How olive oil bioactives regulate genes linked to insulin resistance

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.Feb 5 2025

Review explains how olive oil’s bioactive compounds influence key genetic pathways to improve glucose metabolism, reduce inflammation, and support beta-cell function—offering a natural approach to fighting Type 2 Diabetes.

​​​​​​​Review: Impact of Olive Oil Components on the Expression of Genes Related to Type 2 Diabetes Mellitus. ​​​​​​​Image Credit: sebra / Shutterstock

In a recent review published in the journal Nutrients, researchers examined how bioactive compounds in olive oil influence the expression of genes regulating Type 2 Diabetes Mellitus (T2DM), with a focus on their potential role in improving insulin sensitivity, reducing inflammation, and preserving beta-cell function. The study highlights specific genetic pathways through which olive oil bioactives modulate insulin signaling, lipid metabolism, and oxidative stress, shedding light on their molecular effects.

Background

Can diet truly alter gene expression and metabolic health? With over 537 million adults worldwide affected by diabetes, finding dietary solutions is more crucial than ever. With the rise of non-communicable diseases such as T2DM and cardiovascular disorders, dietary components play a crucial role in disease prevention and management.

Olive oil, a staple of the Mediterranean diet, has long been associated with health benefits, particularly in improving insulin sensitivity and reducing inflammation. The key bioactive compounds in olive oil, including monounsaturated fatty acids (MUFA) and polyphenols, have been shown to exert antioxidant and anti-inflammatory effects. However, the molecular mechanisms underlying these benefits remain unclear.

Current studies suggest that these compounds modulate key pathways related to glucose metabolism, inflammation, and lipid regulation. Specifically, olive oil bioactives influence the insulin receptor substrate (IRS) phosphorylation, peroxisome proliferator-activated receptor-alpha (PPAR-α) activation, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibition, all of which play a role in insulin sensitivity and inflammation. Yet, inconsistencies exist in research methodologies, making it necessary to investigate how different olive oil compositions influence gene expression in human and animal models.

Further research is needed to confirm these findings and establish dietary recommendations.

MUFAs and Insulin Sensitivity

Olive oil is rich in oleic acid, a MUFA that enhances insulin sensitivity. Studies show that diets high in MUFAs improve glycemic control by modulating insulin receptor signaling and glucose uptake in skeletal muscle. Oleic acid activates PPAR-α, which regulates lipid metabolism and reduces lipotoxicity, a key contributor to insulin resistance. Additionally, it enhances GLUT4 translocation to the cell membrane, improving glucose uptake efficiency. Furthermore, it reduces oxidative stress by inhibiting reactive oxygen species (ROS) production, protecting pancreatic beta cells from apoptosis.

Polyphenols: Antioxidant and Anti-Inflammatory Effects

Polyphenols, including hydroxytyrosol, oleuropein, and tyrosol, are potent antioxidants found in extra virgin olive oil (EVOO). These compounds mitigate T2DM progression by modulating inflammatory pathways, such as NF-κB, reducing the expression of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). They also influence the mitogen-activated protein kinase (MAPK) signaling pathway, reducing cellular inflammation and improving insulin receptor function. Furthermore, polyphenols activate nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant defense, enhancing cellular resilience against oxidative damage.

Mechanisms of Beta-Cell Protection

Beta-cell dysfunction is a hallmark of T2DM. Olive oil compounds improve beta-cell survival by modulating endoplasmic reticulum (ER) stress responses and mitochondrial function. Hydroxytyrosol has been shown to reduce ER stress markers, while oleic acid enhances mitochondrial efficiency, preventing excessive ROS generation. Additionally, these bioactives influence the unfolded protein response (UPR), reducing CCAAT-enhancer-binding protein homologous protein (CHOP) expression, which plays a key role in beta-cell apoptosis. These mechanisms collectively support insulin secretion and glucose homeostasis, preserving pancreatic function.

Lipid Metabolism and Glucose Regulation

Beyond direct effects on insulin sensitivity, olive oil influences lipid metabolism. The high MUFA content lowers circulating free fatty acids (FFAs), which contribute to insulin resistance. Oleic acid also enhances fatty acid oxidation via PPAR-α activation, reducing lipid accumulation in non-adipose tissues. Additionally, polyunsaturated fatty acids (PUFAs) in olive oil, including linoleic acid and alpha-linolenic acid, modulate lipid profiles by reducing low-density lipoprotein (LDL) cholesterol and promoting high-density lipoprotein (HDL) cholesterol.

Triterpenoids and Phytosterols: Additional Metabolic Benefits

The study also highlights the role of lesser-known olive oil bioactives, such as triterpenoids and phytosterols, in metabolic regulation. Triterpenoids, such as oleanolic acid, have demonstrated antidiabetic properties by enhancing glucose uptake and reducing inflammation. Phytosterols, structurally similar to cholesterol, compete with dietary cholesterol absorption, leading to improved lipid profiles. These compounds modulate insulin receptor signaling and contribute to overall metabolic health.

Clinical Implications and Future Directions

The Mediterranean diet, with olive oil as a key component, has shown promising results in T2DM prevention and management. Human studies indicate that replacing saturated fats with MUFAs from olive oil leads to improved insulin sensitivity and lower fasting glucose levels. However, variability in olive oil composition due to differences in olive cultivar, production methods, and storage conditions may influence its health benefits, necessitating further standardization in clinical trials.

Further clinical trials are needed to establish optimal dosages and personalized dietary strategies. The researchers emphasize the need for well-designed human studies to validate findings from in vitro and animal models, ensuring that dietary recommendations reflect real-world metabolic effects.

Conclusions

To summarize, this review confirms that olive oil plays a crucial role in supporting metabolic health, potentially reducing the global burden of diabetes and cardiovascular diseases by modulating gene expression related to insulin sensitivity, inflammation, and lipid metabolism. The presence of MUFAs and polyphenols in olive oil contributes to its anti-inflammatory and antioxidant properties, making it a valuable dietary component for preventing and managing metabolic disorders. By influencing key genetic pathways such as IRS phosphorylation, GLUT4 translocation, and PPAR activation, olive oil bioactives enhance insulin signaling efficiency.

Furthermore, the study highlights emerging bioactives, including triterpenoids and phytosterols, that offer additional metabolic benefits beyond MUFAs and polyphenols. Establishing specific dietary recommendations based on olive oil’s bioactive composition could help maximize its therapeutic potential in metabolic health.