Nonalcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of hepatic abnormalities, from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis (1), and is associated with an increased risk of developing hepatocellular carcinoma (2) and extrahepatic disorders such as cardiovascular disease (3). During the last decades, NAFLD has become the most common chronic liver disease worldwide, due to the ongoing epidemics of obesity and type 2 diabetes (4). Both these conditions are strongly associated with (5, 6) and accelerate progression of (7) NAFLD, which is in fact considered as the hepatic expression of the metabolic syndrome (8). For this reason, an international panel of experts has recently proposed to use the term metabolic dysfunction-associated fatty liver disease instead of NAFLD (9).

Current guidelines recommend, in persons with excess adiposity, a weight loss at least 5% and preferably ≥10% through an energy deficit of 500-1000 kcal with adoption of healthy eating patterns and adherence to physical activity (PA) (10–12). Regarding PA, it is advised to participate in a structured exercise program consisting of 3-5 sessions per week (10, 11), with a total duration of 150-300 min of moderate-intensity or, better, 75-150 min of vigorous-intensity aerobic exercise and eventual addition of resistance exercise training (12). Recommendations on PA are based on the evidence from studies (13–16) and meta-analyses (17–20) that engagement in aerobic and/or resistance exercise programs, generally supervised, is associated with beneficial effects on NAFLD/NASH, with significant decreases in intrahepatic fat accumulation as well as in liver enzymes and indices of steatosis and visceral adiposity. Of note, these effects were independent of weight loss (13–20), though losing weight was associated with greater benefits (18, 21, 22) with a dose-response relationship (23). Moreover, these studies were conducted either in the general population or in people with overweight/obesity and/or NAFLD/NASH, which eventually included individuals with type 2 diabetes.

Unfortunately, adherence to PA recommendation is generally poor (24), especially in people with type 2 diabetes (25), pointing to the need for targeted interventions. However, supervised exercise programs, though very effective in favoring the achievement of the high volumes and/or intensities recommended by guidelines (26), are difficult to implement in routine clinical practice. In contrast, counselling interventions may be more suitable for producing a sustained behavior change, but result in only modest increases in moderate-to-vigorous-intensity PA (MVPA) (27–29), which may be insufficient to improve NAFLD. However, sedentary time (SED-time) was found to be associated with NAFLD, independently of MVPA (30, 31), thus suggesting that targeting also this domain of PA behavior by recommending substitution or interruption with time spent in light-intensity PA (LPA) might be effective in ameliorating NAFLD. In the Italian Diabetes and Exercise Study_2 (IDES_2), a counseling intervention targeting both MVPA and SED-time resulted in only modest increases in MVPA (6.4 min·day-1), but larger (0.8 hours·day-1) decreases in SED-time and reciprocal increases in LPA, thus substantially contributing to the 3.3 metabolic equivalents (METs)-hour·week-1 increment in total PA volume (32). These changes were associated with clinically meaningful improvements in physical fitness and glycemic and blood pressure control, with no significant effect on indices of adiposity or lipid profile (32).

This post hoc analysis of the IDES_2 was aimed at evaluating the impact of the counseling intervention and the relative contribution of changes in MVPA and SED-time/LPA on NAFLD markers in people with type 2 diabetes.

Design and methods have been detailed elsewhere (32, 33) and will be briefly reported here.

As previously reported (32), 267 participants completed the study at the final evaluation (CON=134; INT=133), whereas 33 participants (CON=16; INT=17) dropped out for various reasons; of those in the INT group, >90% attended the counselling sessions.

The baseline features of the individuals considered for the present analysis are reported in Table 2 .

This post hoc analysis of the IDES_2 showed that sustained decreases in SED-time and increases in PA promoted by a behavioral counseling were associated with improvements in NAFLD markers, with significant reductions of ALT, γGT, FLI, and HSI, whereas VAI was unchanged, consistent with the lack of effect of the intervention on indices of adiposity such as BMI and waist circumference (32). Though relatively modest, the improvements in NAFLD markers were similar to those reported in previous studies (41, 42) and meta-analyses (17, 19) for supervised exercise programs of shorter duration. In particular, in the previous IDES (42), enzyme levels did not change, whereas FLI and VAI significantly decreased in the supervised exercise intervention group, but not in the control group, in a PA volume-dependent manner.

However, participants in supervised exercise studies were engaged in moderate-to vigorous intensity training or high intensity interval training at least three times a week, thus accumulating large amounts of MVPA, which were shown to be required for obtaining significant decreases in intrahepatic fat accumulation (43). Conversely, in the IDES_2, increments in MVPA were much lower, though sustained over three years, and not sufficient to achieve the recommended target of at least 150-300 min per week. Thus, the novel information provided by our study is that even small increments in MVPA obtained by adopting and maintaining a more active lifestyle can be effective in improving NAFLD markers in individuals with type 2 diabetes, suggesting that “some (MVPA) is better than nothing”. Yet, the findings that participants falling in quartiles III and IV of MVPA change showed the most marked reductions in liver enzymes and indices and that the increase in MVPA was a strong independent predictor of improvements in NAFLD markers confirm the concept that “the more (MVPA) the better”.

Moreover, the modest changes in MVPA were accompanied by larger decrements in SED-time and reciprocal increments in LPA resulting in substantial increases in total PA volume. These changes were also associated with changes in liver enzymes and indices, consistent with previous evidence that sedentary behavior or, inversely, overall PA level are associated with presence of NAFLD or increased liver enzymes (30, 31, 44, 45). These findings suggest that NAFLD may also benefit from reallocation of SED-time to LPA. In fact, though changes in SED-time or LPA were not independent predictors of variations in NAFLD markers, a role for decreases in SED-time through the reciprocal increases in LPA is supported by the independent association of liver enzymes and indices with total PA volume, of which increments in LPA were a main contributor.

Another important finding of this study is that changes in VO_2max and lower body muscle strength predicted changes in NAFLD markers beyond changes in PA/SED-time, thus suggesting that the improvements in physical fitness resulting from the behavioral modification provided additional benefits. This is consistent with the observations that cardiorespiratory fitness is associated with presence of NAFLD, as assessed by FLI, independent of MVPA (46), and that baseline VO_2max is an independent predictor of reduction in liver fat from a lifestyle intervention in individuals with NAFLD (47). Moreover, changes in BMI and, to a lesser extent, waist circumference were also associated, independent of changes in PA/SED-time, with changes in NAFLD markers, including the indices calculated using these parameters.

Several mechanisms have been hypothesized for explaining the beneficial effects on NAFLD of increasing PA and physical fitness and decreasing SED-time in the absence of significant reductions in total and central fat mass. These mechanisms include amelioration of insulin resistance at both the liver and adipose tissue level and increased mitochondrial biogenesis and capillarization favoring fatty acid uptake, β-oxidation, and triglyceride storage at the muscle level (48). The importance of muscle in the pathogenesis of NAFLD is supported by the inverse association of muscle mass and grip strength with risk of severe NAFLD (49) and the correlation between muscle fat accumulation and NASH severity (50). These mechanisms might be operating also for modest increases in MVPA, provided that they are sustained in the long-term.

The main strength of this study is the evaluation of changes in liver enzymes and indices of steatosis associated with long-term, sustained changes in PA/SED-time, as measured objectively by the use of an accelerometer. Other strengths concern the trial design, including the application of an intervention targeting both PA and SED-time, based on solid theoretical grounds, and using several behavioral change techniques, the specific training of investigators, the long study duration, and the large sample size (32, 33). However, this study has some limitations. First, the use of surrogate measures, such as liver enzymes and indices of steatosis, instead of direct methods, such as the gold standard histology or imaging techniques, does not allow to draw definite conclusions regarding the effect of the intervention on NAFLD/NASH. Second, the lack of data on platelet count did not allow calculation of indices of liver fibrosis. Third, generalization requires further investigation and validation in different cohorts or settings. Fourth, results might have been affected by unmeasured confounders, for instance diet, which was not considered in data analysis, though participants received dietary prescriptions and adherence to diet was verified at intermediate visits.

This post hoc analysis of the IDES_2 showed that, in individuals with type 2 diabetes, a counseling intervention for increasing PA and decreasing SED-time was effective in ameliorating NAFLD, as suggested by the improvements in liver enzymes and indices of steatosis over 3 years. Changes in MVPA, though modest, were the main predictors of changes in these surrogate measures, but also the greater decreases in SED-time contributed to this effect, possibly through the reciprocal increases in LPA that resulted in a relatively large increment in total PA volume. These findings indicate that a behavior change involving all domains of PA lifestyle, even if insufficient to achieve the recommended MVPA target, may also provide beneficial effects on NAFLD/NASH in people with type 2 diabetes, eventually combined with treatment with GLP-1 RAs and/or TDZs.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Ethics Committee of Sant’Andrea University Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

JH: Conceptualization, Data curation, Formal analysis, Investigation, Validation, Writing – review & editing. MV: Conceptualization, Data curation, Formal analysis, Investigation, Writing – review & editing. LM: Data curation, Formal analysis, Investigation, Writing – review & editing. CG: Data curation, Formal analysis, Investigation, Writing – review & editing. MS: Investigation, Methodology, Resources, Validation, Writing – review & editing. GO: Investigation, Methodology, Resources, Validation, Writing – review & editing. CI: Investigation, Validation, Writing – review & editing. SM: Investigation, Visualization, Writing – review & editing. SZ: Investigation, Methodology, Resources, Validation, Writing – review & editing. AN: Data curation, Formal analysis, Software, Writing – review & editing. SB: Data curation, Formal analysis, Funding acquisition, Investigation, Project administration, Supervision, Writing – review & editing, Resources. GP: Conceptualization, Data curation, Formal analysis, Investigation, Project administration, Supervision, Writing – original draft.