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Exercise Dose and Insulin Sensitivity: Relevance for Diabetes Prevention

DUBÉ, JOHN J.1; ALLISON, KATELYN F.1; ROUSSON, VALENTIN2; GOODPASTER, BRET H.1; AMATI, FRANCESCA1,3

Medicine & Science in Sports & Exercise: May 2012 - Volume 44 - Issue 5 - p 793–799
doi: 10.1249/MSS.0b013e31823f679f
CLINICAL SCIENCES
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Purpose Exercise improves insulin resistance and is a first line for the prevention and treatment of type 2 diabetes. The extent, however, to which these responses are dose dependent is not known. The purpose of this study was to examine whether exercise dose was associated with improvements in insulin sensitivity after 4 months of exercise training in previously sedentary adults.

Methods Fifty-five healthy volunteers participated in a 16-wk supervised endurance exercise intervention with a pre/postintervention design. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp, peak oxygen uptake by a graded exercise test, and body composition by dual-energy x-ray absorptiometry. The exercise intervention consisted of three to five sessions per week with a minimum of three sessions supervised. A ramped exercise prescription protocol was used to achieve 75% of peak HR for 45 min per session. Exercise dose, expressed as average kilocalories expended per week, was computed as the product of exercise intensity, duration and frequency.

Results Improved insulin sensitivity was significantly related to exercise dose in a graded dose–response relationship. No evidence of threshold or maximal dose–response effect was observed. Age and gender did not influence this dose–response relationship. Exercise intensity was also significantly related to improvements in insulin sensitivity, whereas frequency was not.

Conclusions This study identifies a graded dose–response relationship between exercise dose and improvements in insulin sensitivity. The implication of this observation is of importance for the adaptation of exercise prescription in clinical situations.

1Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA; 2Statistical Unit, Institute for Social and Preventive Medicine, University of Lausanne, Lausanne, SWITZERLAND; and 3Department of Physiology and Service of Endocrinology, Diabetology and Metabolism, University of Lausanne, Lausanne, SWITZERLAND

Address for correspondence: Francesca Amati, M.D., Ph.D., University of Lausanne, Bugnon 7, Lausanne 1005, Switzerland; E-mail: Francesca.amati@unil.ch.

Submitted for publication April 2011.

Accepted for publication October 2011.

Insulin resistance (IR) is a key contributor to the development of type 2 diabetes and is associated with obesity and physical inactivity. Epidemiological studies support the evidence that physical activity is related to the incidence of type 2 diabetes (22,33) and that chronic physical activity prevents or delays the development of type 2 diabetes (19). Thus, chronic exercise, i.e., regular exercise training, is one of the first lines of diabetes prevention.

Cross-sectional (2) and prospective intervention (10,16,28) studies have demonstrated the beneficial effect of endurance exercise interventions on the improvement of insulin sensitivity. This has been shown in healthy volunteers (8) and in “prediabetic” states such as in impaired glucose-tolerant obese volunteers (11). This observation is not universal; some studies report no effect of exercise training on insulin sensitivity (31), whereas others report the effect of exercise only if performed at relatively high intensity (30). The relationship between exercise intensity and the improvement in insulin sensitivity has already been investigated with partly contradictory results. While two studies (6,9) found a gradual positive effect of exercise intensity on insulin sensitivity, another one (18) did not find any difference between groups exercising at different intensities.

The dose of exercise needed to bring about a particular response can be defined by the characteristics of type of activity, frequency, duration, and intensity. The product of frequency, duration, and intensity allows an estimate of total energy expenditure and is a measure of the dose (or volume) of exercise (20). A dose–response effect of the total energy expended while exercising, thus taking into account exercise intensity, frequency, and duration, could help explain why an exercise training effect has not been more consistently observed. The purpose of this study was to examine the dose–response effect of exercise dose on improvements in insulin sensitivity during exercise training in previously sedentary adults.

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METHODS

Study design, subjects, and intervention.

All subjects included in this analysis were enrolled in our clinical trial from 2005 to 2008 and completed a 16-wk exercise intervention. Men and women age 25–75 yr were included if they were in good health, without recent illnesses, currently not engaged in a regular exercise program (≤ 1 d·wk−1 of continuous physical activity), nonsmoker, normal weight to obese (body mass index (BMI) = 20–38 kg·m−2), and weight stable (±3 kg) for at least 6 months before the study. Subjects were excluded if they had a history of type 2 diabetes and/or they were taking chronic medications known to affect glucose homeostasis. The University of Pittsburgh Institutional Review Board approved the protocol, and all volunteers gave written informed consent.

The exercise training protocol consisted of 16 wk of moderate-intensity aerobic exercise as described elsewhere (3). Subjects were asked to engage in three to five sessions per week with at least three sessions supervised in our facility. Supervised exercise modes included mostly stationary bicycling and treadmill walking, some running and rowing. The intensity and duration of the exercise session, both supervised and unsupervised, were monitored by the use of HR monitors (Polar Electro Oy, Kempele, Finland). Exercise prescription was ramped as follows: for the first 4 wk, the intensity was 60%–70% of peak HR for duration of 30 min. In weeks 5–8, intensity was kept similar, and exercise duration was increased to 40 min. During weeks 9–16, intensity was increased to 75% of peak HR and the duration to 45 min. The exercise prescription was based on the subject’s individual peak HR achieved during a graded exercise test conducted at baseline and adapted at the midpoint of the intervention with a submaximal ergometer test (3). HR monitors, recall of mean HR and duration, were used for the unsupervised sessions to quantify exercise. This was done on the next supervised session, thus allowing accurate record of the unsupervised sessions and limiting self-reporting error. Subjects were instructed not to change their dietary habits for the duration of the intervention.

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Outcome measures.

Insulin sensitivity was determined by the glucose infusion rate (GIR, mg·min−1) of the last 30 min of steady state from a 4-h hyperinsulinemic (40 mU·m−2·min−1) euglycemic clamp (12). On the evening before the clamp, subjects were admitted to the Clinical and Translational Research Center. They received a standard dinner (7.5 kcal·kg−1 of body weight; 50% CHO, 30% fat, and 20% protein) and then fasted until completion of the glucose clamp. For the postintervention assessment, the clamp was performed 36–48 h after the last exercise session to avoid the acute effects of exercise on insulin sensitivity. The GIR reflects mostly skeletal muscle insulin sensitivity as it is assumed that hepatic glucose production is nearly completely suppressed at this insulin infusion rate (1).

Weight was measured on a calibrated medical digital scale (BWB-800; Tanita Corporation, Tokyo, Japan) in undergarments. Height was measured at the same time with a wall-mounted stadiometer. BMI was calculated as weight (kg) divided by square height (m2). Fat mass (kg) and fat-free mass (kg) were assessed by dual-energy x-ray absorptiometry (Lunar Prodigy and EnCORE software version 9.30, GE Healthcare, Waukesha, WI).

Physical fitness was determined by the peak aerobic capacity (V˙O2peak) measured using a graded exercise protocol on an electronically braked cycle ergometer (Ergoline 800S; SensorMedics, Yorba Linda, CA) (29). HR, blood pressure, and electrocardiogram were recorded before, during, and after the exercise test. Oxygen consumption was computed by indirect calorimetry (Moxus; AEI Technologies, Pittsburgh, PA). All of the outcome measures were performed at baseline and after the 16-wk exercise intervention under weight-stable conditions. The eighth week submaximal test, performed to extrapolate changes in HRmax and thus to determine appropriate workload adjustments, was similar to the graded exercise test used to assess peak aerobic capacity but was stopped when the subject reached 60% of baseline V˙O2peak (3).

Adherence to the exercise program was evaluated using the duration of the exercise sessions, the average HR per session, and the number of sessions per week. Linear regressions of V˙O2 as a function of HR were performed at three distinct time points using the baseline maximal graded test, the eighth week submaximal graded test, and the postintervention maximal graded test. These regression equations allowed us to compute the average oxygen consumption in liters per minute (L·min−1) for each session based on the average HR obtained at that particular session. The average oxygen uptake was then converted into energy units (1 L of O2 = 5 kcal) to obtain the energy expended per minute for each session. The product of the average kilocalories per minute (kcal·min−1) with the duration of the session, allowed for a kilocalories-expended-per-session computation. These were then summed to obtain the kilocalories expended per week. The fact that we used the baseline regression equation for the first 8 wk of the intervention, followed by the midpoint regression equation for the following 4 wk and finally the postintervention regression equation for the last 4 wk of intervention allowed us to account for the individual changes in fitness of each volunteer. We report “exercise dose” as the average kilocalories expended per week (kcal·wk−1), “intensity” as the average kilocalories expended per minute (kcal·min−1), and “frequency” as the average number of sessions per week.

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Statistical analysis.

Descriptive statistics for continuous variables are presented as mean ± SD. Changes between the premeasures and postmeasures were computed as postintervention values minus preintervention values. Paired t-tests were used to explore significant differences with intervention. Spearman correlations were performed to assess the relationships between these changes. To examine the relationship between dose of exercise and the difference in insulin sensitivity, we used a regression model with the difference of insulin sensitivity as the response variable and the amount of exercise (expressed as exercise dose, intensity, or frequency) as the explanatory variable. To account for a possible “regression-to-the-mean” effect, baseline insulin sensitivity was entered in the model. Because fat-free mass accounts for approximately 80% of the whole body insulin sensitivity (7), fat-free mass was entered into the model. This allowed for an estimation of the expected difference in insulin sensitivity as a function of exercise for a given baseline value of insulin sensitivity and a given fat-free mass. In another model, age and gender were entered to further investigate the significance of these predictors. To facilitate comparison between the models and between the sizes of the effects of the various predictors, all continuous variables have been expressed as a number of SD above or below the average value at baseline. For all analyses, the α level was set a priori at 0.05. All analyses were performed in a two-tailed approach using Stata for Mac, version 10.1 (StataCorp, College Station, TX).

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RESULTS

Clinical characteristics.

Among the 55 volunteers, 38% were men (n = 21) and 62% women (n = 34). According to their BMI, 20% of volunteers had a class II obesity, 35% class I obesity, 33% were overweight, and 13% were in the normal range. The distribution of the GIR before and after intervention is presented in Figure 1A. All other characteristics are presented in Table 1.

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

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Exercise adherence.

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).

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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.

TABLE 2

TABLE 2

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).

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Multivariate analyses.

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.

TABLE 3

TABLE 3

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.

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DISCUSSION

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:

EXERCISE DOSE–RESPONSE; INSULIN RESISTANCE; OBESITY; TYPE 2 DIABETES; EXERCISE PRESCRIPTION

©2012The American College of Sports Medicine