During the 16-wk intervention, subjects expended, on average, 1094.3 ± 518.6 kcal·wk−1 (range = 407.5–2623.3 kcal·wk−1). Mean exercise intensity was 6.40 ± 2.26 kcal·min−1 (range = 2.29–14.65 kcal·min−1). The average number of weekly sessions achieved was 3.91 ± 0.85 sessions per week (range = 2.29–6 sessions per week).
Changes with intervention.
Insulin sensitivity significantly improved with intervention (Table 1; Figs. 1A and B). Further analyses revealed that this change was significantly related to the average kilocalories expended per week (Fig. 1C) and to the average kilocalories expended per minute (Fig. 1D) but not of the amount of sessions per week (Table 2). From Figure 1 (C and D), it can be seen that these relationships are approximately linear and that there is no evidence of threshold or maximal effect.
V˙O2peak followed the same pattern with a significant improvement after the intervention (Table 1), which was significantly related to the average kilocalories expended per week and per minute of exercise, but not with the number of sessions (Table 2). BMI and fat mass were also significantly improved by intervention, and these changes were significantly related to the average kilocalories expended per week, per minute, and the amount of sessions per week (Tables 1 and 2). Fat-free mass did not change with intervention (Table 1).
After controlling for baseline insulin sensitivity and fat-free mass, the improvement in insulin sensitivity remained significantly related to the average kilocalories expended per week (Table 3A). In this model, the intercept was estimated to be 0.716, meaning that an average hypothetical subject (with respect to all predictors entered in the model) would achieve a GIR gain corresponding to 0.716 SD (i.e., a gain of 0.716 × 111.8 = 80 mg·min−1), which is clinically relevant.
The fact that the estimated coefficient for the factor baseline insulin sensitivity was −0.197 indicates that the expected GIR gain would still correspond to 0.716 − 0.197 = 0.519 SD (i.e., to 0.519 × 111.8 = 58 mg·min−1) for a subject with a baseline GIR value 1 SD above average, whereas the expected GIR gain would attain 0.716 + 0.197 = 1.633 SD (i.e., 1.633 × 111.8 = 183 mg·min−1) for a subject with a baseline GIR value 1 SD below average. Thus, the model accounts for the fact that the expected GIR gain will be higher for those subjects starting with a lower GIR value.
The estimated coefficient for the factor of interest, exercise dose expressed in kilocalories per week (kcal·wk−1), was 0.275. Thus, the expected GIR gain would be increased another 0.275 SD (i.e., of another 0.275 × 111.8 = 31 mg·min−1) for those subjects expending 1 SD above the mean of kilocalories per week (i.e., 1094 + 519 = 1613 kcal·wk−1).
Finally, for this first model, the estimated coefficient for the factor fat-free mass was 0.258, which was comparable with the coefficient for kilocalories per week, meaning that the expected GIR gain would increase another 0.258 SD (i.e., another 0.258 × 111.8 = 29 mg·min−1) for those subjects with a fat-free mass of 1 SD above average.
When introducing baseline V˙O2peak in the model instead of fat-free mass, we obtained similar results, although fat-free mass was more significant than V˙O2peak at baseline. In subsequent models with kilocalories per week as explanatory variable (not shown), we entered age and gender, none of which were significant.
To examine the existence of a possible threshold, we entered a binary variable based on the physical activity guidelines of 900 kcal·wk−1; thus, in this model, the intercept and the slope were allowed to change above or below 900 kcal·wk−1. Subsequently, after the observation of Figure 1C where it can be seen that a small number of subjects exercising above 1500 kcal·wk−1 may have modified the regression, we performed the same model but with a binary variable of 1500 kcal·wk−1. No significant improvements were found compared with the simpler model (Table 1A) with just one intercept and one slope for exercise dose (P = 0.93 and P = 0.89, respectively, for 900 and 1500 kcal·wk−1). The same was true when only allowing the intercept to change (keeping the same slope above and below the threshold). Thus, we did not find any evidence for the existence of a threshold. Our results are suggesting a graded relationship between exercise dose and the improvement in insulin sensitivity as illustrated in Figure 1C.
Because exercise intensity and frequency are key components of exercise dose, we explored in ancillary models their relationship with insulin sensitivity. Table 3B presents the model with intensity as explanatory variable, Table 3C represents frequency as explanatory variable, and Table 3D is the combination of both variables in the same model. It can be seen that the average kilocalories per minute of exercise expended significantly predicted the change in GIR, although in this model, the baseline GIR was not found to be significant. In contrast, the amount of sessions per week was not significantly related to the change in GIR. The last model including both intensity and frequency allows observing that the directions are maintained but that the coefficients (corresponding to the effects) are smaller and nonsignificant. Thus, we have not proven statistically that these two components are independent predictors on the change in insulin sensitivity.
The primary finding of this study is the positive dose–response relationship between the dose of exercise performed and the improvements in insulin sensitivity. Although exercise is encouraged for the prevention and treatment of type 2 diabetes (14,17,32), dose–response studies are warranted (34).
The dose–response effect observed in this study was graded. We did not evidence a threshold, neither in the lower nor on the higher end of the spectrum of the exercise volume performed by previously sedentary adult women and men with a wide range of age and BMI. Notably, even an exercise dose of ∼400 kcal·wk−1 (about 40%–50% of the guidelines for physical activity) was associated with a significant improvement in insulin sensitivity. This is an important finding from a clinical point of view.
The present observation of the shape of the relationship between exercise dose and direct assessments of peripheral insulin sensitivity is in accord with previous studies that used indirect measures of insulin sensitivity and self-reported exercise data (24) or exercise prescription resulting in groups of different exercise doses (16).
Similar to this graded dose–response relationship, Church et al. (5) observed a graded dose–response relationship between exercise dose and improvements in cardiorespiratory fitness. In agreement with others (4), we believe that the largely prescribed common dose of 150 min·wk−1 of moderate-intensity physical activity, based on epidemiological data, is based on insufficient evidence, particularly regarding the cardiometabolic risk outcomes, including IR. Therefore, this may not necessarily be the best cutoff point for exercise prescription. To examine the relevance for the guidelines promoting physical activity for health (27), we entered in the regression model a dichotomous variable based on a weekly volume of 900 kcal·wk−1 (∼150 min·wk−1 at a moderate intensity). We found no statistical evidence that the relationship between the amount of exercise and the improvement of insulin sensitivity was different for those subjects above or below a weekly volume of 900 kcal·wk−1.
Interestingly, our data show that for the same volume of physical activity, a person with a lower baseline insulin sensitivity improves to a greater degree than an individual with relatively higher insulin sensitivity values. A further increase in exercise volume promotes additional improvement in insulin sensitivity. Baseline muscle mass and physical capacity was also positively related to the improvement in insulin sensitivity. Taken together, these data corroborate the notion that one exercise prescription does not fit all clinical circumstances and that a little is better than nothing.
It is important to differentiate the acute effect of exercise (25) from the chronic effect of training (26). A single bout of moderate-intensity exercise increases insulin sensitivity for 12–48 h; Magkos et al. (23) reported a curvilinear dose–response relationship between exercise energy expenditure and insulin sensitivity assessed by the HOMAIR score. A threshold of approximately 900 kcal (∼60–90 min of exercise at 60% V˙O2peak) was suggested to improve insulin sensitivity in healthy untrained individuals. Dela et al. (8) observed that the effect of training on insulin sensitivity was an adaptation of repeated exercise and not the consequence of the last exercise bout. The molecular mechanisms by which acute and chronic exercise improve insulin sensitivity have been extensively studied (15,35), but have not yet been fully elucidated (13), and are beyond the scope of this project.
This study was focused on the effect on insulin sensitivity of the total exercise dose per week of training, i.e., the product of the mean exercise intensity, mean duration, and frequency. Our objective was not to imply that any of the three components is more important than the others. Previous studies looking at exercise intensity reported changes in insulin sensitivity with higher intensity training (80%–75% of V˙O2max) but not with moderate intensity (65%–50% of V˙O2max) while controlling for energy expenditure, thus with the same exercise dose in all groups (6,9). In another study controlling for energy expenditure, Hughes et al. (18) found similar improvement in insulin sensitivity in groups exercising at high or moderate intensity. In this study, we found a stronger and more significant relationship with the improvement in insulin sensitivity when considering exercise dose than when considering only one of its components. When taken alone, exercise intensity was still significantly related to an improvement of insulin sensitivity. In fact, when we add exercise intensity to the multivariate model including exercise dose (data not shown), the regression coefficient for exercise dose remained similar (0.258 instead of 0.275), while the coefficient of intensity became almost zero. This result would suggest that, for a fixed amount of exercise dose, an increase of exercise intensity (and thus a decrease of exercise frequency and/or duration) would not affect the change of insulin sensitivity in the context of this population and for the range of exercise intensity and exercise dose observed in our study. Furthermore, this supports the fact that exercise dose is a good summary measure, allowing us to get a higher statistical power than when considering exercise intensity alone.
Only the subjects who finished the exercise intervention were included. Another limitation of this study is that only sedentary volunteers were studied, thus the same magnitude of improved insulin sensitivity may not be transposable to long-term active lifestyle individuals. Regarding the mode of training, the primary mode of activity of this intervention was stationary cycling and walking, with some running and rowing. To our knowledge, there are no data to support the hypothesis that a particular endurance training exercise mode improves insulin sensitivity more than another.
In this diverse group of subjects, in terms of BMI and adiposity, weight loss was not a goal per se; thus, we instructed our subjects not to modify their dietary patterns. For this reason and the fact that weight loss could not be taken as predictive values at the start of intervention, we chose a priori not to enter the difference in BMI, weight, or adiposity in the regression model. Indeed, for a given patient, this would be a rather confusing and complex message, “if you lose X amount of weight, you will increase your insulin sensitivity by X amount.” It is important to note that a recent study has shown improvements of insulin sensitivity with exercise independently of weight loss (21). Moreover, an epidemiological study reported an independent association of low cardiorespiratory fitness and high BMI with the incidence of type 2 diabetes (33).
In summary, in previously sedentary adults, diverse in terms of BMI, age, and gender, there is evidence for a graded exercise dose–response change in insulin sensitivity. This observation is relevant for clinical settings and particularly diabetes prevention programs. These data reinforce the concept that more insulin-resistant individuals at greater risk for developing type 2 diabetes and cardiovascular disease can attain greater benefit by performing more exercise but that there is no obvious exercise volume threshold for these benefits. It appears that, in terms of improving insulin sensitivity, more is likely better than a little, and a little is better than nothing.
This study was supported by an ADA Clinical Research Award (B.H.G), an American College of Sports Medicine research grant (F.A.), a National Institutes of Health R01 (AG20128), the National Institutes of Health’s General Clinical Research Center (5M01RR00056), and Obesity Nutrition Research Center (1P30DK46204).
The authors thank the volunteers for the participation in this study. The authors also acknowledge the valuable contributions of Steven Anthony for directing the exercise programs.
The authors have nothing to disclose.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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Keywords:©2012The American College of Sports Medicine
EXERCISE DOSE–RESPONSE; INSULIN RESISTANCE; OBESITY; TYPE 2 DIABETES; EXERCISE PRESCRIPTION