Type 2 diabetes mellitus (T2DM) is among the fastest-growing noncommunicable diseases worldwide, driven by genetic predisposition, sedentary lifestyles, unhealthy diets, and obesity-related insulin resistance 1. More than 460 million adults currently live with diabetes, and projections suggest that this figure will exceed 640 million by 2045, underscoring the substantial epidemiological and economic burden of the disease (International Diabetes Federation, IDF Diabetes Atlas, 10th edition, 2021) 2. Pathophysiologically, T2DM is characterized by impaired insulin sensitivity, progressive β-cell dysfunction, chronic low-grade inflammation, and metabolic inflexibility, leading to dysregulated glucose and lipid homeostasis 3. These disturbances extend beyond glycemic control, contributing to endothelial dysfunction, hepatic steatosis, dyslipidemia, and heightened cardiovascular risk 4,5.

Dietary composition serves as a central determinant of metabolic health. Beyond mere caloric intake, the quality of dietary fats strongly influences insulin sensitivity, lipid metabolism, inflammatory processes, and cardiometabolic outcomes 6. Saturated fatty acids (SFAs) are consistently linked to lipotoxicity, inflammation, and impaired insulin signaling, whereas unsaturated fatty acids—particularly monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs)—exert beneficial metabolic effects 7. These benefits include improved membrane fluidity, enhanced lipid oxidation, the precise modulation of inflammatory pathways, and favorable changes in circulating lipoproteins 8. Among the unsaturated fats, oleic acid (OA), the predominant MUFA, and linoleic acid (LA), the major dietary ω-6 PUFA, are of particular clinical interest 9. OA supports membrane fluidity, activates the PPARα/γ pathways, and suppresses pro-inflammatory signaling cascades such as TLR4–NF-κB 10. Furthermore, LA contributes to membrane structure and generates bioactive metabolites that can exert either pro- or anti-inflammatory effects depending on the specific enzymatic pathways and tissue context 11.

This review synthesizes current evidence regarding the metabolic roles of OA and LA in T2DM management, highlighting mechanistic insights, findings from clinical and experimental studies, dietary sources, intake recommendations, and future research directions. Unlike earlier reviews that have examined MUFAs and PUFAs collectively, this work provides a direct mechanistic and clinical comparison between OA and LA, thereby clarifying their distinct yet complementary contributions to diabetes care.

This study was conducted as a narrative review aimed at critically evaluating the existing evidence regarding the roles of monounsaturated and polyunsaturated fatty acids—particularly oleic acid (OA) and linoleic acid (LA)—in the management of type 2 diabetes mellitus (T2DM). The review focused on the underlying mechanisms of action, preclinical evidence, and clinical findings relevant to glucose and lipid metabolism.

A comprehensive literature search was performed using the PubMed, Scopus, Google Scholar, and Web of Science databases 16. Studies published between 2000 and 2025 were prioritized, while seminal older works were included to provide foundational context 16. Search terms combined keywords and Medical Subject Headings (MeSH) terms, such as "oleic acid," "linoleic acid," "monounsaturated fatty acids," "polyunsaturated fatty acids," "type 2 diabetes mellitus," "insulin resistance," "mechanism of action," "preclinical studies," "clinical trials," "glycemic control," "lipid metabolism," and "dietary fatty acids.". Boolean operators (“AND” and “OR”) were applied to refine the literature retrieval process 17.

Eligibility criteria encompassed in vitro experiments, animal studies, preclinical investigations, randomized controlled trials, cohort and observational studies, as well as systematic reviews and meta-analyses evaluating OA and LA in relation to T2DM. Only full-text articles published in English were included. Exclusions comprised duplicates, conference abstracts lacking methodological detail, and studies falling outside the scope of the review 18. Screening was conducted at the title, abstract, and full-text levels.

Data extraction captured the study design, population or experimental model, intervention duration, dosage and source of fatty acids, molecular pathways investigated, metabolic outcomes assessed, and principal findings relevant to diabetes management 18.

Findings were narratively synthesized and organized thematically under the categories of mechanisms of action, preclinical evidence, and clinical evidence. This approach enabled an integrated discussion of current knowledge, therapeutic implications, and research gaps regarding the potential roles of OA and LA in the prevention and management of T2DM.

Oleic acid (OA), the principal monounsaturated fatty acid (MUFA), and linoleic acid (LA), the predominant dietary ω-6 polyunsaturated fatty acid (PUFA), exert complementary effects on metabolic regulation in type 2 diabetes mellitus (T2DM), particularly in preclinical models 19. Evidence from cellular, animal, and human studies highlights their roles in insulin signaling, β-cell preservation, inflammation, lipid metabolism, oxidative stress, and immune modulation 20,21,22.

In preclinical models, OA enhances insulin sensitivity by activating AMPK and augmenting Akt phosphorylation in cardiomyocytes, endothelial cells, and smooth muscle cells. Mechanistically, OA prevents the serine phosphorylation of IRS1 induced by TNF-α or palmitate, thereby preserving insulin receptor signaling under lipotoxic conditions 23. In contrast, palmitate activates the JNK/NF-κB pathways and disrupts insulin transduction 24. In vitro, LA strengthens insulin action by inhibiting protein tyrosine phosphatase 1B (PTP1B), increasing Akt phosphorylation, and activating the PI3K/AMPK pathways 25. Unsaturated fatty acids, including OA and LA, also protect pancreatic β-cells against palmitate-induced apoptosis, thereby promoting glycogen synthesis and glucose transport 26.

Both fatty acids significantly influence β-cell function 25,26,27,28,29. OA stimulates insulin secretion, reduces oxidative and endoplasmic reticulum (ER) stress, and rescues β-cells from palmitate-induced apoptosis 25,26,27. LA likewise protects β-cells; however, chronically high intake—especially in combination with high-sugar diets—may impair insulin secretion via endocannabinoid pathways 28,29.

OA demonstrates robust anti-inflammatory actions by increasing membrane fluidity, displacing arachidonic acid, reducing pro-inflammatory eicosanoids, and suppressing JNK/NF-κB activation while elevating IL-10 and adiponectin levels 28,30. Unlike saturated fats, OA does not activate the NLRP3 inflammasome 30. LA exerts more complex effects: it can suppress adaptive immune responses but may enhance innate immune activation 31. Conversely, moderate LA intake generally improves adipose tissue function via PPAR-γ activation 32.

Both fatty acids improve lipid metabolism through distinct pathways 18,33. OA protects against intracellular lipotoxicity by channeling saturated fats into triglyceride pools and enhancing mitochondrial β-oxidation 34. LA improves systemic lipid profiles by lowering LDL cholesterol, upregulating hepatic LDL receptors, and enriching adipose tissue PUFA pools 35. OA also exerts antioxidant and cytoprotective effects, lowering reactive oxygen species (ROS) and stabilizing mitochondria 4,27. Conversely, LA is more prone to peroxidation, carrying theoretical risks at very high intakes; however, clinical evidence regarding its role in oxidative stress in humans remains limited 36,37.

Taken together, OA and LA act through overlapping but distinct mechanisms to improve insulin sensitivity, reduce lipotoxic stress, and protect against diabetes-related complications 18,21. Their complementary roles suggest that a balanced dietary intake of MUFA- and PUFA-rich foods provides synergistic benefits in T2DM management.

The evidence reviewed highlights the multifaceted roles of oleic acid (OA, a MUFA) and linoleic acid (LA, a PUFA) in the management of type 2 diabetes mellitus (T2DM), underscoring their complementary contributions to metabolic regulation. Mechanistically, OA enhances insulin signaling by activating AMPK and Akt, preserving IRS1 function under lipotoxic conditions, and supporting β-cell insulin secretion, while counteracting the deleterious effects of saturated fatty acids such as palmitate 27. LA strengthens insulin action indirectly by inhibiting protein tyrosine phosphatase 1B (PTP1B), thereby amplifying the Akt and PI3K/AMPK pathways and protecting β-cells from lipotoxic stress 25. These complementary mechanisms highlight the potential of both fatty acids to preserve metabolic homeostasis under conditions of inflammation and nutrient excess 21,33.

Beyond glucose metabolism, OA demonstrates consistent anti-inflammatory and lipid-modulating properties 18. By displacing arachidonic acid in cellular membranes and suppressing cytokine-driven signaling pathways, OA reduces pro-inflammatory mediators while promoting an anti-inflammatory cytokine profile characterized by increased IL-10 and adiponectin levels 18. LA exerts more complex and context-dependent effects 31. While it can suppress adaptive immune responses by reducing Th1/Th17 differentiation and cytokine release, it may simultaneously enhance innate immune activation in neutrophils and macrophages 25,31,32. Human studies generally suggest that moderate LA intake does not exacerbate inflammation and may modestly improve adipose tissue function through PPAR-γ activation and increased adiponectin secretion 48. Thus, OA provides consistent anti-inflammatory protection 18, whereas LA modulates immune responses bidirectionally 50.

Both fatty acids contribute to improved lipid metabolism through distinct pathways 18,33. OA protects against intracellular lipotoxicity by channeling saturated fats into neutral triglyceride pools and enhancing mitochondrial β-oxidation, thereby preventing toxic lipid accumulation 34. LA improves systemic lipid profiles by lowering LDL cholesterol, upregulating hepatic LDL receptors, and shifting adipose tissue toward healthier PUFA-rich pools 35. Together, these actions reduce lipotoxic stress and support insulin sensitivity, further reinforcing their complementary metabolic roles 21.

In terms of oxidative stress, OA exerts strong antioxidant and cytoprotective effects, lowering reactive oxygen species (ROS) and reinforcing mitochondrial stability in β-cells, muscle, and endothelial cells 4,27. LA, being more prone to peroxidation, carries a theoretical risk of oxidative damage at very high intakes 36,37. However, human studies evaluating standard dietary levels do not show significant increases in oxidative biomarkers, and its insulin-sensitizing and lipid-modulating effects generally outweigh the potential risks 36,37. OA therefore provides more consistent direct antioxidant protection, while LA requires moderation to avoid peroxidative stress 57.

Despite the breadth of the evidence reviewed, the absence of a systematic methodology remains a major limitation. Although multiple databases were searched to capture a wide range of studies, the review process was narrative rather than systematic. Without a reproducible search strategy, it is difficult to guarantee that all relevant studies were included, and it is possible that contradictory findings may have been overlooked. This limitation undermines both transparency and reproducibility, which are essential for scientific rigor, and thus must be explicitly acknowledged.

Another limitation pertains to the heterogeneity of dietary interventions and the potential for residual confounding in observational studies. Clinical trials and cohort studies often combine whole foods (such as olive oil or nuts), supplemented diets, and isolated fatty acids; however, these are not metabolically equivalent. This variability complicates data interpretation and makes it challenging to isolate the independent metabolic effects of oleic and linoleic acids. In observational studies, higher oleic acid intake frequently correlates with healthier dietary patterns, while linoleic acid intake may reflect a broader dietary composition. Even with statistical adjustments, disentangling these specific lipid effects from overall lifestyle factors remains difficult, leaving residual confounding as an unresolved issue.

Finally, limited geographic and ethnic diversity, along with the inability to assess publication bias, further constrain the evidence base. Most studies have been conducted in Western populations, with relatively little data derived from African, Asian, or Latin American cohorts. Given the genetic and cultural differences in dietary patterns, the generalizability of these findings across global populations remains uncertain. In addition, publication bias cannot be excluded, as positive findings are more likely to be published than null or negative results. Dose-dependent risks also require careful consideration: excessive oleic acid intake has been linked to adipogenesis 35, while excessive linoleic acid in high-sugar contexts may impair β-cell insulin secretion via endocannabinoid pathways 29,35. Although these risks have been identified, they remain insufficiently quantified. Collectively, these limitations highlight the need for long-term randomized controlled trials across diverse populations, utilizing systematic methodologies and explicit strategies to detect and mitigate publication bias.

The complementary actions of OA and LA underscore the importance of a balanced dietary intake in T2DM management. OA exerts consistent anti-inflammatory, antioxidant, and β-cell protective effects, while LA contributes to systemic lipid improvements and immune modulation 27,60. Together, these fatty acids enhance insulin sensitivity, reduce lipotoxic stress, and mitigate diabetes-related complications 18.

Clinically, substituting saturated fats with MUFA- and PUFA-rich foods represents a practical strategy to improve metabolic outcomes 18. Olive oil, nuts, seeds, and vegetable oils are accessible dietary sources that can be readily incorporated into daily diets 33. Moderate consumption of both OA and LA appears beneficial, whereas excessive intake may pose potential metabolic risks 57. Very high LA intake coupled with high-sugar diets has been linked to impaired β-cell insulin secretion, while excessive OA consumption may promote adipogenesis, thereby highlighting the need for dietary moderation 35,46.

The cardiometabolic benefits of these fatty acids are particularly relevant in T2DM, a condition characterized by a markedly elevated cardiovascular risk 18. The antioxidant properties of OA and the LDL-lowering effects of LA act synergistically to reduce oxidative stress and improve lipid profiles 21, offering dual protection against diabetes-related cardiovascular complications. Personalized nutrition approaches may further optimize clinical outcomes, as genetic, metabolic, and lifestyle factors significantly influence fatty acid metabolism and individual responsiveness 18.

Future research should prioritize long-term randomized controlled trials to establish optimal intake ranges, clarify dose-dependent effects, and explore the synergistic interactions between MUFAs and PUFAs, thereby refining dietary guidelines for individualized diabetes care.

Oleic acid (a MUFA) and linoleic acid (a PUFA) play complementary but distinct roles in the management of T2DM. OA enhances insulin signaling, reduces inflammation, protects β-cell viability, and provides antioxidant defenses, while LA improves lipid handling, lowers LDL cholesterol, and modulates immune responses in a context-dependent manner. Together, they mitigate lipotoxic stress, enhance insulin sensitivity, and reduce cardiometabolic risk, thereby underscoring their dietary relevance. Clinical evidence supports replacing saturated fats with MUFA- and PUFA-rich foods, such as olive oil, nuts, seeds, and vegetable oils. However, dose-dependent effects and methodological limitations must be considered, as excessive intake may pose metabolic risks. Personalized nutrition approaches may further optimize clinical outcomes. Future trials should define optimal intake ranges and clarify synergistic interactions, thereby supporting balanced consumption to improve overall metabolic health.

AMPK: AMP-activated protein kinase; DAG: Diacylglycerol; ER: Endoplasmic reticulum; GLUT4: Glucose transporter type 4; GPR119: G protein-coupled receptor 119; HbA1c: Glycated hemoglobin; IDF: International Diabetes Federation; IL-1β: Interleukin-1 beta; IL-6: Interleukin-6; IL-10: Interleukin-10; IRS1: Insulin receptor substrate 1; JNK: c-Jun N-terminal kinase; LA: Linoleic acid; LDL: Low-density lipoprotein; MeSH: Medical Subject Headings; MUFA: Monounsaturated fatty acid; NF-κB: Nuclear factor kappa B; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; Nrf2: Nuclear factor erythroid 2-related factor 2; OA: Oleic acid; OEA: Oleoylethanolamide; PI3K: Phosphoinositide 3-kinase; PPAR-α: Peroxisome proliferator-activated receptor alpha; PPAR-γ: Peroxisome proliferator-activated receptor gamma; PTP1B: Protein tyrosine phosphatase 1B; PUFA: Polyunsaturated fatty acid; ROS: Reactive oxygen species; SFA: Saturated fatty acid; T2DM: Type 2 diabetes mellitus; Th1/Th17: T helper type 1 / T helper type 17; TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor-alpha.

The author(s) thank colleagues and peers for their valuable input during manuscript preparation.

All authors equally contributed to this work, read and approved the final manuscript.

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The authors declare that they have not used generative AI (a type of artificial intelligence technology that can produce various types of content including text, imagery, audio and synthetic data).

The authors declare that they have no competing interests.