Obesity is strongly associated with type 2 diabetes mellitus (T2DM) (1). Adipose tissue can secrete proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα), which contribute to insulin resistance (IR) (2). Adiponectin is also involved on inflammatory response, insulin sensibility and energetic balance. Chronic inflammation associated with obesity contributes to increased prevalence of T2DM (3, 4). Chronic inflammatory responses may also be induced by atherosclerosis, diabetes, rheumatoid arthritis, inflammatory bowel disease, cancer, or neurodegenerative disease (5). The Mediterranean diet (DietMed), which includes an adequate amount of extra-virgin olive oil, has been shown to improve the pathophysiology associated with obesity, T2DM, cardiovascular diseases (6–10), and reduce inflammatory cytokines (5, 11–13). The major cytokines involved in the inflammatory pathophysiology i.e. TNF-α and IL-6 are reduced in obese individuals receiving the DietMed intervention (14).

Previous studies of T2DM individuals with different ranges of body mass index (BMI) reported beneficial effects of DietMed on glycemic profiles (12, 15–18). The effects of olive oil on inflammatory markers in eutrophic, overweight and obese individuals with T2DM have also been reported (3, 19–24). These promising benefits of DietMed may be related to the anti-inflammatory and antioxidant properties of extra-virgin olive oil, as the latter is rich in monounsaturated fatty acids (MUFAs), polyphenols, hydrocarbons, phytosterols, and tocopherols (25). However, most of these studies were conducted in Mediterranean countries and the effect of an olive oil-rich diet may not be extrapolated to other dietary patterns. In addition, it may be difficult to implement DietMed in other countries where such a diet is not part of their usual diet. Furthermore, there is a lack of randomized clinical trials evaluating the role of olive oil alone or in combination with another dietary intervention pattern in reducing inflammatory markers among adults with T2DM and class II/III obesity.

Given the serious complications associated with T2DM and severe obesity and the limited interventions in this area, this study aimed to evaluate the effects of extra-virgin olive oil and the traditional Brazilian diet (DietBra) (26, 27) on inflammatory markers and glycemic profiles in adults with both T2DM and class II/III obesity. This study is clinically relevant since it can contribute to improve the treatment of individuals with both clinical conditions.

A total of 40 participants with both T2DM and class II/III obesity were eligible to entry the study. After randomization, we found no sociodemographic characteristics or study outcomes differences between the groups at baseline ( Table 1 ).

At baseline the protein intake (% TEV) in the Oil Olive group was 18.1 ± 4.3 (Mean ± SD), in the Olive Oil + DieTBra group was 18.7 ± 4.7 (Mean ± SD) and the energy intake (kcal/day) of the Oil Olive group was 1674.8 ± 610.8 (Mean ± SD), in the Olive Oil + DieTBra group was 1701.1 ± 1021.1 (Mean ± SD). There was no statistical difference in both groups.

During the intervention, the intake of olive oil was 37.88 ± 12.50 mL/day for the olive oil group and 37.71 ± 12.23 mL/day for the olive oil + DietBra group, with no significant difference between groups (p = 0.484).

At the end of the intervention, the olive oil + DietBra group had significantly lower fasting insulin (p = 0.047) while other glycemic parameters did not differ compared to those in the olive oil only group ( Figure 2 ). The serum levels of inflammatory cytokines IL-1α (p = 0.006) and adiponectin (p=0.0087) were lower and TNFα levels were higher (p = 0.037) in the olive oil + DietBra group compared to those in the olive oil only group ( Figure 3 ).

Compared to the baseline values, significant reductions in BMI and weight were observed in the olive oil + DietBra group (p = 0.015) at the end of the intervention but not in the olive oil group ( Figure 4 ). Numerical and descriptive data are presented in the Tables 2 – 4 .

Table 2 shows no significant difference in IL-10 levels in both intervention groups. However, in Table 1 we can observe that this anti-inflammatory cytokine had increased after the olive oil intervention. There was an increase in both intervention groups, but this increase was statistically significant only in olive oil group.

As far as we know, this is the first RCT to assess how extra-virgin olive oil and DietBra affects inflammatory parameters and glycemic profiles in adults with both T2DM and class II/III obesity. Our main findings showed that the supplementation with extra virgin olive oil combined with the DietBra can decrease fasting insulin, inflammation markers such as IL-1α and adiponectin, as well as weight and BMI in class II/III obese adults with T2DM. These results are clinically relevant and can contribute to the current knowledge on T2DM and severe obesity, as these two nutritional interventions are relatively inexpensive with easy adherence in many countries that have similar dietary patterns.

Previous studies of olive oil have been conducted in overweight/obese T2DM individuals. However, in these studies olive oil was delivered in capsules and compared to other sources of isolated fats such as fish oil (3, 23, 24). In our study, olive oil was offered as a real food, which is an important aspect in nutritional interventions. Real food may be more favorable and effective to be incorporated into one’s daily food routine compared to adding more olive oil capsules to T2DM individuals’ existing medications.

The reduction in BMI in the olive oil + DietBra group is corroborated by a systematic review and meta-analysis investigating DietMed, also rich in olive oil, that reported a significant reduction in weight and BMI (45). Thus, appropriate eating plans compatible with regional food habits should be emphasized, since there is a greater probability of diet adherence and related benefits (35, 46). Furthermore, a study of dietary patterns provides more accurate and relevant results than a study of nutrients in isolation (47, 48). The food intake, macronutrients, and caloric intake of the participants at baseline have been previous analyzed, which showed no significant differences between groups (26, 49).

Although the intervention group i.e. olive oil + DietBra had greater weight loss and BMI reduction, the percentage fat was not significantly reduced. Therefore, it is likely that this intervention impacted on lean mass reduction. Reduction on lean mass should be avoid not only in individuals with class II/III obesity but also everybody in a weight loss treatment or dietary patterns modification. Weight loss with no percentage of body fat loss can indicated lean mass reduction which could lead to sarcopenic obesity, an inadequate clinical outcome in adults such as the population study. The ideal weight loss occurs when there is more percentage fat reduction and lean mass preservation and it should be achieved through a physical activity routine including both resistance training and aerobic exercises. A high body fat percentage is also associated with adiponectin production and tissue insulin resistance which may lead to catabolic effects on muscle mass (50–53). Because the high-fat diet has been prescribed with the inclusion of a healthy oil (extra virgin olive oil) the hypothesis was that it could reduce the pro-inflammatory cytokines when consumed with a healthy diet such as the Traditional Brazilian Diet.

Despite the lack of significant difference in the reduction of IL-1α between groups, the observed reduction is clinically relevant in both interventions i.e. approximately 50% reduction compared to the baseline values. IL-1α is an important inflammatory mediator and regulates micro-inflammation observed in participants with obesity and/or diabetes.

Furthermore, this study did not find significant changes in IL-6 levels with the dietary interventions. A new meta-analysis review with thirty RCTs using olive oil presented a reduction in IL-6 levels compared to the controls (54). The main difference between this study and others is the clinical characteristics of the participants. On this study the participants have both severe obesity and T2DM, which might be associated with different blood cytokine profiles that may hinder substantial reductions in cytokines levels in response to the dietary interventions. Therefore, our findings demonstrate that the understanding of inflammation in chronic diseases, such as diabetes and obesity, is rather limited and the anti-inflammatory effect of olive oil outside the context of DietMed requires further investigation (18, 55).

TNFα is an important inflammatory mediator normally present in high concentrations in the bloodstream of obese individuals (56). However, in this study, TNFα did not decrease at the end of the intervention in the olive oil + DietBra group. Notably, a positive correlation between TNFα levels and the development of insulin resistance has been previous reported in obese individuals (57). It is difficult to explain why the olive oil + DietBra intervention reduced the serum levels of insulin but not TNFα. A possible explanation may be the fact that TNFα is produced mainly by the adipose tissue in individuals with obesity (58), and there was no significant change in the percentage of body fat in this group despite the reduction in BMI. As a result, the intervention may not be able to affect the production of TNFα in these individuals. Additionally, the onset of insulin resistance is a complex process that involves various metabolic pathways (59). The improved serum levels of insulin by olive oil + DietBra may be mediated by factors other than TNFα, since other inflammatory markers were also reduced.

In this study, the olive oil + DietBra group had increased levels of TNF-α and decreased levels of adiponectin, which is consistent with previous research indicating that TNF-α suppresses adiponectin dimerization and secretion in adipocytes (60). Moreover, mice deficient in adiponectin presented higher levels of TNF-α in the blood, which was reduced when treated with adiponectin (61). Besides that, we highlight that there are controversies regarding the effect of olive oil on adiponectin and TNF-α levels. A study has shown that oleic acid in combination with the antioxidant phenol hydroxytyrosol prevented the suppression of adiponectin induced by TNF-α in adipocytes (62). However, whether this combination could be reflected in a diet remains debatable. On the other hand, Luo et al. (63) showed that treating adipocytes with oleic acid reduced the mRNA levels of adiponectin. Therefore, the role of olive oil rich in oleic acid in increasing TNF-α and reducing adiponectin needs further investigation.

Unfortunately, the analysis of covariance evaluating the influence of covariates (e.g. BMI and glycemic profiles) on the outcomes in both intervention groups could not be performed considering that the following requirements were not met: 1) the study outcomes were not normally distributed, and 2) no linear relationship existed between the covariates and the response variable (64).

The absence of a control group with no dietary intervention (e.g. Brazilian diet group alone) in this study could be a potential limitation. However, having a “no treatment” group is not ethically feasible for this population. For some inflammatory markers such as MCP-1, the methodology used may have not been efficient for the evaluation in this specific group, since the values from several individuals were below the detection limit. The technique used for the measurement of TNFα was the same used for the measurement of IL-10, monocyte chemoattractant protein 1 (MCP-1), through the Bio-Plex ^® Pro Human Cytokine 27-Plex kit (Bio-Rad, Hercules, CA), according to the manufacturer’s instructions Bio-Plex 200. It is a technique used worldwide and is therefore widely recommended. There is a limit of detection of the test, which for TNF-α is 1.13 pg/ml, according to what was done in the BioRad (https://www.biorad.com/webroot/web/pdf/lsr/literature/Bulletin_6335.pdf). It is possible that the levels found in this group of obese people are below the detection levels of the Bio-Plex 200 curve, causing the values to be very low, according to the sensitivity of the test. Nevertheless, the study has several strengths. The nutritional intervention with DietBra was based on natural and minimally processed foods, and extra-virgin olive oil was supplemented in the food form, not in capsules. There was a low loss to follow-up rate (15.0%), considering that obese individuals with or without T2DM generally have low adherence to treatments (65, 66). Given the prevalence of around 4% of the general population, it is hard to perform studies with a large number of individuals with both class II/III obesity and T2DM.

Olive oil combined with DietBra decreased fasting insulin, IL-1α and adiponectin, while inducing a reduction in BMI and weight in individuals with T2DM and class II/III obesity. Future studies should consider the use of different amounts of olive oil in combination with DietBra or another healthy dietary pattern, an intervention period longer than 12 weeks and, finally, assessing more inflammatory parameters.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Ethics Committee of the Universidade Federal de Goiás (protocol no. 747.792/2014). The patients/participants provided their written informed consent to participate in this study.

Conceptualization, ES. Methodology, ES and LR. Formal analysis, ES, LR, DR, and MN. Investigation, ES, LR, APR, DR, and AC. Resources, ES, APR, MN, and AJ-K. Data curation, ES, MN, and AJ-K. Writing, ES, LR, AC, MN, AJ-K, ATR, and CO. Review and editing, ES, MN, AJ-K, ATR, and CO. Supervision, ES and AJ-K. Project administration, ES. Funding acquisition, ES, APR, MN, and AJ-K. The principal investigator of the DietBra Trial is ES. All authors contributed to the article and approved the submitted version.

FAPEG foundation provided partial funding for the DietBra Trial (grant number 201310267000003). CAPES foundation provided a doctoral scholarship. Instituto Federal Goiano provided partial funding. CO was supported by the Economic and Social Research Council (ESRC) (grant ES/T008822/1).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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