Omega-3 Polyunsaturated Fatty Acids in Diabetic-Associated Cognitive Dysfunction: A Nutritional Therapeutic Perspective

Chunying Cui¹Yan Yang²Pengfei Liu³Yan Gao²Daqing Song^1*Shangbin Li^4*

• ¹Emergency Department, Jining No.1 People’s Hospital, Jining, Shandong, China
• ²Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
• ³Department of Cardiology, Jining No.1 People’s Hospital, Jining, Shandong, China
• ⁴Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

The intersection between metabolic dysfunction and cognitive impairment represents one of the most pressing yet under-addressed challenges in modern medicine.With the global prevalence of diabetes reaching epidemic proportions, currently affecting more than 800 million adults worldwide, the neurological sequelae of this condition-particularly diabetes-associated cognitive dysfunction (DACD)-have emerged as a critical public health concern requiring immediate attention (1). DACD manifests through progressive memory impairment, executive function decline, and accelerated neurodegenerative processes (2,3). These neurological deficits significantly impair quality of life while simultaneously exacerbating diabetes selfmanagement challenges, thereby establishing a detrimental feedback loop between metabolic dysregulation and cognitive deterioration. Although the mechanisms underlying cognitive dysfunction in patients with diabetes are currently unclear, emerging evidence suggests that the interplay of insulin resistance (IR), chronic neuroinflammation, synaptic dysfunction, and gut-brain axis dysregulation are pivotal drivers of DACD pathogenesis (4)(5)(6). Contemporary therapeutic strategies for DACD demonstrate limited efficacy, predominantly emphasizing glycemic management while inadequately addressing the complex pathophysiology of diabetes-induced neural injury. This therapeutic gap highlights the critical need for interventions that simultaneously target the metabolic, inflammatory, and neurodegenerative components of DACD. Accumulating evidence suggests that omega-3 polyunsaturated fatty acids (PUFAs), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may represent promising therapeutic candidates for DACD. (18). Sirtuin1 (SIRT1) is a conservative nicotinamide adenine dinucleotide (NAD) + -dependent deacetylase that is mainly located in the nucleus, which closely correlates with mitochondrial biogenesis, lipid metabolism, and metabolic fluxes (19).Available evidence suggests that omega-3 PUFAs enhance mitochondrial biogenesis and oxidative metabolism by upregulating SIRT1 expression, which in turn counteracts diabetes-induced cerebral hypometabolism (20,21). The pleiotropic actions of omega- that correlate strongly with observed cognitive impairments (26). Furthermore, in db/db mice, the hyperglycemic environment of diabetes stimulates microglia to produce reactive oxygen species and activates the NF-κB/NLRP3 signaling pathway, leading to the production of NLRP3 inflammasome (e.g., IL1β, IL6, and IL18), which in turn mediates cognitive dysfunction (27). Oxidative stress is a major pathogenic culprit that leads to metabolic anomalies, as well as neurodegeneration and aging. Accumulating preclinical and clinical studies suggest that oxidative stress contributes to neuronal loss and synaptic disruption through impairment of mitochondrial homeostasis in the brain, ultimately resulting in cognitive dysfunction (28,29).Omega-3 PUFAs, particularly DHA and EPA, exhibit multifaceted neuroprotective effects in DACD by modulating interconnected inflammatory and oxidative pathways.First, omega-3 PUFAs mitigate chronic low-grade neuroinflammation associated with hyperglycemia by inhibiting the release of proinflammatory cytokines (e.g., IL-1β, TNF-α) and NF-κB inflammatory signaling pathway transduction (30,31). Second, they inhibit inflammasome activation (e.g., NLRP3) by reducing oxidative stress and mitochondrial dysfunction, critical drivers of neuronal damage in diabetes (32). Third, omega-3 PUFAs regulate microglia-mediated synaptic pruning and plasticity by suppressing 12/15-lipoxygenase (LOX)/12-HETE signaling, thereby preventing excessive phagocytosis of synaptic elements during neurodevelopment (33).Additionally, omega-3 PUFAs are indispensable components of cell membranes and play an important role in maintaining the membrane structural integrity and fluidity of immune and neuronal cells (31). Moreover, DHA integrates into neuronal membranes, stabilizing lipid rafts and suppressing microglial overactivation triggered by advanced glycation end products (34). Finally, omega-3 PUFAs, particularly EPA, mitigate DACD by suppressing oxidative stress through activation of the P62/KEAP1/NRF2 antioxidant pathway, which reduces reactive oxygen species generation and subsequent neuronal damage (35). In conclusion, omega-3 PUFAs represent a promising dietary intervention targeting the neuroinflammatory-oxidative axis in DACD. Emerging as a neural epicenter of DACD, the hippocampus exhibits signature neurodegenerative changes -particularly synaptic diminution and dendritic retractionthat correlate strongly with clinical disease progression. The function of the hippocampus depends on communication among neurons, and the synapse is the basic information-processing unit that mediates neuronal communication. Preclinical investigations in diabetic models reveal marked synaptic alterations, characterized by diminished spine density, downregulation of synaptic scaffolding proteins (postsynaptic density protein-95, microtubule-associated protein 2), and ultrastructural abnormalities including truncated postsynaptic densities and expanded synaptic clefts (36,37). These pathological changes correlate strongly with cognitive deficits observed in db/db mice.Omega-3 PUFAs, notably DHA which comprises approximately 30% of brain phospholipid content, exhibit significant neuroprotective effects at synaptic sites.Experimental studies demonstrate their ability to enhance long-term potentiation, maintain synaptic ultrastructural integrity, and increase expression of activity-regulated cytoskeleton-associated protein, a critical molecular mediator of synaptic plasticity and memory consolidation processes (38,39). Phosphatidylserine is predominantly localized on the cytoplasmic side of neuronal cell membranes, in facilitating the action of signaling proteins that underpin neuronal survival, neurite growth, and synaptogenesis. DHA orchestrates neural membrane homeostasis through dual actionsstimulating phosphatidylserine-dependent signaling hubs for neurodevelopment while structurally optimizing bilayer fluidity for synaptic transmission efficiency (40). This bifunctional capacity underlies its essential role in neuronal circuit formation and function.Transcending their membrane-stabilizing functions, omega-3 PUFAs emerge as master regulators of neurotrophic signaling networks, orchestrating complex interactions between growth factor systems and synaptic efficacy pathways. Dietary supplementation with DHA enhances brain-derived neurotrophic factor (BDNF) expression via cAMP response element-binding protein-dependent transcriptional activation, thereby promoting synaptogenesis and supporting cognitive processes (41,42). DHA-derived neuroprotectin D1 provides additional protection by balancing Bcl-2/Bax ratios to inhibit apoptosis and promote autophagy of damaged organelles. DHA can also clear damaged mitochondria and alleviate mitochondrial dysfunction through PINK1/Parkin mediated mitophagy and also increases acetylcholine and γ-aminobutyric acid levels while decreasing glutamate levels, ultimately counteracting the synaptotoxic effects of diabetes (43,44). Additionally, omega-3 PUFAs as master regulators of a gutbrain circuit, stimulating short-chain fatty acids (SCFA) production that bridges microbial metabolism to neuronal plasticity. Notably, these synaptic alterations may be further modulated by gut-derived inflammatory signals, as discussed in the following gut-brain axis section. The gut-brain axis represents a sophisticated bidirectional communication network linking gut microbiota with brain function through immune, neuroendocrine, and metabolic pathways. Diabetes-associated gut dysbiosis orchestrates a dual-hit mechanism: SCFAs depletion undermines epithelial integrity while lipopolysaccharide and toll-like receptor 4 engagement activate pro-inflammatory NF-κB cascades, establishing a systemic-to-neural inflammatory axis (45,46). Dysbiosis of gut microbiota can also induce deficits in synaptic plasticity through the ER stressmediated PERK signaling pathway (47). These pathological changes correlate strongly with the microbial alterations and intestinal damage observed in diabetic patients.Omega-3 PUFAs, especially EPA and DHA, emerge as potent modulators of this axis.Omega-3 PUFAs modulate gut microbiota diversity, enriching beneficial taxa (e.g., Bifidobacterium, Lactobacillus) and increasing SCFAs production, which enhances intestinal barrier integrity (11,48). SCFAs, particularly butyrate, cross the BBB to suppress microglial activation and upregulate BDNF expression. Omega-3 PUFAs and DHA also up-regulated expression of the intestinal tight junction protein occludin and zonula occluden-1, improved the intestinal barrier functions and repaired BBB damage (49). Moreover, omega-3-derived endocannabinoids interact with gut vagal afferents to regulate appetite and glucose homeostasis, creating a holistic approach to metabolic and cognitive protection in diabetes (46,50). Omega-3 PUFAs, especially DHA and EPA, exhibit pleiotropic therapeutic effects against DACD through multiple complementary mechanisms (Figure 1). These