Omega-3 and prediabetes: 'Fish oil' linked to lower risk of type 2 diabetes

The journal Research (Science Partner Journals, AAAS) published a paper by a Chinese-American team, which combined a large population cohort and muscle mechanics. In the UK Biobank database, the researchers followed 48,358 people with prediabetes for an average of 7.8 years and found that habitual intake of fish oil supplements was associated with a 9% lower risk of developing type 2 diabetes. In parallel, models showed that marine omega-3 (DHA and EPA) "tighten" glucose transport in skeletal muscle - they enhance the translocation of the GLUT4 transporter and improve muscle carbohydrate metabolism. This links the "pharmacy pill" to a specific target in the tissue that consumes the lion's share of glucose.

Background of the study

Prediabetes is a “border zone” in which blood sugar is elevated but does not yet reach the criteria for type 2 diabetes. The scale of the problem is enormous and is growing along with diabetes itself: according to the 11th edition of the IDF Diabetes Atlas (2025), 1 in 9 adults (11.1%) already lives with diabetes, and by 2050 the forecast is 1 in 8; a significant proportion of new cases are formed from prediabetes. This is not only about glucose: at the prediabetes stage, atherogenicity accelerates, low-intensity inflammation and the nocturnal metabolic profile is disrupted - this is why “slowing down” the transition to diabetes is considered one of the most beneficial public health strategies.

Where does the metabolism end up? In the skeletal muscle: it takes up to 80% of postprandial glucose under the influence of insulin. The key gateway is the GLUT4 transporter, which in response to the insulin signal quickly “moves” from intracellular depots to the muscle fiber membrane. Disruption of this GLUT4 translocation is the core of insulin resistance; entire “logistics teams” of proteins (Rab-GTPase, SNARE complex and their regulators) are responsible for the movement of vesicles. In parallel, the fate of glucose is affected by the PDH/PDK4 “switch”: when PDK4 is active, glucose oxidation in mitochondria is inhibited, and the muscle is more willing to burn fatty acids - a typical shift in insulin resistance.

Why the focus on omega-3? Marine polyunsaturated fatty acids (EPA/DHA) can theoretically improve muscle insulin sensitivity by influencing membrane composition, inflammatory pathways, and mitochondrial biochemistry. But in humans, the picture has long been mixed: some reviews have found modest improvements in glycemic markers with supplements, while others have found no significant effect on diabetes risk per se. There have been some positive signals at the level of large cohorts - for example, in the UK Biobank, regular fish oil intake was associated with an approximately 9% lower risk of developing T2D - which has prompted the search for a biological mechanism in muscle and factors that personalize the response.

Finally, the “no rose-colored glasses” background: omega-3 supplements are not a universal panacea and carry a risk profile that depends on the dose and the health of the individual. In a large prospective study in BMJ Medicine, regular fish oil intake was associated with a higher risk of atrial fibrillation and stroke in initially healthy individuals, while in those with existing CVD, there was a potential benefit for “transitions” to severe events. This argues for a personalized approach and trials that select not only for phenotype (prediabetes) but also for target tissue (skeletal muscle, GLUT4/PDH axis) and associated risks.

How this was checked and what was “cleaned” from the statistics

The cohort was limited to people with prediabetes at baseline, and new cases of diabetes were searched for in hospital records. "Fish oil" is a self-report of regular supplement intake. The association was processed in multistage models: from basic adjustment for age/sex to extended options, where race, recruitment centers, BMI, education, income, smoking/alcohol, physical activity, family history, as well as other supplements and diet (including the frequency of fatty fish and the integral "healthy dietary score") were additionally taken into account. The signal was stable at a level of ≈-9% to the risk (hazard ratio ~0.91). In addition, the authors found an interaction with variants in the GLUT4 gene (SLC2A4): the genetics of glucose transport modified the benefit of supplements - an important hint for future personalization.

What the experiments showed: from “fish oil” to muscle switch proteins

To go beyond the associations, the authors performed a 10-week DHA/EPA intervention in db/db mice and experiments on human myotubes. In muscles, the omega-3 shifted the metabolome: markers of glucose oxidation, creatine and branched-chain amino acid circuits shifted towards better glucose utilization; glycogen synthase and pyruvate dehydrogenase (PDH) increased, and PDK4, the PDH “brake,” was suppressed. The critical node is GLUT4: DHA/EPA enhanced its translocation to the membrane by increasing Rab-GTPases and t-SNARE proteins, i.e., simplified the “docking” of GLUT4 vesicles with the membrane. In total, this means faster glucose uptake by muscle under the influence of insulin.

Why is this important?

Prediabetes is a "pre-emergency" condition for hundreds of millions of people; in some, it is stable for years, while in others it quickly "falls" into diabetes. New work connects human epidemiology and muscle biology: habitual intake of omega-3 is associated with inhibition of progression, and a plausible muscle mechanism has been demonstrated in the lab - GLUT4 translocation + improvement of the aerobic pathway. An important detail is the genetic interaction in the glucose transporter: this explains why "fish oil" does not work the same for everyone and where to look for selection in future trials.

What this doesn't (yet) prove: A careful reading of the results

The study is not a randomized clinical trial in humans - we are talking about associations in an observational cohort plus preclinical mechanics. "Fish oil" is self-reported, residual confounding is possible (healthy behavior, treatment adherence, etc.), and the dose/form of DHA and EPA in real life varies greatly. Therefore, the next step is an RCT in prediabetes, with recruitment by SLC2A4/GLUT4 genotype and muscle biomarkers of response (e.g., GLUT4 dynamics in biopsies/non-invasive surrogates).

Who might find this especially useful?

• People with prediabetes, whose main problem is insulin resistance of skeletal muscle (often combined with low physical activity).
• Those with glucose transport genetics (GLUT4 zone) are expected to have stronger responses - this is exactly the moderation of the effect that the authors saw in the UK Biobank.
• For patients whose "fish" diet is limited, it is important to remember that supplements are a complement to lifestyle (movement, weight, sleep), not a replacement for it.

Practical meaning

• What you can definitely do:
  • Maintain regular aerobic and strength training - the main driver of GLUT4 translocation;
  • eat fatty sea fish 1-2 times a week as a primary source of DHA/EPA;
  • discuss omega-3 supplements with your doctor if you have prediabetes, especially if your blood profile/diet is "low in omegas."
• What not to do:
  • do not take the news as a “green light” for self-medication with capsules;
  • don't expect quick results without working on your lifestyle;
  • do not ignore the quality/composition of the supplement (DHA/EPA content, purity certification).

What will science ask next?

• Randomized trials of DHA/EPA in prediabetes with glycemic/incident diabetes endpoints stratified by GLUT4 genotypes and muscle markers.
• Dose/Form: DHA vs EPA and combinations, esters vs triglycerides, role of co-protein/exercise in delivering muscle effects.
• Target tissues: microbiota and liver versus skeletal muscle contributions - and long-term tolerability and safety in a real-life prediabetic population.

Research source: Li H. et al. Marine N-3 Fatty Acids Mitigate Hyperglycemia in Prediabetes by Improving Muscular Glucose Transporter 4 Translocation and Glucose Homeostasis. Research, April 29, 2025 (Article 0683). DOI: 10.34133/research.0683