Exercise and Insulin Resistance in Youth: A Meta-Analysis Michael V. Fedewa, Nicholas H. Gist, Ellen M. Evans and Rod K. Dishman Pediatrics 2014;133;e163; originally published online December 2, 2013; DOI: 10.1542/peds.2013-2718
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/133/1/e163.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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Exercise and Insulin Resistance in Youth: A Meta-Analysis AUTHORS: Michael V. Fedewa, MA,a Nicholas H. Gist, PhD,a,b Ellen M. Evans, PhD,a and Rod K. Dishman, PhDa
abstract
aDepartment
BACKGROUND AND OBJECTIVES: The prevalence of obesity and diabetes is increasing among children, adolescents, and adults. Although estimates of the efficacy of exercise training on fasting insulin and insulin resistance have been provided, for adults similar estimates have not been provided for youth. This systematic review and meta-analysis provides a quantitative estimate of the effectiveness of exercise training on fasting insulin and insulin resistance in children and adolescents.
of Kinesiology, University of Georgia, Athens, Georgia; and bDepartment of Physical Education, United States Military Academy, West Point, New York KEY WORDS adolescent, child, exercise training, insulin, insulin resistance ABBREVIATIONS BIC—Bayesian information criterion CI—confidence interval ES—effect size HOMA—homeostasis model assessment IR—insulin resistance T2DM—type 2 diabetes mellitus Mr Fedewa conceptualized and designed the study, conducted the initial analysis, and drafted the initial manuscript; Dr Gist coded and analyzed effects and reviewed and revised the initial manuscript; Dr Evans assisted with conceptualizing and designing the study and reviewed and revised the initial manuscript; Dr Dishman assisted with conceptualizing and designing the study, performed additional statistical analysis, and critically reviewed and revised the initial manuscript; and all authors approved the final manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2013-2718 doi:10.1542/peds.2013-2718 Accepted for publication Oct 23, 2013 Address correspondence to Michael V. Fedewa, MA, Department of Kinesiology, 330 River Rd, Ramsey Center, University of Georgia, Athens, GA 30602-6554. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2014 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
METHODS: Potential sources were limited to peer-reviewed articles published before June 25, 2013, and gathered from the PubMed, SPORTDiscus, Physical Education Index, and Web of Science online databases. Analysis was limited to randomized controlled trials by using combinations of the terms adolescent, child, pediatric, youth, exercise training, physical activity, diabetes, insulin, randomized trial, and randomized controlled trial. The authors assessed 546 sources, of which 4.4% (24 studies) were eligible for inclusion. Thirty-two effects were used to estimate the effect of exercise training on fasting insulin, with 15 effects measuring the effect on insulin resistance. Estimated effects were independently calculated by multiple authors, and conflicts were resolved before calculating the overall effect. RESULTS: Based on the cumulative results from these studies, a small to moderate effect was found for exercise training on fasting insulin and improving insulin resistance in youth (Hedges’ d effect size = 0.48 [95% confidence interval: 0.22–0.74], P , .001 and 0.31 [95% confidence interval: 0.06–0.56], P , .05, respectively). CONCLUSIONS: These results support the use of exercise training in the prevention and treatment of type 2 diabetes. Pediatrics 2014;133:e163– e174
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The global prevalence of pediatric type 2 diabetes mellitus (T2DM) has paralleled the rise in obesity, increasing steadily since the late 1970s.1 This endocrine disorder is caused by a combination of peripheral insulin resistance (IR) in muscle and adipose tissue and inadequate insulin secretion from the pancreas, eventually resulting in a relative insulin deficiency.2 Early dysfunction in b-cell activity and cellular IR appear long before manifestation of the signs and symptoms of T2DM.3 Deterioration of peripheral insulin sensitivity and b-cell dysfunction can be observed as the disease progresses in youth at risk for developing metabolic syndrome and T2DM.4 Puberty is marked by a decrease in physical activity5 and an increase in adiposity,6 and both are associated with IR in youth.7,8 In the clinical setting, physical activity and dietary intervention are recommended as the primary treatment methods for pediatric patients in the early stages of IR and prediabetes, with pharmacologic treatment reserved as an alternative course of action as the disease progresses.9–11
and adolescents with type 1 diabetes.20 The current study expands on the body of literature by providing a quantitative estimate of the effect size (ES) of exercise training on fasting insulin and IR for use in future research and program design with children and adolescents.
The American College of Sports Medicine presents a strong body of evidence supporting the inclusion of physical activity and exercise in the treatment and management of diabetes in adults and youth.12,13 Together, physical activity and lifestyle modifications can effectively reduce the development of and/or slow the progression of IR.14 Previous reviews have established that aerobic and resistance training can be used to improve the regulation of glucose, as well as provide a synergistic effect when combined in a structured exercise program across all ages.15–17 Although previous original research and subsequent reviews provide the basis for including physical activity and exercise training in the treatment program for the prevention of T2DM, meta-analytic reviews of exercise and fasting insulin have been limited to adults18,19 or children
The inclusion criteria for our analysis were as follows: (1) peer-reviewed publication; (2) available in English; (3) involving human subjects; (4) randomized to exercise training or a nonexercise comparison; and (5) fasting insulin or IR measures at baseline, during, and/orafter exercise training. Excluded records had the following characteristics: (1) were non–peer reviewed; (2) provided a review, meta-analysis, position statement, or proposed study design; (3) sampled subjects aged ,6 or .19 years; (4) used a cross-sectional or prospective study design; (5) included exercise as 1 part of a multicomponent treatment (eg, exercise + diet), from which an ES for exercise alone could not be calculated; or (6) compared exercise only with an active treatment (eg, nutritional intervention or another mode of exercise). A total of 546 articles were
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METHODS The review was conducted in accordance with PRISMA (Preferred Reporting Items forSystematicReviewsandMeta-analyses) statement guidelines.21 Articles published by June 25, 2013, were located by using searches of the PubMed, SPORTDiscus, Physical Education Index, and Web of Science online databases using combinations of the terms adolescent, child, pediatric, youth, exercise training, physical activity, diabetes, insulin, randomized trial, and randomized controlled trial. Duplicate publications were removed. The authors manually reviewed reference lists from retrieved articles for additional publications not discovered by using the database search. Study Selection
identified during the initial search process. A flowchart of study selection is provided in Fig 1. Manual searches revealed 5 additional publications.22–27 Six articles reported fasting insulin measurements as median and interquartile range (25th–75th percentile), reported data in change scores from baseline, or did not report either premeasurement or postmeasurement data. A request for missing data was sent to each of the corresponding authors. Two of the 6 authors26,27 provided missing information and 1 author28 provided an additional publication not obtained during our initial literature search; these 3 articles were included in the final meta-analysis. ES Calculation ES values were calculated by subtracting the mean change in the comparison condition from the mean change in the exercise condition and dividing the difference by the pooled SD of the baseline scores.29 SDs from the largest study available were used to estimate the ES30 when group mean values and measures of variability were not provided.31–33 Postintervention values in these publications were reported as change scores31,32 or in figures provided by the authors.33 ES values were calculated after adjusting for small sample bias.29 IR was calculated by using fasting levels of insulin and glucose by using the homeostasis model assessment (HOMA) technique in each study included in this analysis.22,25,31,32,34–41 A decrease in fasting insulin levels or IR among participants in exercise interventions resulted in a positive ES. Two authors (M.V.F. and N. H.G.) independently calculated ES from each study, and discrepancies were resolved before aggregating effects. Statistical Analysis Random effects models were used to aggregate a mean ES and 95% confidence interval (CI) for fasting insulin and IR and to test variation in effects
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FIGURE 1 Flowchart of study selection.
according to moderator variables by using macros (MeanES and MetaReg) in IBM SPSS version 20.0 (IBM SPSS Statistics, IBM Corporation, Armonk, NY). The number of potential moderators was restricted due to the small number of effects. Univariate linear regression was then used to estimate the independent effect of exercise on fasting insulin level based on baseline pubertal status, gender, and BMI, chosen a priori due to their strong influence on fasting insulin and metabolic syndrome in this population.7,42 Because
effects were nested within studies, a multilevel mixed model linear regression model with robust maximum likelihood estimation was also used to adjust for between-study variance and correlated effects within studies according to standard procedures43,44 by using Mplus 7.0.45 Parameters and their errors were estimated with clustering on study by using the Huber-White sandwich estimator to calculate SEs that are robust to heteroscedasticity and correlated effects.46–48 The effect of each moderator on fasting
insulin effects was tested separately by comparing each conditional model (which included the intercept and the moderator) with the unconditional intercept-only model by using a likelihood ratio test and the adjusted Bayesian information criterion (BIC).45 Significant interactions were decomposed by using 95% CIs.44,49
RESULTS Thirty-two effects were derived from 24 studies, with 1599 children measured at
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baseline. Data available for study and participant characteristics are presented as mean 6 SD. Sample size ranged from 8 to 140 subjects per treatment group (25.4 6 23.8 subjects per group). Each of the exercise training interventions varied in design and included aerobic, resistance, and a combination of training modes. Study intervention length, frequency, duration, and intensity were reported inconsistently across effects. Exercise training consisted of 3.2 6 1.0 sessions per week, 53.4 6 20.0 minutes at a moderate to vigorous intensity physical activity per session for 15.5 6 11.4 weeks, when reported. The descriptive characteristics of studies included in the analysis are provided in Table 1. Participant characteristics for each exercise treatment condition were inconsistently reported as well. When reported, the exercise treatment conditions were 54.3 6 30.8% female and 11.4 6 2.8 years of age. The ages of participants ranged from 6 to 19 years, with 30 of the 32 effects involving children and adolescents with a mean age .9 years. Effects were derived from treatment groups of normal weight, overweight, and obese participants, with a mean BMI of 27.2 6 4.9. Mean weight and relative adiposity (ie, percentage of body fat) were 64.5 6 19.8 kg and 34.9 6 7.5%, respectively. The cumulative results of 32 effects gathered from 24 studies published between 1999 and 2013 agree that exercise training effectively reduces fasting insulin levels in children and adolescents with a mean ES equal to 0.48 (95% CI: 0.22–0.74; z = 3.57; P , .001) (Figure 2). In the multilevel, intercept-only model (x 2 [2] = 142.0, BIC = 144.8), the mean ES was 0.54 (95% CI: 0.21–0.87) with significant variance (0.537, SE = 0.211, z = 2.55, P = .011) between effects. Twenty-six (81.3%) of the 32 effects were larger than zero. Similar results were found for IR, as the cumulative results of 15 effects gathered from 12 studies published between 2006 e166
and 2013 agree that exercise training effectively reduces IR with a mean ES of 0.31 (95% CI: 0.06–0.56), z = 2.39, P , .05) (Figure 3). In the multilevel, interceptonly model (x2 [2] = 49.4, BIC = 48.7), the mean ES for IR was 0.32 (95% CI: 0.06–0.58) with marginally significant variance (0.116, SE = 0.068, z = 1.69, P = .09) between effects. Twelve (80.0%) of the 15 effects were larger than zero. These results were consistent for male and female subjects, regardless of age or ethnicity. Forest plots for the effect of exercise training on fasting insulin and IR are shown in Figs 2 and 3, respectively. Moderatoranalysis furtheradjusted for nesting of effects within a single study and to reduce the likelihood of potential bias being introduced into the analysis. Sixteen of the 32 effects for fasting insulin were gathered from studies that provided multiple effects. Two effects could be calculated when information was reported for multiple demographic groups,32 disease populations,31 training intensities,23 session durations,33 or training modes within a single study.26,40,50,51 Six of the 15 effects examining IR were gathered studies providing multiple effects.31,32,40 Rater Agreement Two-way (effects 3 raters) intraclass correlation coefficients for absolute agreement were calculated to examine interrater reliability for fasting insulin and IR ES. The initial intraclass correlation coefficients for fasting insulin, based on 32 effects, were $0.99. After performing the intraclass correlation analysis for the 15 effects measuring the effect of exercise on IR, the coefficients were $0.93. Intraclass correlation increased to 100% after adjusting for discrepancies between reviewers (M. V.F. and N.H.G.). Homogeneity of Results Heterogeneity was indicated if Q total reached a significance level of P , .05
and the sampling error accounted for ,75% of the observed variance.29 Heterogeneity was also assessed by examination of the I2 statistic.52 An I2 value was categorized as low, moderate, or high based on calculations equal to 25%, 50%, or 75%, respectively. The significant improvement in fasting insulin levels after exercise training was highly heterogeneous (Q31 = 162.9, P , .001, I2 = 81.6%), with sampling error accounting for 24.4% of the observed variance. The significant improvement in IR after exercise training was moderately heterogeneous (Q14 = 30.67, P , .01, I2 = 57.6%), with sampling error accounting for 48.5% of the observed variance. Based on a significant Q statistic and an I2 .50% indicating moderate heterogeneity, the variability among fasting insulin is greater than would have occurred naturally based on study sample error. The null hypothesis for homogenous distribution was rejected, and regression analysis was thus used to identify potential moderators. Pubertal status was determined according to reported Tanner stage. Eleven studies did not provide pubertal status in ausableformforouranalysisbecause:(1) it was not reported at all23,24,26,27,38–40,53; (2) it was reported in a range of stages34; or (3) it was reported for the entire sample.22,32 The initial regression model based on baseline BMI (k = 28) was significant (R2 = 0.15, b = 0.38, z = 2.25, P , .05). Gender (k = 27) and pubertal status (k = 16) were not independently associated with the effect of exercise on fasting insulin in the age range of our analysis (R2 = 0.07, b = 0.26, z = 1.44 and R2 = 0.08, b = –0.28, z = –1.18, respectively; all P . .05). BMI remained significant after controlling for gender in a multivariate regression analysis based on 26 effects reporting both moderating variables (b = 0.44, z = 2.61, P , .01). Because the number of effects included in the regression analysis decreased to 13 when gender, pubertal status, and BMI
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TABLE 1 Studies Examining the Effect of Exercise Training on Fasting Insulin and IR in Children and Adolescents Source
N
Gender (M/F)
Age (y)
Benson et al,35 2008 Ben Ounis et al,34 2008 Buchan et al,23 2011
78 24 57
46/32 24/0 10/47
12.3 6 1.3 12–14 16.4 6 0.7
Davis et al,33 2012 Davis et al,50 2009 Davis et al,22 2009 Davis et al,36 2011 de Piano et al,31 2012 Farpour-Lambert et al,37 2009 Ferguson et al,57 1999 Gutin et al,28 2011 Hasson et al,32 2012 Karacabey,53 2009 Kelly et al,58 2004 Kim et al,38 2007 Kim et al,27 2008 Lau et al,24 2004 Lee et al,51 2012 McCormack et al,41 2013 Meyer et al,39 2006 Shaibi et al,59 2006 Shalitin et al,25 2009 Suh et al,26 2011 Sun et al,40 2011
222 41 54 38 58 44
94/128 0/41 28/26 0/38 27/31 16/28
79 242 100 40 20 26 17 36 45 18 67 21 162 30 93
Intervention Groups
Duration (min/d)
Frequency (d/wk)
Study Length (wk)
— 90 3–20
2 4 3
8 8 7
9.4 6 1.1 15.2 6 1.1 15.5 6 1.0 15.8 6 1.1 16.5 6 1.4 8.9 6 1.5
RT or CON AT, AT + diet, or diet Moderate-intensity AT, high-intensity AT, or CON High-dose AT, low-dose AT, or CON RT + diet, RT + AT + diet, or CON RT + diet, diet, or CON RT + diet, RT + AT + diet, diet, or CON RT + diet, RT + AT + diet, or diet RT + AT or CON
20–40 60 60 60–90 60 60
5 2 2 2 3 3
13 16 16 16 52 12
26/53 0/242 39/61 40/0 9/11 26/0 17/0 24/12 45/0 5/13
9.5 6 1.0 8–11 15.4 6 1.1 11.8 6 0.5 10.9 6 2.0 17.0 6 0.1 11.0 6 0.0 10–17 12–18 13.0 6 1.9
AT or CON RT + AT + games or CON RT + diet or diet AT or CON AT or CON AT or CON RT + AT or CON AT + diet or diet RT, AT, or CON RT + AT or CON
40 80 — 30–60 30–50 40 50 60 60 60
5 5 2 3 4 5 2 3 3 3
16 10 16 12 8 6 12 6 12 8
34/33 21/0 81/81 15/15 46/47
14.7 6 2.2 15.4 6 1.6 6–11 13.1 6 0.5 13.6 6 0.7
AT or CON RT or CON RT + AT, RT + AT + diet, or diet RT + diet, AT + diet, or diet AT, diet, AT + diet, or CON
60–90 60 90 40–60 40
3 2 3 3 4
24 16 12 12 10
Age is reported as mean 6 SD when available or the age range of participants included in the study. Empty cells are present when a component of the training protocol was not provided by the author. AT, aerobic training; CON, control group; F, female; M, male; RT, resistance training.
were included together in the model, a thorough multivariate analysis including all 3 moderators was not performed. In the multilevel model, adding BMI (b = 0.05, SE = 0.026, z = 1.97, P = .049) improved model fit (x 2 [3] = 119.6, BIC = 120.28) compared with the interceptonly model (D x 2 [1] = –10.8, P , .001). The residual variance was 0.301 (SE = 0.177, z = 1.70, P = .089), indicating that 44% of the variance between fasting insulin effects was explained by BMI.
model for IR (b = 0.03, SE = 0.014, z = 1.78, P = .075) improved model fit (x2 [3] = 40.4, BIC = 39.0) compared with the intercept-only model (D x2 [1] = –70.2, P , .001). The residual variance was 0.066 (SE = 0.047, z = 1.40, P = .161), indicating that 43% of the variance between IR effects was explained by BMI after adjusting for nesting of effects within studies.
The regression analysis was repeated to examine the potential moderating influence of gender, pubertal status, and BMI on IR. Based on the univariate analysis of each potential moderator, the regression models were not significant (all P . .05). Gender (b = –0.05, z = –0.17), pubertal status (b = 0.11, z = 0.20), and BMI (b = 0.35, z = 1.30) were not significantly associated with IR. However, adding BMI to the multilevel
Fail Safe-N The number of unpublished or unretrieved null effects that would diminish the significance of observed effects to P , .05 was estimated as the fixed effects fail-safe N. A fail-safe N1 represents the relative sample size of 1 additional effect that would be needed to lower the average ES to a nonsignificant value. A fail-safe N+ represents the minimal number of additional null effects
from multiple studies of average sample size needed to reach a similar null conclusion.54 The fail-safe N for the measures of fasting insulin estimated N1 = 340.7 and N+ = 368.1 effects by using the calculations for a fixed effects model suggested by Rosenberg. The estimated random effects model resulted in N1 = 16.5, while N+ collapsed to a fixed effects model. The fail-safe N for the effect of exercise on IR estimated with the fixed effects model was N1 = 22.9 and N+ = 27.2. The estimated random effects model resulted in N1 = 2.1 and N+ = 2.6. Based on earlier research from Rosenthal,55 the fail-safe N is considered robust when the value exceeds 5N+10, in which N represents the number of original effects. A fail-safe N is a calculation that provides a method to estimate when publication bias can be “safely ignored” and should not be considered as a method for identifying or controlling for potential
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FIGURE 2 Forest plot of Hedges’ d ES. The aggregated Hedges’ d is the random effects mean ES for exercise training on fasting insulin weighted by the pooled SD.
publication bias.54 Potential publication bias was addressed by using a funnel plot and the Egger test.56 Funnel plots provide a visual assessment of possible publication bias and identify potential outliers. Funnel plots for the effect of exercise training on fasting insulin and IR can be found in Figs 4 and 5, respectively. e168
The Egger test was used to assess whether the variation in ES was due to potential publication bias. Our results suggest the mean effect of exercise training on fasting insulin and IR was not subject to publication bias (F[1,30] = 0.003 [P = .95] and F[1,13] = 0.05 [P = .83], respectively).
Effect of Potential Outliers Nine effects from the 8 studies outside of the 95% CI were identified by using the forest plot to identify potential outliers.23,25,28,40,51,53,57,58 Sensitivity analysis removing these 9 effects decreased the mean effect of exercise on fasting insulin in children and adolescents from
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FIGURE 3 Forest plot of Hedges’ d ES. The aggregated Hedges’ d is the random effects mean ES for exercise training on IR weighted by the pooled SD.
0.48 (95% CI: 0.22–0.74; z = 3.57; P , .001) to 0.34 (95% CI: 0.19–0.48; z = 4.51; P , .001) for the remaining 24 effects. When examining IR, 3 effects from 2 studies outside of the 95% CI were identified by using the forest plot to identify potential outliers.40,57 Removing these 3 effects increased the mean effect of exercise on fasting insulin in children and adolescents from 0.31 (95% CI: 0.04–0.57; z = 2.39; P , .05) to 0.38 (95% CI: 0.19– 0.57; z = 3.97; P , .001) for the remaining 12 effects.
DISCUSSION The cumulative results of our analysis support the belief that exercise is effective in decreasing fasting insulin and improving IR in children and adolescents. Our results are unique in that they provideaquantitativeestimateoftheeffectof exercise on outcome measures of insulin, while assessing the influence of potential moderators, including BMI and sexual maturation. Although performed in a separate clinical population, our results
are consistent with a previous metaanalysis that evaluated the effect of exercise on glycemic control in children and adolescents with type 1 diabetes (ES = 0.37 [95% CI: 0.02–0.77]).20 Regular physical activity and exercise training should be included as an effective component of a treatment program for T2DM in children and adolescents. Exercise seems to be most effective in improving insulin status in children and adolescents with high BMI, most likely because these individuals exhibit the greatest deviation from normal values. Physical activity interventions designed to improve cardiometabolic risk may have a small effect in children unless they are selected specifically for their unfavorable risk profiles.28 Obese adolescents showed significantly greater IR than their lean peers, which may provide a “floor effect” and greater room for improvement after training in overweight and obese adolescents.38 As hypothesized, BMI was found to moderate the effect of exercise on fast-
ing insulin in our study sample such that a greater effect was observed in children and adolescents with higher BMI. Translating these research findings into a measurable improvement in clinical outcomes would equate to a 11.4-U/mL (95% CI: 5.2–17.5) improvement in fasting insulin and an improvement in HOMA-IR of 2.0 (95% CI: 0.4–3.6) in obese children, based on recent estimates from Körner et al.59 Based on the results of the regression analysis, the effect of exercise training on fasting insulin was not affected by pubertal status of the child. Puberty is marked by significant changes in fasting insulin and IR. The transient physiologic IR experienced at the beginning of puberty (Tanner stage 2) typically peaks during Tanner stage 3 and returns to prepubertal levels during Tanner stage 5.7,60 Over a 2-year period, children who remained at Tanner stage 1 experienced a small increase in insulin-like growth factor 1, whereas children who matured from stage 1 to stage 3 or 4
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FIGURE 4 Funnel plot of Hedges’ d ES versus study SE. The aggregated Hedges’ d is the random effects mean ES for exercise training on fasting insulin weighted by the pooled SD.
experienced a 1.7-fold increase in insulinlike growth factor 1, accompanied by a 39% decrease in insulin sensitivity.60 It is intuitive that exercise training may be the most effective for children and adolescents when IR is greatest; however, our analysis was not sufficiently powered to detect these differences. Further research is needed to fully examine the effect of exercise training on fasting insulin and IR when accounting for other moderators because changes in insulin sensitivity during puberty are attenuated when controlling for changes in body mass.61 In our regression model, the percentage of male participants in each effect did not significantly influence the effect of exercise on fasting insulin or IR. Female subjects typically exhibit higher e170
fasting insulin, greater IR, and are less insulin sensitive during adolescence; however, the changes are consistent across genders.7,61 One-half of the gender-related differences in fasting insulin and IR could be explained by differences in adiposity in a group of 357 white and African-American adolescents.7 Fasting insulin among 11 adolescent girls was significantly higher than among 13 adolescent boys; however, BMI was again found to be a significant covariate.61 Further research is needed to examine the moderating effect of gender on fasting insulin and IR after exercise training. A variety of training interventions were used across studies, including resistance training, aerobic training, and circuit training, as well as nontraditional
games and play to increase the physical activity levels of the participants. However, afteraccounting for the influenceof participant BMI, these potential moderators did not affect our outcome. We found no difference between aerobic or resistance training protocols, suggesting the most important component of an exercise program designed to target fasting insulin and IR in children and adolescents may not be “how” they are encouraged to move but simply that they encouraged to move at all. More research is needed to determine the most effective delivery mode for the intervention that will be sustainable and to encourage longer term adherence and behavior change in participants. For example, a circuit training approach
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FIGURE 5 Funnel plot of Hedges’ d ES versus study SE. The aggregated Hedges’ d is the random effects mean ES for exercise training on IR weighted by the pooled SD.
allowed sedentary overweight and obese adolescents to train at 70% to 85% of their maximum heart rate for 60 to 90 minutes by dividing their exercise training into 2-minute bouts followed by 1 minute of recovery between activities.36 Davis et al50 suggest training programs involving a combination of aerobic and resistance training can incorporate short aerobic intervals into circuit training and allow overweight and obese adolescents with low aerobic fitness to accumulate the required duration of aerobic exercise and improve adherence by incorporating smaller, more manageable exercise bouts. Study duration of the exercise intervention was not a significant moderator of the effect of exercise on fasting
insulin secretion, despite a previous hypothesis by other researchers that short and long interventions could influence fasting insulin secretion differently.38 Improvement in fasting insulin and IR can occur after exercise training in the absence of improvements in weight or body composition.41 Short-term interventions may improve IR by acting peripherally to improve insulin sensitivity in the muscle, whereas long-term interventions may improve body composition and improve IR through other mechanisms.62 Because our results suggest the length of the intervention may not significantly influence insulin response to training, further research is needed to thoroughly evaluate this hypothesis in children.
These results provide the basis for including physical activity and exercise training in the treatment program for the prevention of T2DM. However, a void in the literature has been identified, and additional well-designed randomized controlled trials are needed to determine the individual effects of exercise mode, duration, intensity, and frequency on fasting insulin levels in children because a larger body of evidence has found that these components influence glycemic control in adults.15,63 It should not be assumed that the physiologic response to these exercise moderators is similar in children, and future published research should provide a clear description of the exercise intervention (eg, intensity, duration,
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frequency, attendance) to allow for a more thorough meta-regression analysis, with adequate statistical power to determine the influence of these potential moderators in pediatric populations. In addition, this analysis provides a quantitative estimate of the effect of exercise training and provides justification for including physical activity in interventions aimed at improving fasting insulin or IR. To provide the most accurate estimate of the effect of exercise training alone, interventions that combined diet and exercise components were excluded from our analysis only when an independent effect of exercise could not be estimated. Determining the effect of dietary modification in addition to exercise training was beyond the scope of the current review. However, health professionals and researchers would be remiss to not suggest dietary change in addition to regular exercise; well-designed lifestyle education
involving a combination of diet and physical activity treatment therapies could provide health benefits beyond that of exercise alone.
CONCLUSIONS
race, and age, our results suggest that this analysis is an accurate estimate of the magnitude of the effect in youth aged 6 to 19 years. Although the relatively small body of published literature did not allow for a thorough analysis of the effect of frequency, duration, intensity, mode, or volume of exercise, the beneficial effects of exercise training on fasting insulin and IR are clear. In the absence of a clear consensus on the most effective type of exercise for treating these outcomes, emphasis should be placed on ways to incorporate daily physical activity, in addition to “exercise training,” into the lives of children and adolescents, especially those at risk for developing obesity and diabetes.
Based on the cumulative results from peer-reviewed research published between 1999 and 2013, a small to moderate effect was found for exercise training improvements in fasting insulin levels and IR in children and adolescents. Measurable improvements in clinically relevant insulin outcomes (11.4 U/mL [95% CI: 5.2–17.5] and 2.0 [95% CI: 0.4–3.6] in fasting insulin and HOMA-IR, respectively) will help physicians and health care professionals implement research findings into patient treatment and disease prevention. Because this small to moderate effect in fasting insulin and IR in children and adolescents was consistent across gender,
ACKNOWLEDGMENT The authors thank Dr. Timothy W. Puetz for his assistance with graphical representation of results.
7. Moran A, Jacobs DR Jr, Steinberger J, et al. Insulin resistance during puberty: results from clamp studies in 357 children. Diabetes. 1999;48(10):2039–2044 8. Rizzo NS, Ruiz JR, Oja L, Veidebaum T, Sjöström M. Associations between physical activity, body fat, and insulin resistance (homeostasis model assessment) in adolescents: the European Youth Heart Study. Am J Clin Nutr. 2008;87(3):586–592 9. Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet. 2011;378(9786):169–181 10. Rosenbloom AL, Silverstein JH, Amemiya S, Zeitler P, Klingensmith GJ. Type 2 diabetes in children and adolescents. Pediatr Diabetes. 2009;10(suppl 12):17–32 11. Levy-Marchal C, Arslanian S, Cutfield W, et al; ESPE-LWPES-ISPAD-APPES-APEG-SLEP-JSPE; Insulin Resistance in Children Consensus Conference Group. Insulin resistance in children: consensus, perspective, and future directions. J Clin Endocrinol Metab. 2010;95 (12):5189–5198 12. Albright A, Franz M, Hornsby G, et al. American College of Sports Medicine position
stand. Exercise and type 2 diabetes. Med Sci Sports Exerc. 2000;32(7):1345–1360 Colberg SR, Sigal RJ, Fernhall B, et al; American College of Sports Medicine; American Diabetes Association. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement executive summary. Diabetes Care. 2010;33 (12):2692–2696 Carrel AL, Allen DB. The influence of fitness on insulin resistance in obese children. Rev Endocr Metab Disord. 2009;10(3):189–196 Zanuso S, Jimenez A, Pugliese G, Corigliano G, Balducci S. Exercise for the management of type 2 diabetes: a review of the evidence. Acta Diabetol. 2010;47(1):15–22 Gutin B, Owens S. The influence of physical activity on cardiometabolic biomarkers in youths: a review. Pediatr Exerc Sci. 2011;23 (2):169–185 Guinhouya BC, Samouda H, Zitouni D, Vilhelm C, Hubert H. Evidence of the influence of physical activity on the metabolic syndrome and/or on insulin resistance in pediatric populations: a systematic review. Int J Pediatr Obes. 2011;6(5–6):361–388
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31. de Piano A, de Mello MT, Sanches PL, et al. Long-term effects of aerobic plus resistance training on the adipokines and neuropeptides in nonalcoholic fatty liver disease obese adolescents. Eur J Gastroenterol Hepatol. 2012;24(11):1313–1324 32. Hasson RE, Adam TC, Davis JN, et al. Randomized controlled trial to improve adiposity, inflammation, and insulin resistance in obese African-American and Latino youth. Obesity (Silver Spring). 2012;20(4): 811–818 33. Davis CL, Pollock NK, Waller JL, et al. Exercise dose and diabetes risk in overweight and obese children: a randomized controlled trial. JAMA. 2012;308(11):1103–1112 34. Ben Ounis O, Elloumi M, Ben Chiekh I, et al. Effects of two-month physical-endurance and diet-restriction programmes on lipid profiles and insulin resistance in obese adolescent boys. Diabetes Metab. 2008;34(6 pt 1):595–600 35. Benson AC, Torode ME, Fiatarone Singh MA. The effect of high-intensity progressive resistance training on adiposity in children: a randomized controlled trial. Int J Obes (Lond). 2008;32(6):1016–1027 36. Davis JN, Gyllenhammer LE, Vanni AA, et al. Startup circuit training program reduces metabolic risk in Latino adolescents. Med Sci Sports Exerc. 2011;43(11):2195–2203 37. Farpour-Lambert NJ, Aggoun Y, Marchand LM, Martin XE, Herrmann FR, Beghetti M. Physical activity reduces systemic blood pressure and improves early markers of atherosclerosis in pre-pubertal obese children. J Am Coll Cardiol. 2009;54(25): 2396–2406 38. Kim ES, Im JA, Kim KC, et al. Improved insulin sensitivity and adiponectin level after exercise training in obese Korean youth. Obesity (Silver Spring). 2007;15(12):3023–3030 39. Meyer AA, Kundt G, Lenschow U, SchuffWerner P, Kienast W. Improvement of early vascular changes and cardiovascular risk factors in obese children after a six-month exercise program. J Am Coll Cardiol. 2006; 48(9):1865–1870 40. Sun MX, Huang XQ, Yan Y, et al. One-hour after-school exercise ameliorates central adiposity and lipids in overweight Chinese adolescents: a randomized controlled trial. Chin Med J (Engl). 2011;124(3):323–329 41. McCormack SE, McCarthy MA, Harrington SG, et al. Effects of exercise and lifestyle modification on fitness, insulin resistance, skeletal muscle oxidative phosphorylation and intramyocellular lipid content in obese children and adolescents [published online ahead of print June 25, 2013]. Pediatr Obes. doi: 10.1111/j.2047-6310.2013.00180.x
42. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med. 2003;157(8):821–827 43. Hox J. Multilevel Analysis: Techniques and Applications. 2nd ed. Marcoulides G, ed. New York, NY: Routledge; 2010:205–232 44. Cheung MW. A model for integrating fixed-, random-, and mixed-effects meta-analyses into structural equation modeling. Psychol Methods. 2008;13(3):182–202 45. Muthén L, Muthén B. Mplus User’s Guide. 7th ed. Los Angeles, CA: Muthen & Muthen; 1998–2012 46. White H. A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity. Econometrica. 1980;(4)817–838 47. Froot K. Consistent covariance matrix estimation with cross-sectional dependence and heteroskedasticity in financial data. J Financ Quant Anal. 1989;24(3):333–355 48. Williams RL. A note on robust variance estimation for cluster-correlated data. Biometrics. 2000;56(2):645–646 49. Preacher K, Curran P, Bauer D. Computational tools for probing interactions in multiple linear regression, multilevel modeling, and latent curve analysis. J Educ Behav Stat. 2006;31(4):437–448 50. Davis JN, Tung A, Chak SS, et al. Aerobic and strength training reduces adiposity in overweight Latina adolescents. Med Sci Sports Exerc. 2009;41(7):1494–1503 51. Lee S, Bacha F, Hannon T, Kuk JL, Boesch C, Arslanian S. Effects of aerobic versus resistance exercise without caloric restriction on abdominal fat, intrahepatic lipid, and insulin sensitivity in obese adolescent boys: a randomized, controlled trial. Diabetes. 2012;61(11):2787–2795 52. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560 53. Karacabey K. The effect of exercise on leptin, insulin, cortisol and lipid profiles in obese children. J Int Med Res. 2009;37(5): 1472–1478 54. Rosenberg MS. The file-drawer problem revisited: a general weighted method for calculating fail-safe numbers in metaanalysis. Evolution. 2005;59(2):464–468 55. Rosenthal R. Meta-Analytic Procedures for Social Research. 2nd ed. Newbury Park, CA: SAGE Publications; 1991 56. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315 (7109):629–634
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Exercise and Insulin Resistance in Youth: A Meta-Analysis Michael V. Fedewa, Nicholas H. Gist, Ellen M. Evans and Rod K. Dishman Pediatrics 2014;133;e163; originally published online December 2, 2013; DOI: 10.1542/peds.2013-2718 Updated Information & Services
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/133/1/e163.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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Exercise and Insulin Resistance in Youth: A Meta-Analysis AUTHORS: Michael V. Fedewa, MA,a Nicholas H. Gist, PhD,a,b Ellen M. Evans, PhD,a and Rod K. Dishman, PhDa
abstract
aDepartment
BACKGROUND AND OBJECTIVES: The prevalence of obesity and diabetes is increasing among children, adolescents, and adults. Although estimates of the efficacy of exercise training on fasting insulin and insulin resistance have been provided, for adults similar estimates have not been provided for youth. This systematic review and meta-analysis provides a quantitative estimate of the effectiveness of exercise training on fasting insulin and insulin resistance in children and adolescents.
of Kinesiology, University of Georgia, Athens, Georgia; and bDepartment of Physical Education, United States Military Academy, West Point, New York KEY WORDS adolescent, child, exercise training, insulin, insulin resistance ABBREVIATIONS BIC—Bayesian information criterion CI—confidence interval ES—effect size HOMA—homeostasis model assessment IR—insulin resistance T2DM—type 2 diabetes mellitus Mr Fedewa conceptualized and designed the study, conducted the initial analysis, and drafted the initial manuscript; Dr Gist coded and analyzed effects and reviewed and revised the initial manuscript; Dr Evans assisted with conceptualizing and designing the study and reviewed and revised the initial manuscript; Dr Dishman assisted with conceptualizing and designing the study, performed additional statistical analysis, and critically reviewed and revised the initial manuscript; and all authors approved the final manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2013-2718 doi:10.1542/peds.2013-2718 Accepted for publication Oct 23, 2013 Address correspondence to Michael V. Fedewa, MA, Department of Kinesiology, 330 River Rd, Ramsey Center, University of Georgia, Athens, GA 30602-6554. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2014 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
METHODS: Potential sources were limited to peer-reviewed articles published before June 25, 2013, and gathered from the PubMed, SPORTDiscus, Physical Education Index, and Web of Science online databases. Analysis was limited to randomized controlled trials by using combinations of the terms adolescent, child, pediatric, youth, exercise training, physical activity, diabetes, insulin, randomized trial, and randomized controlled trial. The authors assessed 546 sources, of which 4.4% (24 studies) were eligible for inclusion. Thirty-two effects were used to estimate the effect of exercise training on fasting insulin, with 15 effects measuring the effect on insulin resistance. Estimated effects were independently calculated by multiple authors, and conflicts were resolved before calculating the overall effect. RESULTS: Based on the cumulative results from these studies, a small to moderate effect was found for exercise training on fasting insulin and improving insulin resistance in youth (Hedges’ d effect size = 0.48 [95% confidence interval: 0.22–0.74], P , .001 and 0.31 [95% confidence interval: 0.06–0.56], P , .05, respectively). CONCLUSIONS: These results support the use of exercise training in the prevention and treatment of type 2 diabetes. Pediatrics 2014;133:e163– e174
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The global prevalence of pediatric type 2 diabetes mellitus (T2DM) has paralleled the rise in obesity, increasing steadily since the late 1970s.1 This endocrine disorder is caused by a combination of peripheral insulin resistance (IR) in muscle and adipose tissue and inadequate insulin secretion from the pancreas, eventually resulting in a relative insulin deficiency.2 Early dysfunction in b-cell activity and cellular IR appear long before manifestation of the signs and symptoms of T2DM.3 Deterioration of peripheral insulin sensitivity and b-cell dysfunction can be observed as the disease progresses in youth at risk for developing metabolic syndrome and T2DM.4 Puberty is marked by a decrease in physical activity5 and an increase in adiposity,6 and both are associated with IR in youth.7,8 In the clinical setting, physical activity and dietary intervention are recommended as the primary treatment methods for pediatric patients in the early stages of IR and prediabetes, with pharmacologic treatment reserved as an alternative course of action as the disease progresses.9–11
and adolescents with type 1 diabetes.20 The current study expands on the body of literature by providing a quantitative estimate of the effect size (ES) of exercise training on fasting insulin and IR for use in future research and program design with children and adolescents.
The American College of Sports Medicine presents a strong body of evidence supporting the inclusion of physical activity and exercise in the treatment and management of diabetes in adults and youth.12,13 Together, physical activity and lifestyle modifications can effectively reduce the development of and/or slow the progression of IR.14 Previous reviews have established that aerobic and resistance training can be used to improve the regulation of glucose, as well as provide a synergistic effect when combined in a structured exercise program across all ages.15–17 Although previous original research and subsequent reviews provide the basis for including physical activity and exercise training in the treatment program for the prevention of T2DM, meta-analytic reviews of exercise and fasting insulin have been limited to adults18,19 or children
The inclusion criteria for our analysis were as follows: (1) peer-reviewed publication; (2) available in English; (3) involving human subjects; (4) randomized to exercise training or a nonexercise comparison; and (5) fasting insulin or IR measures at baseline, during, and/orafter exercise training. Excluded records had the following characteristics: (1) were non–peer reviewed; (2) provided a review, meta-analysis, position statement, or proposed study design; (3) sampled subjects aged ,6 or .19 years; (4) used a cross-sectional or prospective study design; (5) included exercise as 1 part of a multicomponent treatment (eg, exercise + diet), from which an ES for exercise alone could not be calculated; or (6) compared exercise only with an active treatment (eg, nutritional intervention or another mode of exercise). A total of 546 articles were
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METHODS The review was conducted in accordance with PRISMA (Preferred Reporting Items forSystematicReviewsandMeta-analyses) statement guidelines.21 Articles published by June 25, 2013, were located by using searches of the PubMed, SPORTDiscus, Physical Education Index, and Web of Science online databases using combinations of the terms adolescent, child, pediatric, youth, exercise training, physical activity, diabetes, insulin, randomized trial, and randomized controlled trial. Duplicate publications were removed. The authors manually reviewed reference lists from retrieved articles for additional publications not discovered by using the database search. Study Selection
identified during the initial search process. A flowchart of study selection is provided in Fig 1. Manual searches revealed 5 additional publications.22–27 Six articles reported fasting insulin measurements as median and interquartile range (25th–75th percentile), reported data in change scores from baseline, or did not report either premeasurement or postmeasurement data. A request for missing data was sent to each of the corresponding authors. Two of the 6 authors26,27 provided missing information and 1 author28 provided an additional publication not obtained during our initial literature search; these 3 articles were included in the final meta-analysis. ES Calculation ES values were calculated by subtracting the mean change in the comparison condition from the mean change in the exercise condition and dividing the difference by the pooled SD of the baseline scores.29 SDs from the largest study available were used to estimate the ES30 when group mean values and measures of variability were not provided.31–33 Postintervention values in these publications were reported as change scores31,32 or in figures provided by the authors.33 ES values were calculated after adjusting for small sample bias.29 IR was calculated by using fasting levels of insulin and glucose by using the homeostasis model assessment (HOMA) technique in each study included in this analysis.22,25,31,32,34–41 A decrease in fasting insulin levels or IR among participants in exercise interventions resulted in a positive ES. Two authors (M.V.F. and N. H.G.) independently calculated ES from each study, and discrepancies were resolved before aggregating effects. Statistical Analysis Random effects models were used to aggregate a mean ES and 95% confidence interval (CI) for fasting insulin and IR and to test variation in effects
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FIGURE 1 Flowchart of study selection.
according to moderator variables by using macros (MeanES and MetaReg) in IBM SPSS version 20.0 (IBM SPSS Statistics, IBM Corporation, Armonk, NY). The number of potential moderators was restricted due to the small number of effects. Univariate linear regression was then used to estimate the independent effect of exercise on fasting insulin level based on baseline pubertal status, gender, and BMI, chosen a priori due to their strong influence on fasting insulin and metabolic syndrome in this population.7,42 Because
effects were nested within studies, a multilevel mixed model linear regression model with robust maximum likelihood estimation was also used to adjust for between-study variance and correlated effects within studies according to standard procedures43,44 by using Mplus 7.0.45 Parameters and their errors were estimated with clustering on study by using the Huber-White sandwich estimator to calculate SEs that are robust to heteroscedasticity and correlated effects.46–48 The effect of each moderator on fasting
insulin effects was tested separately by comparing each conditional model (which included the intercept and the moderator) with the unconditional intercept-only model by using a likelihood ratio test and the adjusted Bayesian information criterion (BIC).45 Significant interactions were decomposed by using 95% CIs.44,49
RESULTS Thirty-two effects were derived from 24 studies, with 1599 children measured at
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baseline. Data available for study and participant characteristics are presented as mean 6 SD. Sample size ranged from 8 to 140 subjects per treatment group (25.4 6 23.8 subjects per group). Each of the exercise training interventions varied in design and included aerobic, resistance, and a combination of training modes. Study intervention length, frequency, duration, and intensity were reported inconsistently across effects. Exercise training consisted of 3.2 6 1.0 sessions per week, 53.4 6 20.0 minutes at a moderate to vigorous intensity physical activity per session for 15.5 6 11.4 weeks, when reported. The descriptive characteristics of studies included in the analysis are provided in Table 1. Participant characteristics for each exercise treatment condition were inconsistently reported as well. When reported, the exercise treatment conditions were 54.3 6 30.8% female and 11.4 6 2.8 years of age. The ages of participants ranged from 6 to 19 years, with 30 of the 32 effects involving children and adolescents with a mean age .9 years. Effects were derived from treatment groups of normal weight, overweight, and obese participants, with a mean BMI of 27.2 6 4.9. Mean weight and relative adiposity (ie, percentage of body fat) were 64.5 6 19.8 kg and 34.9 6 7.5%, respectively. The cumulative results of 32 effects gathered from 24 studies published between 1999 and 2013 agree that exercise training effectively reduces fasting insulin levels in children and adolescents with a mean ES equal to 0.48 (95% CI: 0.22–0.74; z = 3.57; P , .001) (Figure 2). In the multilevel, intercept-only model (x 2 [2] = 142.0, BIC = 144.8), the mean ES was 0.54 (95% CI: 0.21–0.87) with significant variance (0.537, SE = 0.211, z = 2.55, P = .011) between effects. Twenty-six (81.3%) of the 32 effects were larger than zero. Similar results were found for IR, as the cumulative results of 15 effects gathered from 12 studies published between 2006 e166
and 2013 agree that exercise training effectively reduces IR with a mean ES of 0.31 (95% CI: 0.06–0.56), z = 2.39, P , .05) (Figure 3). In the multilevel, interceptonly model (x2 [2] = 49.4, BIC = 48.7), the mean ES for IR was 0.32 (95% CI: 0.06–0.58) with marginally significant variance (0.116, SE = 0.068, z = 1.69, P = .09) between effects. Twelve (80.0%) of the 15 effects were larger than zero. These results were consistent for male and female subjects, regardless of age or ethnicity. Forest plots for the effect of exercise training on fasting insulin and IR are shown in Figs 2 and 3, respectively. Moderatoranalysis furtheradjusted for nesting of effects within a single study and to reduce the likelihood of potential bias being introduced into the analysis. Sixteen of the 32 effects for fasting insulin were gathered from studies that provided multiple effects. Two effects could be calculated when information was reported for multiple demographic groups,32 disease populations,31 training intensities,23 session durations,33 or training modes within a single study.26,40,50,51 Six of the 15 effects examining IR were gathered studies providing multiple effects.31,32,40 Rater Agreement Two-way (effects 3 raters) intraclass correlation coefficients for absolute agreement were calculated to examine interrater reliability for fasting insulin and IR ES. The initial intraclass correlation coefficients for fasting insulin, based on 32 effects, were $0.99. After performing the intraclass correlation analysis for the 15 effects measuring the effect of exercise on IR, the coefficients were $0.93. Intraclass correlation increased to 100% after adjusting for discrepancies between reviewers (M. V.F. and N.H.G.). Homogeneity of Results Heterogeneity was indicated if Q total reached a significance level of P , .05
and the sampling error accounted for ,75% of the observed variance.29 Heterogeneity was also assessed by examination of the I2 statistic.52 An I2 value was categorized as low, moderate, or high based on calculations equal to 25%, 50%, or 75%, respectively. The significant improvement in fasting insulin levels after exercise training was highly heterogeneous (Q31 = 162.9, P , .001, I2 = 81.6%), with sampling error accounting for 24.4% of the observed variance. The significant improvement in IR after exercise training was moderately heterogeneous (Q14 = 30.67, P , .01, I2 = 57.6%), with sampling error accounting for 48.5% of the observed variance. Based on a significant Q statistic and an I2 .50% indicating moderate heterogeneity, the variability among fasting insulin is greater than would have occurred naturally based on study sample error. The null hypothesis for homogenous distribution was rejected, and regression analysis was thus used to identify potential moderators. Pubertal status was determined according to reported Tanner stage. Eleven studies did not provide pubertal status in ausableformforouranalysisbecause:(1) it was not reported at all23,24,26,27,38–40,53; (2) it was reported in a range of stages34; or (3) it was reported for the entire sample.22,32 The initial regression model based on baseline BMI (k = 28) was significant (R2 = 0.15, b = 0.38, z = 2.25, P , .05). Gender (k = 27) and pubertal status (k = 16) were not independently associated with the effect of exercise on fasting insulin in the age range of our analysis (R2 = 0.07, b = 0.26, z = 1.44 and R2 = 0.08, b = –0.28, z = –1.18, respectively; all P . .05). BMI remained significant after controlling for gender in a multivariate regression analysis based on 26 effects reporting both moderating variables (b = 0.44, z = 2.61, P , .01). Because the number of effects included in the regression analysis decreased to 13 when gender, pubertal status, and BMI
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TABLE 1 Studies Examining the Effect of Exercise Training on Fasting Insulin and IR in Children and Adolescents Source
N
Gender (M/F)
Age (y)
Benson et al,35 2008 Ben Ounis et al,34 2008 Buchan et al,23 2011
78 24 57
46/32 24/0 10/47
12.3 6 1.3 12–14 16.4 6 0.7
Davis et al,33 2012 Davis et al,50 2009 Davis et al,22 2009 Davis et al,36 2011 de Piano et al,31 2012 Farpour-Lambert et al,37 2009 Ferguson et al,57 1999 Gutin et al,28 2011 Hasson et al,32 2012 Karacabey,53 2009 Kelly et al,58 2004 Kim et al,38 2007 Kim et al,27 2008 Lau et al,24 2004 Lee et al,51 2012 McCormack et al,41 2013 Meyer et al,39 2006 Shaibi et al,59 2006 Shalitin et al,25 2009 Suh et al,26 2011 Sun et al,40 2011
222 41 54 38 58 44
94/128 0/41 28/26 0/38 27/31 16/28
79 242 100 40 20 26 17 36 45 18 67 21 162 30 93
Intervention Groups
Duration (min/d)
Frequency (d/wk)
Study Length (wk)
— 90 3–20
2 4 3
8 8 7
9.4 6 1.1 15.2 6 1.1 15.5 6 1.0 15.8 6 1.1 16.5 6 1.4 8.9 6 1.5
RT or CON AT, AT + diet, or diet Moderate-intensity AT, high-intensity AT, or CON High-dose AT, low-dose AT, or CON RT + diet, RT + AT + diet, or CON RT + diet, diet, or CON RT + diet, RT + AT + diet, diet, or CON RT + diet, RT + AT + diet, or diet RT + AT or CON
20–40 60 60 60–90 60 60
5 2 2 2 3 3
13 16 16 16 52 12
26/53 0/242 39/61 40/0 9/11 26/0 17/0 24/12 45/0 5/13
9.5 6 1.0 8–11 15.4 6 1.1 11.8 6 0.5 10.9 6 2.0 17.0 6 0.1 11.0 6 0.0 10–17 12–18 13.0 6 1.9
AT or CON RT + AT + games or CON RT + diet or diet AT or CON AT or CON AT or CON RT + AT or CON AT + diet or diet RT, AT, or CON RT + AT or CON
40 80 — 30–60 30–50 40 50 60 60 60
5 5 2 3 4 5 2 3 3 3
16 10 16 12 8 6 12 6 12 8
34/33 21/0 81/81 15/15 46/47
14.7 6 2.2 15.4 6 1.6 6–11 13.1 6 0.5 13.6 6 0.7
AT or CON RT or CON RT + AT, RT + AT + diet, or diet RT + diet, AT + diet, or diet AT, diet, AT + diet, or CON
60–90 60 90 40–60 40
3 2 3 3 4
24 16 12 12 10
Age is reported as mean 6 SD when available or the age range of participants included in the study. Empty cells are present when a component of the training protocol was not provided by the author. AT, aerobic training; CON, control group; F, female; M, male; RT, resistance training.
were included together in the model, a thorough multivariate analysis including all 3 moderators was not performed. In the multilevel model, adding BMI (b = 0.05, SE = 0.026, z = 1.97, P = .049) improved model fit (x 2 [3] = 119.6, BIC = 120.28) compared with the interceptonly model (D x 2 [1] = –10.8, P , .001). The residual variance was 0.301 (SE = 0.177, z = 1.70, P = .089), indicating that 44% of the variance between fasting insulin effects was explained by BMI.
model for IR (b = 0.03, SE = 0.014, z = 1.78, P = .075) improved model fit (x2 [3] = 40.4, BIC = 39.0) compared with the intercept-only model (D x2 [1] = –70.2, P , .001). The residual variance was 0.066 (SE = 0.047, z = 1.40, P = .161), indicating that 43% of the variance between IR effects was explained by BMI after adjusting for nesting of effects within studies.
The regression analysis was repeated to examine the potential moderating influence of gender, pubertal status, and BMI on IR. Based on the univariate analysis of each potential moderator, the regression models were not significant (all P . .05). Gender (b = –0.05, z = –0.17), pubertal status (b = 0.11, z = 0.20), and BMI (b = 0.35, z = 1.30) were not significantly associated with IR. However, adding BMI to the multilevel
Fail Safe-N The number of unpublished or unretrieved null effects that would diminish the significance of observed effects to P , .05 was estimated as the fixed effects fail-safe N. A fail-safe N1 represents the relative sample size of 1 additional effect that would be needed to lower the average ES to a nonsignificant value. A fail-safe N+ represents the minimal number of additional null effects
from multiple studies of average sample size needed to reach a similar null conclusion.54 The fail-safe N for the measures of fasting insulin estimated N1 = 340.7 and N+ = 368.1 effects by using the calculations for a fixed effects model suggested by Rosenberg. The estimated random effects model resulted in N1 = 16.5, while N+ collapsed to a fixed effects model. The fail-safe N for the effect of exercise on IR estimated with the fixed effects model was N1 = 22.9 and N+ = 27.2. The estimated random effects model resulted in N1 = 2.1 and N+ = 2.6. Based on earlier research from Rosenthal,55 the fail-safe N is considered robust when the value exceeds 5N+10, in which N represents the number of original effects. A fail-safe N is a calculation that provides a method to estimate when publication bias can be “safely ignored” and should not be considered as a method for identifying or controlling for potential
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FIGURE 2 Forest plot of Hedges’ d ES. The aggregated Hedges’ d is the random effects mean ES for exercise training on fasting insulin weighted by the pooled SD.
publication bias.54 Potential publication bias was addressed by using a funnel plot and the Egger test.56 Funnel plots provide a visual assessment of possible publication bias and identify potential outliers. Funnel plots for the effect of exercise training on fasting insulin and IR can be found in Figs 4 and 5, respectively. e168
The Egger test was used to assess whether the variation in ES was due to potential publication bias. Our results suggest the mean effect of exercise training on fasting insulin and IR was not subject to publication bias (F[1,30] = 0.003 [P = .95] and F[1,13] = 0.05 [P = .83], respectively).
Effect of Potential Outliers Nine effects from the 8 studies outside of the 95% CI were identified by using the forest plot to identify potential outliers.23,25,28,40,51,53,57,58 Sensitivity analysis removing these 9 effects decreased the mean effect of exercise on fasting insulin in children and adolescents from
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FIGURE 3 Forest plot of Hedges’ d ES. The aggregated Hedges’ d is the random effects mean ES for exercise training on IR weighted by the pooled SD.
0.48 (95% CI: 0.22–0.74; z = 3.57; P , .001) to 0.34 (95% CI: 0.19–0.48; z = 4.51; P , .001) for the remaining 24 effects. When examining IR, 3 effects from 2 studies outside of the 95% CI were identified by using the forest plot to identify potential outliers.40,57 Removing these 3 effects increased the mean effect of exercise on fasting insulin in children and adolescents from 0.31 (95% CI: 0.04–0.57; z = 2.39; P , .05) to 0.38 (95% CI: 0.19– 0.57; z = 3.97; P , .001) for the remaining 12 effects.
DISCUSSION The cumulative results of our analysis support the belief that exercise is effective in decreasing fasting insulin and improving IR in children and adolescents. Our results are unique in that they provideaquantitativeestimateoftheeffectof exercise on outcome measures of insulin, while assessing the influence of potential moderators, including BMI and sexual maturation. Although performed in a separate clinical population, our results
are consistent with a previous metaanalysis that evaluated the effect of exercise on glycemic control in children and adolescents with type 1 diabetes (ES = 0.37 [95% CI: 0.02–0.77]).20 Regular physical activity and exercise training should be included as an effective component of a treatment program for T2DM in children and adolescents. Exercise seems to be most effective in improving insulin status in children and adolescents with high BMI, most likely because these individuals exhibit the greatest deviation from normal values. Physical activity interventions designed to improve cardiometabolic risk may have a small effect in children unless they are selected specifically for their unfavorable risk profiles.28 Obese adolescents showed significantly greater IR than their lean peers, which may provide a “floor effect” and greater room for improvement after training in overweight and obese adolescents.38 As hypothesized, BMI was found to moderate the effect of exercise on fast-
ing insulin in our study sample such that a greater effect was observed in children and adolescents with higher BMI. Translating these research findings into a measurable improvement in clinical outcomes would equate to a 11.4-U/mL (95% CI: 5.2–17.5) improvement in fasting insulin and an improvement in HOMA-IR of 2.0 (95% CI: 0.4–3.6) in obese children, based on recent estimates from Körner et al.59 Based on the results of the regression analysis, the effect of exercise training on fasting insulin was not affected by pubertal status of the child. Puberty is marked by significant changes in fasting insulin and IR. The transient physiologic IR experienced at the beginning of puberty (Tanner stage 2) typically peaks during Tanner stage 3 and returns to prepubertal levels during Tanner stage 5.7,60 Over a 2-year period, children who remained at Tanner stage 1 experienced a small increase in insulin-like growth factor 1, whereas children who matured from stage 1 to stage 3 or 4
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FIGURE 4 Funnel plot of Hedges’ d ES versus study SE. The aggregated Hedges’ d is the random effects mean ES for exercise training on fasting insulin weighted by the pooled SD.
experienced a 1.7-fold increase in insulinlike growth factor 1, accompanied by a 39% decrease in insulin sensitivity.60 It is intuitive that exercise training may be the most effective for children and adolescents when IR is greatest; however, our analysis was not sufficiently powered to detect these differences. Further research is needed to fully examine the effect of exercise training on fasting insulin and IR when accounting for other moderators because changes in insulin sensitivity during puberty are attenuated when controlling for changes in body mass.61 In our regression model, the percentage of male participants in each effect did not significantly influence the effect of exercise on fasting insulin or IR. Female subjects typically exhibit higher e170
fasting insulin, greater IR, and are less insulin sensitive during adolescence; however, the changes are consistent across genders.7,61 One-half of the gender-related differences in fasting insulin and IR could be explained by differences in adiposity in a group of 357 white and African-American adolescents.7 Fasting insulin among 11 adolescent girls was significantly higher than among 13 adolescent boys; however, BMI was again found to be a significant covariate.61 Further research is needed to examine the moderating effect of gender on fasting insulin and IR after exercise training. A variety of training interventions were used across studies, including resistance training, aerobic training, and circuit training, as well as nontraditional
games and play to increase the physical activity levels of the participants. However, afteraccounting for the influenceof participant BMI, these potential moderators did not affect our outcome. We found no difference between aerobic or resistance training protocols, suggesting the most important component of an exercise program designed to target fasting insulin and IR in children and adolescents may not be “how” they are encouraged to move but simply that they encouraged to move at all. More research is needed to determine the most effective delivery mode for the intervention that will be sustainable and to encourage longer term adherence and behavior change in participants. For example, a circuit training approach
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FIGURE 5 Funnel plot of Hedges’ d ES versus study SE. The aggregated Hedges’ d is the random effects mean ES for exercise training on IR weighted by the pooled SD.
allowed sedentary overweight and obese adolescents to train at 70% to 85% of their maximum heart rate for 60 to 90 minutes by dividing their exercise training into 2-minute bouts followed by 1 minute of recovery between activities.36 Davis et al50 suggest training programs involving a combination of aerobic and resistance training can incorporate short aerobic intervals into circuit training and allow overweight and obese adolescents with low aerobic fitness to accumulate the required duration of aerobic exercise and improve adherence by incorporating smaller, more manageable exercise bouts. Study duration of the exercise intervention was not a significant moderator of the effect of exercise on fasting
insulin secretion, despite a previous hypothesis by other researchers that short and long interventions could influence fasting insulin secretion differently.38 Improvement in fasting insulin and IR can occur after exercise training in the absence of improvements in weight or body composition.41 Short-term interventions may improve IR by acting peripherally to improve insulin sensitivity in the muscle, whereas long-term interventions may improve body composition and improve IR through other mechanisms.62 Because our results suggest the length of the intervention may not significantly influence insulin response to training, further research is needed to thoroughly evaluate this hypothesis in children.
These results provide the basis for including physical activity and exercise training in the treatment program for the prevention of T2DM. However, a void in the literature has been identified, and additional well-designed randomized controlled trials are needed to determine the individual effects of exercise mode, duration, intensity, and frequency on fasting insulin levels in children because a larger body of evidence has found that these components influence glycemic control in adults.15,63 It should not be assumed that the physiologic response to these exercise moderators is similar in children, and future published research should provide a clear description of the exercise intervention (eg, intensity, duration,
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frequency, attendance) to allow for a more thorough meta-regression analysis, with adequate statistical power to determine the influence of these potential moderators in pediatric populations. In addition, this analysis provides a quantitative estimate of the effect of exercise training and provides justification for including physical activity in interventions aimed at improving fasting insulin or IR. To provide the most accurate estimate of the effect of exercise training alone, interventions that combined diet and exercise components were excluded from our analysis only when an independent effect of exercise could not be estimated. Determining the effect of dietary modification in addition to exercise training was beyond the scope of the current review. However, health professionals and researchers would be remiss to not suggest dietary change in addition to regular exercise; well-designed lifestyle education
involving a combination of diet and physical activity treatment therapies could provide health benefits beyond that of exercise alone.
CONCLUSIONS
race, and age, our results suggest that this analysis is an accurate estimate of the magnitude of the effect in youth aged 6 to 19 years. Although the relatively small body of published literature did not allow for a thorough analysis of the effect of frequency, duration, intensity, mode, or volume of exercise, the beneficial effects of exercise training on fasting insulin and IR are clear. In the absence of a clear consensus on the most effective type of exercise for treating these outcomes, emphasis should be placed on ways to incorporate daily physical activity, in addition to “exercise training,” into the lives of children and adolescents, especially those at risk for developing obesity and diabetes.
Based on the cumulative results from peer-reviewed research published between 1999 and 2013, a small to moderate effect was found for exercise training improvements in fasting insulin levels and IR in children and adolescents. Measurable improvements in clinically relevant insulin outcomes (11.4 U/mL [95% CI: 5.2–17.5] and 2.0 [95% CI: 0.4–3.6] in fasting insulin and HOMA-IR, respectively) will help physicians and health care professionals implement research findings into patient treatment and disease prevention. Because this small to moderate effect in fasting insulin and IR in children and adolescents was consistent across gender,
ACKNOWLEDGMENT The authors thank Dr. Timothy W. Puetz for his assistance with graphical representation of results.
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Exercise and Insulin Resistance in Youth: A Meta-Analysis Michael V. Fedewa, Nicholas H. Gist, Ellen M. Evans and Rod K. Dishman Pediatrics 2014;133;e163; originally published online December 2, 2013; DOI: 10.1542/peds.2013-2718 Updated Information & Services
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