The work was funded by FAPESP and focused on Goto-Kakizaki rats, a well established animal model used to study non-obese type 2 diabetes. Type 2 diabetes is marked by high blood sugar that occurs when insulin, the hormone that helps move glucose from the blood into cells, does not work effectively.

Fish Oil and Insulin Resistance

Omega-3 supplements, including fish oil, are often used by people with cardiovascular disease and type 2 diabetes. However, scientists still know much less about how these fatty acids affect insulin resistance when obesity is not involved.

That question matters because obesity is one of the strongest risk factors for type 2 diabetes, but it is not the whole story. An estimated 10% to 20% of people with type 2 diabetes worldwide are not obese. For these patients, the biological roots of insulin resistance may differ from the better known obesity-linked pathways.

In the study, researchers gave the rats fish oil at a dose of 2 grams per kilogram of body weight (equivalent to 540 mg/g of eicosapentaenoic acid, or EPA, and 100 mg/g of docosahexaenoic acid, or DHA) three times weekly for eight weeks. By the end of the experiment, the treated animals showed lower insulin resistance, better blood sugar control, reduced inflammatory markers, and improvements in several lipid measures, including total cholesterol, LDL ("bad cholesterol") and triglycerides.

The results came from preclinical experiments, so they do not prove that fish oil will have the same effects in people. Still, the findings point to inflammation as a powerful target in non-obese diabetes and suggest that omega-3 fatty acids deserve closer study in this group.

A Shift in Immune Cells

"Our experiments involved Goto-Kakizaki [GK] rats, an animal model for non-obese type 2 diabetes. We found that insulin resistance can be reduced in these animals by modulating the inflammatory response so as to change the profile of defense cells [lymphocytes] from a pro-inflammatory state to an anti-inflammatory state. This process parallels the response of obese individuals with insulin resistance to omega-3 fatty acid supplementation," said Rui Curi, Director of Butantan Institute's Education Center, Professor of Interdisciplinary Graduate Studies in Health Sciences at Cruzeiro do Sul University (UNICSUL), and coordinator of the study.

Lymphocytes are white blood cells that help direct the adaptive immune response. When their behavior changes, the effects can spread through the immune system and influence other cells involved in inflammation.

"In previous studies, we observed alterations in both lymphocytes and macrophages [large white blood cells that often reside in adipose tissue and are part of the innate immune system, engulfing and destroying pathogens] in non-obese rats with insulin resistance. In such cases, these cells produce more pro-inflammatory cytokines, as is central in obese people with diabetes," Curi explained.

"The main aim of the study, therefore, was to find out whether supplementation with fish oil [rich in omega-3] could reverse specific alterations in lymphocytes that had been observed in previous research. Our findings increased our knowledge of the link between inflammation and insulin resistance in non-obese animals, confirming that this is a key factor in diabetes even in the absence of obesity," said Renata Gorjão, last author of the article, and Co-Director of UNICSUL's Program of Graduate Studies in Health Sciences.

Inflammation Without Obesity

The Nutrients study, conducted during the PhD candidacy of Tiago Bertola Lobato, was part of a broader FAPESP-supported project exploring how insulin resistance develops in non-obese animals.

Curi noted that obesity is a major diabetes risk factor, but not the only one. In people who develop diabetes without obesity, one leading hypothesis is that genetic factors may play an important role. In another study published in Cells, Curi, Gorjão, and colleagues investigated whether delayed intestinal transit might also contribute to insulin resistance in non-obese individuals.

"Most obese people have chronic low-level inflammation, which is known to affect the insulin signaling pathways. Adipose tissue, which is augmented in obesity, releases pro-inflammatory cytokines that affect the insulin signaling pathways, promoting insulin resistance. In the non-obese model, this impactful characteristic of adipose tissue is absent, but systemic inflammation is present," Curi said.

The group had previously shown systemic inflammation in non-obese GK rats with insulin resistance in a study published in the International Journal of Molecular Sciences.

Another paper from the same project reported that anti-inflammatory defenses appear to break down early in non-obese GK rats with insulin resistance. Lymph nodes (part of the immune system) from newly weaned 21-day-old GK pups already showed reduced markers of regulatory T-cells (Tregs, cells with anti-inflammatory characteristics). The researchers also detected other early inflammatory changes. That work was published in FEBS Letters, a journal of the Federation of European Biochemical Societies.

How Omega-3s May Help

The Nutrients study suggests that fish oil may work by moving immune activity away from a damaging inflammatory pattern and toward a more protective one.

"Fish oil supplementation reversed this pro-inflammatory profile, displaying a significant anti-inflammatory effect and reducing polarization of Th1 and Th17 cells [lymphocyte subtypes that perform crucial functions in inflammation], followed by a rise in the percentage of Tregs, which can inhibit the activation of pro-inflammatory lymphocytes. Thus the action of omega-3 fatty acids on lymphocytes, modulating them from a pro-inflammatory state to an anti-inflammatory state, may have triggered the reduction in insulin resistance in these animals," Lobato said.

That immune shift is important because insulin resistance is not only a problem of sugar metabolism. It is also deeply connected to inflammation. When inflammatory signals remain elevated, they can interfere with insulin signaling and make it harder for cells to respond to the hormone.

The study adds to a growing view of type 2 diabetes as a disease shaped by both metabolism and the immune system. In this case, fish oil appeared to improve blood sugar regulation not simply by changing fat levels, but by changing the inflammatory environment that helps drive insulin resistance.

What Later Studies Add

Since the Nutrients paper was published, related human research has continued to examine how omega-3 fatty acids may influence early diabetes risk and metabolic health.

A 2025 double blind randomized controlled trial in Food and Function tested fish oil supplementation in healthy middle aged and older adults. Over 12 weeks, the fish oil groups had dose related increases in serum EPA and DHA. The researchers also reported decreases in fasting insulin and the HOMA-IR index, a common marker of insulin resistance. Fasting blood glucose trended downward across groups, and several lipid related measures also improved.

Another 2024 analysis in Nutrition and Diabetes used modeling data from 161 patients with type 2 diabetes to explore the relationship between omega-3 levels and HbA1c, a longer term marker of blood sugar control. The authors reported a dose related association and proposed that omega-3 intake could be studied in a more individualized way, while also noting that the role of omega-3s in type 2 diabetes remains debated.

Together, these studies do not settle the question of whether fish oil should be used to manage diabetes. Human evidence remains mixed, and the Brazilian study was conducted in animals, not people. However, the newer findings are consistent with the idea that omega-3 fatty acids may affect insulin resistance and inflammation in ways worth testing more carefully.

More Research Still Needed

Despite the promising findings, the researchers stressed that the results should be interpreted cautiously. Animal studies are useful for uncovering biological mechanisms, but clinical trials are needed before scientists can know whether the same strategy works in people with non-obese type 2 diabetes.

"These studies involved well-established experimental models that mimic insulin resistance in non-obese individuals. Trials in humans are needed to estimate the ideal dose and the most indicated type of omega-3 fatty acid," Curi said.

For now, the study offers a compelling clue: in diabetes, body weight may not be the only driver of insulin resistance. Inflammation can play a central role even without obesity, and fish oil may help reveal how that hidden process can be changed.