Consumption of omega-3 weakens insulin resistance in non-obese rats, study shows

A Brazilian study published in the journal Nutrients suggests that fish oil can weaken insulin resistance and reduce glucose intolerance by modulating the body’s inflammatory response. 

The findings of the study, which was funded by FAPESP, were based on experiments with rats, which were not obese but exhibited a condition similar to type 2 diabetes, a disease characterized by elevated blood sugar due to reduced action of the hormone insulin.

As the authors explain, supplementation with omega-3 fatty acids such as those present in fish oil has been prescribed for individuals with cardiovascular problems and type 2 diabetes, but the effects of these nutrients on insulin resistance without obesity are poorly understood.

In this study, the researchers observed that administration of 2 grams of fish oil 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 per week for eight weeks reduced insulin resistance in non-obese rats, which also displayed improved levels of blood sugar, inflammatory markers and lipid features, including total cholesterol, LDL (“bad cholesterol”) and triglycerides.

Although the findings resulted from preclinical trials, they offer hope for non-obese type 2 diabetes patients, or 10%-20% of the worldwide total with the disease.

“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.

Alterations in lymphocytes, white blood cells that orchestrate the adaptive immune response, tend to have an impact on other immune system cells, triggering a cascade effect. “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.

Systemic inflammation

The investigation described in the Nutrients article, conducted during the PhD candidacy of Tiago Bertola Lobato, was part of a larger project supported by FAPESP that is deepening scientists’ understanding of insulin resistance in non-obese animals.

According to Curi, obesity is a major risk factor for diabetes, albeit not the only one. In the case of non-obese diabetes patients, the primary hypothesis is that the cause is genetic. In an article published in the journal Cells, Curi, Gorjão et al. describe an investigation into the possibility that insulin resistance in the non-obese may also be linked to delayed intestinal transit.

“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.

Systemic inflammation in non-obese GK rats with insulin resistance was demonstrated by the group in a previous study published in the International Journal of Molecular Sciences. 

In another article relating to the same project, the researchers reported an early breakdown of anti-inflammatory mechanisms in non-obese GK rats with insulin resistance. Lymph nodes (part of the immune system) in newly weaned 21-day-old GK pups already exhibited a reduction in markers of regulatory T-cells (Tregs, cells with anti-inflammatory characteristics). Other early inflammatory alterations were also observed in the rats. The article is published in FEBS Letters, a journal of the Federation of European Biochemical Societies.

“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.

Despite the good news, the researchers stressed that more research is needed to confirm their findings. “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.

About FAPESP

The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the state of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration.