was found to enhance insulin sensitivity and glucose uptake, and was found to suppress the hepatic glucose production, probably by modulating the IRS/PI3K/Akt/FoxO1 signaling pathway and by mitigating oxidative stress through regulating MAPK pathways. Future randomized controlled clinical trials to assess the potential benefit of OA as new therapeutic and preventive strategies for IR are warranted.

Keywords: Olea europaea; bioactive compounds; inflammation; insulin resistance; insulin signaling; oleanolic acid; oxidative stress; pathways; triterpenes; type 2 diabetes mellitus.

Figure 1

Flow diagram of the study selection process.

Figure 2

SYRCLE’s RoB tool results for each study. Yes (low risk of bias); No (high risk of bias); Unclear (item not reported, unknown risk of bias); n (number of studies).

Figure 3

Oleanolic acid improves insulin signaling in peripheral tissues through a multimolecular mechanism. (1) OA is an activator of the insulin receptor, exerting an insulin mimetic role; (2) OA upregulates insulin sensitivity by inhibition of the tyrosine phosphatase PTP1B and TCPTP; (3) OA increases glucose uptake by activation of the PI3K/Akt pathway and GLUT-4 translocation; (4) OA also enhances glucose uptake and fatty acid oxidation in muscle and liver by activating the ERK1/2-AMPK axis; (5) OA preserves the glycogen pool in muscle and liver by stimulating glucokinase and repressing the glucose-6-phosphatase and glycogen phosphorylase activities.

Figure 4

Oleanolic acid exerts antioxidant and anti-inflammatory actions against the supraphysiological production of mitochondrial ROS (mitROS) via transcription factors NRF2 and NFκB. (1) OA activates NRF2 by direct interaction with Keap1, the primary sensor that retains NRF2 for ubiquitin-dependent degradation in cytoplasm; (2) OA also activates NRF2 through the stimulation of stress kinase pathways such as ERK1/Akt and AMPK; (3) OA preserves the glutathione pool and increases the expression of antioxidant enzymes; (4) OA conserves the NADPH levels by upregulating genes of the pentose phosphate pathway and downregulating lipogenic genes; (5) OA reduces the production of inflammatory mediators, avoiding NFκB activation through competitive inhibition of IKKβ.