To the best of our knowledge, this is the first RCT analysing the long-term impact of combined training with different intensities, on lipid and inflammatory profile in individuals with T2DM. The main finding was that long-term HIIT aerobic exercise, while combined with RT, can be used to improve the total cholesterol and LDL-C and IL-6 markers in individuals with T2DM. Regarding the MCT group, we observed favourable changes only on IL-6, with no impact on the lipid profile after a 1-year of intervention.
Low-grade systemic inflammation has been independently implicated in metabolic disorders, such as insulin resistance and T2DM, and is typically presented with elevated levels of pro-inflammatory cytokines (i.e. IL-6, TNF-α, and CRP) (24, 25). On the other hand, exercise can be used to prevent or counter the detrimental metabolic effects of elevated pro-inflammatory cytokines on different organs and tissues of the body (12). In our investigation, both the MCT and HIIT combined with RT regimens reduced the circulating levels of IL-6 following 1-year of exercise when compared with the control group, whereas no results were observed for the remaining inflammatory markers. The number of investigations that have analysed the impact of HIIT on the inflammatory profile in T2DM are scarce, with only two short-term interventions (< 12-week duration) reporting no substantial effects on IL-6, TNF-α, and CRP (16, 17).
However, both investigations lacked a non-exercise control group, which would have provided valuable information on the changes occurring in the control group over the investigation period.
Similar results to the ones in our investigation were found with reduced levels of IL-6, as well as CRP, while using a different protocol of high-intensity continuous training, either alone or combined with RT, in individuals with T2DM (26). However, only the combination of aerobic and RT had a significant impact on the circulating levels of TNF-α. Moreover, in overweight/obese individuals without T2DM, short and medium-term interventions have observed a reduction in IL-6 following 2 weeks (27), and 16 weeks of HIIT (28).
Another important finding from this investigation concerns the long-term impact of different exercise permutations on the sCD163 biomarker. Our results suggest that regardless of the exercise group there were no changes on the sCD163. The sCD163 molecule is increased after macrophage activation, with individuals with higher levels of adipose tissue having higher expression of this biomarker (29). In fact, sCD163 has been positively associated with, obesity (6) and T2DM (7). However, little is known about the effects of exercise on sCD163, with no study addressing the impact of different exercise intensities in T2DM. In individuals with non-alcoholic liver disease, a 3-month lifestyle intervention program, with both PA and dietary counselling, reduced the levels of sCD163 (30). In contrast, decreased values have only been observed with dietary-induced weight loss (6), suggesting that sCD163 changes are dependent on body weight loss, particularly that of adipose tissue, which leads to a reduction of infiltrated active macrophages. Nevertheless, even with total and abdominal body fat reduction, as previously reported in the main findings of this study (18), the MCT group did not display corresponding decreases in sCD163 following the 1-year intervention. Future studies are warranted to further understand relationships among exercise training, sCD163, adiposity, in individuals with T2DM.
Some of the proposed mechanisms for the improvements in the inflammatory profile following an exercise intervention are the reduction of visceral fat mass and the increased production of muscular anti-inflammatory myokines (12, 31). The reduction of abdominal obesity, even in the absence of body weight loss, is associated with decreased pro-inflammatory cytokines (25). Another of the mentioned mechanisms relies on the production of exercise myokines, such as IL-6 produced during muscle contraction (32). This specific myokine, when produced in the muscle following exercise, has anti-inflammatory properties, whereas in the sepsis model, IL-6 is preceded by an increase in TNF- α and Il-1β, reflecting a low-grade inflammatory state (33). Acute exercise is, therefore, responsible for increasing IL-6 several-fold in the muscle, leading to the stimulation and production of Interleukine-10 and IL-1 receptor antagonist, which are known for having anti-inflammatory properties (33). This downstream anti-inflammatory cascade is responsible for inhibiting the secretion of other pro-inflammatory cytokines (e.g. TNF-α) (34). The exact mechanism through which HIIT induces this anti-inflammatory effect is not clear, but previous studies suggest that increases in IL-6 are related to exercise intensity, duration, the mass of muscle recruited, and cardiorespiratory fitness (34).
Regular exercise has also been shown to improve the lipid profile in individuals with T2DM (35, 36). In our investigation, only the HIIT group observed significant changes in the circulating levels of LDL-C and total cholesterol compared to controls, whereas no changes were observed for the MCT group after 1-year of intervention. A recent meta-analysis in individuals with T2DM, examined the effects of HIIT and MCT on several biomarkers, including the lipid profile (37). The analysis suggests that there are no differences between higher and moderate exercise intensities. However, the results were inconsistent between studies, with two reporting no effects of HIIT and MCT on LDL-C, HDL-C, total cholesterol and triglycerides (38, 39), and only one study observing changes in HDL-C and LDL-C following both HIIT and MCT, whereas only the HIIT group decreased total cholesterol i(21). The differences between these results and those reported in the present investigation may be explained by the baseline values of the participants, with most of our participants having relatively normal ranges of total cholesterol, HDL-C, and LDL-C levels, which did not change greatly after exercise. However, the biggest impact of the HIIT group on the lipid profile lies in differences against the control group, who incurred adverse changes in their lipid profile over the course of 1-year without any exercise intervention. Moreover, the exercise protocols differed substantially between studies (21, 38, 39), with none of the interventions using the 1:1 (active-to-rest period ratio) protocol on a cycle ergometer and the duration of these interventions being no longer than 16-weeks. Another possible confounding factor is the baseline MVPA values, which were higher in the HIIT group. However, both HIIT and MCT had similar frequencies of patients fulfilling the PA guidelines and the results of the intervention remained the same after adjusting the models for baseline MVPA.
Despite the encouraging results observed, there are limitations in the present investigation that should be addressed. The lack of mid-term assessments during the 1-year intervention period did not allow for the assessment of the evolution of the inflammatory and lipid profile, especially in the first months of the intervention, where the adherence to the exercise programs may be higher. In addition, energy intake was not controlled during the intervention, which might have affected the lipid profile. As far as the strengths of our investigation are concerned, we used a 1-year intervention with supervised exercise sessions, which provides, for the first time, information on the long-term implications of combined HIIT and MCT protocols combined with RT in patients with T2DM.