Accepted Article Preview: Published ahead of advance online publication

Physical activity intensity and type 2 diabetes risk in overweight

youth: A randomized trial

J Hay, K Wittmeier, A MacIntosh, B Wicklow, T Duhamel, E

Sellers, H Dean, E Ready, L Berard, D Kriellaars, G X Shen,
P Gardiner, J McGavock

Cite this article as: J Hay, K Wittmeier, A MacIntosh, B Wicklow, T Duhamel, E

Sellers, H Dean, E Ready, L Berard, D Kriellaars, G X Shen, P Gardiner, J
McGavock, Physical activity intensity and type 2 diabetes risk in overweight
youth: A randomized trial, International Journal of Obesity accepted article
preview 30 November 2015; doi: 10.1038/ijo.2015.241.

This is a PDF file of an unedited peer-reviewed manuscript that has been accepted
for publication. NPG are providing this early version of the manuscript as a service
to our customers. The manuscript will undergo copyediting, typesetting and a proof
review before it is published in its final form. Please note that during the production
process errors may be discovered which could affect the content, and all legal
disclaimers apply.

Received 22 July 2015; accepted 13 August 2015; Accepted article preview online
30 November 2015

© 2015 Macmillan Publishers Limited. All rights reserved.

Physical Activity Intensity and Type 2 Diabetes Risk in Overweight Youth: A randomized trial.

Jacqueline Hay MSc1,2,4*, Kristy Wittmeier PhD1,2*, Andrea MacIntosh BSc1, Brandy Wicklow
PhD1,2 Todd Duhamel PhD4,7,3,8, Elizabeth Sellers MD1,2, Heather Dean MD1,2, Elizabeth Ready
PhD4,7, Lori Berard RN6, Dean Kriellaars PhD5, Garry X. Shen, MD6, Phillip Gardiner PhD3,4,7,
Jonathan McGavock PhD1-4

Affiliations: (1) Children’s Hospital Research Institute of Manitoba, Winnipeg, Manitoba,

Canada (2) Department of Pediatrics and Child Health, Faculty of Medicine, University of
Manitoba, Winnipeg, Manitoba, Canada (3) Department of Physiology, Faculty of Medicine,
University of Manitoba, Winnipeg, Manitoba, Canada (4) Faculty of Kinesiology and Recreation
Management, University of Manitoba, Winnipeg, Manitoba, Canada (5) Faculty of Medical
Rehabilitation, University of Manitoba, Winnipeg, Manitoba, Canada (6) Diabetes Research
Group, Health Sciences Centre of Winnipeg, Manitoba, Canada (7) Health, Leisure and Human
Performance Research Institute, Winnipeg, Manitoba, Canada (8) Institute of Cardiovascular
Sciences, St. Boniface Research Centre, Winnipeg, Manitoba, Canada.

*Both authors contributed equally to this work.

Address of Correspondence: Jonathan McGavock, PhD, Department of Pediatrics and Child

Health; Faculty of Medicine, University of Manitoba. Children’s Hospital Research Institute of
Manitoba. 511D - 715 McDermot Ave, Winnipeg, MB R3E 3P4 [jmcgavock@chrim.ca]
Phone: 204-480-1359

Running Title: Exercise and diabetes risk in youth

Key words: Steatosis, vigorous intensity, insulin sensitivity, visceral obesity

Abbreviations: ET = endurance training

Word count: 3250

Abstract word count: 199
References: 40
Number of Tables: 4
Number of Figures: 2

1|Page © 2015 Macmillan Publishers Limited. All rights reserved.

ABSTRACT

Background: The chronic effects of high intensity endurance training on metabolic health
outcomes in overweight adolescents remains poorly understood.

Objective: To test the hypothesis that high intensity endurance training (ET) is superior to
moderate intensity ET for improving risk factors for type 2 diabetes in overweight adolescents.

Design and Methods: In this randomized trial, 106 overweight and obese adolescents (15.2
years; 76% female; 62% Caucasian) were randomly assigned to high intensity ET (70-85% of
heart rate reserve, n=38), moderate intensity ET (40-55% heart rate reserve; n=32), or control for
6 months (n=36). The primary and secondary outcome measures were insulin sensitivity assessed
using a frequently sampled intravenous glucose tolerance test and hepatic triglyceride content
with magnetic resonance spectroscopy. Exploratory outcomes were cardiorespiratory fitness,
physical activity and MRI and dual x-ray absorptiometry-derived measures of adiposity.

Results: The study had 96% retention and attendance was 61 ± 21% and 55 ± 24% in the high
and moderate-intensity ET arms. Intention to treat analyses revealed that, at follow-up, insulin
sensitivity was not different between high intensity (-1.0 mU/kg/min; 95% CI: -1.6, +1.4
mU/kg/min) and moderate intensity (+0.26 mU/kg/min; 95% CI: -1.3, +1.8 mU/kg/min) ET arms
compared to controls (interaction, p = 0.97). Similarly, hepatic triglyceride at follow-up was not
different in high intensity (-1.7 %F/W; 95% CI: -7.0, +3.6 %F/W) and moderate intensity (-0.40
%FW; 95% CI: -6.0, +5.3 %F/W) ET compared to controls. Both high intensity (+4.4 mL/kg-
FFM/min; 95% CI: 1.7, 7.1 mL/kg-FFM/min) and moderate intensity +4.4 mL/kg-FFM/min;
95% CI: 1.6, 7.3 mL/kg-FFM/min) increased cardiorespiratory fitness, relative to controls
(interaction p < 0.001).

Conclusions: ET improves cardiorespiratory fitness among obese adolescents; however, due to

lack of compliance, the influence of exercise intensity on insulin sensitivity and hepatic
triglycerides remains unclear.

Trial Registration: Clinical Trials Identifier: NCT00755547

2|Page © 2015 Macmillan Publishers Limited. All rights reserved.

INTRODUCTION

Randomized trials have documented dose-dependent improvements in risk factors for

type 2 diabetes mellitus with increased duration of physical activity in overweight children1 2.

Less evidence exists for the importance of exercise intensity on measures of diabetes risk,

particularly among obese and overweight adolescents3. High intensity endurance training (ET) is

a promising training approach for improving health benefits4, including risk factors for type 2

diabetes. A series of small randomized trials recently documented significant improvements in

several diabetes-related outcomes, including glucose control5, vascular health6, insulin

sensitivity6 , and hepatic triglyceride content7 when short bouts of high intensity ET were added

to moderate intensity training sessions. These data suggest high intensity ET is a promising

training approach for improving health benefits4, however the effectiveness of high intensity

exercise on diabetes risk among obese and overweight adolescents remains poorly understood.

Studies by our group and others reveal that ectopic lipid accumulation is a robust

predictor of type 2 diabetes among overweight adolescents8,9,10. Specifically, the presence of

excessive hepatic triglyceride is associated with reduced insulin sensitivity, an increased risk of

the metabolic syndrome and elevated post-prandial glucose8,9,10. The role of modifiable lifestyle

factors in the prevention and treatment of hepatic steatosis in adolescents is very poorly

understood. A limited number of efficacy trials suggest that high intensity ET significantly

reduces hepatic triglyceride in the short term, however the effectiveness of ET when delivered

over a longer intervention for the prevention of lipid accumulation in the liver of obese

adolescents remains unclear7,11.

The only experimental trial comparing the effects of varying exercise intensities on

measures of diabetes risk in overweight youth suffered from poor adherence to the intervention

3|Page © 2015 Macmillan Publishers Limited. All rights reserved.

and high loss to follow-up3 12
. Therefore, the effectiveness of high intensity endurance ET

compared with moderate intensity ET on risk factors for type 2 diabetes in overweight and obese

adolescents remains unclear. Consequently, we performed a 3-arm randomized trial to test the

hypothesis that high intensity ET improves risk factors for type 2 diabetes, particularly insulin

sensitivity and hepatic triglyceride content, to a greater extent than moderate intensity ET and

control conditions.

METHODS AND PROCEDURES

To test the study hypotheses, we conducted a parallel arm randomized trial comparing the

effect of 6 months of high intensity (70-85% of heart rate reserve) interval ET or moderate

intensity (40-55% of heart rate reserve) continuous ET on measures of insulin sensitivity and

hepatic triglyceride to a control condition (Clinical Trials Identifier: NCT0075554). We

randomized 106 participants between May 2008 and July 2012. Fourteen of the control

participants were re-randomized after the 6-month control period into one of the exercise arms

however data for these youth were not included in the final analysis. Six youth were lost to

follow up, valid data for insulin sensitivity and hepatic triglyceride content were unavailable in 3

and 11 participants at baseline, respectively (Figure 1). All youth were studied at a local pediatric

research centre and the interventions were delivered at community recreation facilities. Eligible

youth were 13-19 years of age, overweight or obese based on age and sex-specific BMI

standards13 and displayed at least one additional risk factor for type 2 diabetes: (1) a family

history of type 2 diabetes, (2) member of a high-risk ethnic group14 (i.e. South Asian or

Indigenous), (3) fetal exposure to diabetes (mother had gestational or pre-gestational diabetes)15,

evidence of non-alcoholic fatty liver disease (peak hepatic triglyceride to water ratio > 5.5%)8, or

4|Page © 2015 Macmillan Publishers Limited. All rights reserved.

(4) elevated liver enzymes (>30 U/L) 9. The study was approved by the University of Manitoba

Biomedical Research Ethics Board and performed according to the Declaration of Helsinki.

Parents and adolescents provided written informed consent to participate in the study.

Adolescents were excluded if they presented with (1) a diagnosis of type 2 diabetes or

dysglycemia; (2) severe obesity or an injury that would prevent them from exercising; (3)

experienced significant weight loss in the 6 months prior to enrollment, (4) were enrolled in a

weight loss program; (5) were receiving medications known to affect metabolism; or (6) were

pregnant .

Participants that completed at least four of six scheduled training sessions during a 2-

week run-in phase were randomized (Figure 1) in a 1:1:1 allocation ratio in blocks of 15. The

sequences were generated from an online tool by an investigator not involved in the allocation of

participants to study arms. All participants originally randomized to the control arm were

provided with an opportunity to be re-randomized to one of the two intervention arms following

the 6 month wait-list period. The re-randomization sequence was not blocked and the sequence

was generated from the same on-line tool, by an investigator not involved in the allocation of

participants to the study arms. Allocation was performed using an opaque envelope by an

investigator unfamiliar with the randomization scheme. Participants randomized to the control

condition were asked to continue with their activities of daily living and refrain from beginning

an exercise program during the 6-month study period. Participants were not blinded to allocation,

however, investigators assessing outcomes were blinded to participant allocation.

Intervention: The intervention consisted of structured endurance ET offered three times weekly

for six months at local YMCA locations in Winnipeg, Canada under the supervision of

kinesiologists, kinesiology students or study investigators. For both intervention arms, ET was

5|Page © 2015 Macmillan Publishers Limited. All rights reserved.

offered for 30-45 minutes at either 40-55% (moderate intensity arm) or 70-85% (high intensity

arm) of heart rate reserve. Both the exercise intensities selected for the ET arms encompass the

lower and higher ranges recommended to attain health benefits16, however, the intensity selected

for the high intensity ET arm is hypothesised to improve insulin sensitivity 17,18, secondary to the

activation of the enzyme 5`-AMP activated protein kinase (AMPK)19-21and by reducing the

burden of intracelllular steatosis via increased mitochondrial fatty acid oxidation22 23

. The

exercise intensity was prescribed using heart rate reserve, which was calculated from resting and

maximal heart rate values collected at baseline. Exercise intensity was monitored throughout

each session with a Polar Heart Rate Monitor (Polar Electro, Finland) by the supervising

kinesiologist or staff member. Participants self-selected exercise mode; however treadmill

walking and running were encouraged. The duration of each exercise session was adjusted to

match caloric expenditure in the two exercise arms at ~350kcal/session24 25.

Energy expenditure during exercise was estimated from a submaximal exercise test with

three workloads lasting four to five minutes performed at the beginning of the intervention.

Oxygen uptake and heart rate in the final minute of each workload were used to create a

regression for each participant to estimate caloric expenditure assuming an energy cost of 5

kcals/L of oxygen consumed.

Outcome Measures: The primary and secondary outcome measures were insulin sensitivity and

hepatic triglyceride content respectively. Measures of central adiposity, cardiorespiratory fitness

and physical activity levels were considered exploratory measures.

Insulin sensitivity was measured with a modified frequently sampled intravenous glucose

tolerance test8. Glucose and insulin kinetics were modeled using the Bergman Minimal Model

using customized software (MINMOD) to quantify insulin sensitivity and beta cell function26.

6|Page © 2015 Macmillan Publishers Limited. All rights reserved.

Follow-up measures of insulin sensitivity were performed at least 72 hours after the last training

session to distinguish the chronic effects of ET from the acute effects of exercise. Hepatic

triglyceride was quantified from 64 sequentially acquired spectra using proton magnetic

resonance spectroscopy on a 1.5 (General Electric Medical Systems, Milwaukee, WI) or 3 Tesla

(Trio, Siemens) whole-body magnet, as previously described8. LC Model software was used to

quantify the area under each peak8. Hepatic steatosis was defined as a peak triglyceride to water

ratio of greater than 5.5%, as previously described8.

Exploratory Outcomes: Visceral adipose tissue was quantified by a single axial slice using a

1.5 or 3.0 Tesla whole body magnet at the level of the 4th lumbar vertebrae, as previously

described8 27 28. Total visceral and subcutaneous adipose tissue volumes at the 4th vertebrae were

quantified offline using 3D Slicer software (Version 3.6). Waist circumference was measured in

duplicate at the height of the iliac crest with a flexible tape to the nearest 0.5 cm 29. Total fat

mass, percent body fat and trunk fat were quantified using standard dual energy x-ray

absorptiometry. Cardiorespiratory fitness was determined from expired gas analysis

(ParvoMedics, Salt Lake UT) during a graded maximal exercise test on a cycle ergometer10.

Daily physical activity was determined at baseline and post intervention by recording daily step-

counts collected over seven consecutive days using waist-mounted pedometers (StepCounts,

Deep River, Ontario, Canada)10. Resting systolic and diastolic blood pressure were measured in

triplicate in a sitting position by a Dinamap automatic machine (Laval QC.; Dinamap, Critikon,

Tampa, FL), as recommended by expert panels30.

Covariates: Puberty was measured using a self-reported Tanner staging instrument31 32

.

Ethnicity was self-declared with Aboriginal participants being First Nation or Metis.

7|Page © 2015 Macmillan Publishers Limited. All rights reserved.

Statistical Analyses

A sample of 30 youth per study arm provided 80% power to detect a 35% improvement

in insulin sensitivity between the exercise and control arms, assuming 10% variability in the

change in insulin sensitivity following ET. A sample of 40 youth per arm provided 80% power to

detect a 40% reduction in hepatic triglyceride content between the exercise arms and the control

arm assuming 10% variability in the response to training. Of the 106 randomized, 14 initially

randomized to the control group, were re-randomized to one of the two intervention arms,

providing the target sample of 120. Due to the risk of selection bias, we have restricted analyses

to the initial 106 randomized participants.

Kolmogorov-Smirnoff tests were used to test for normality and non-normally distributed

variables were analyzed using non-parametric tests (Kruskal-Wallis or Mann-Whitney U).

Group-wise differences in outcome measures and covariates measured at follow-up were

determined using a one-way analysis of variance. Post-hoc comparisons were made between

intervention arms and the control group using a Dunnett Test. Data were analyzed according to

an intention-to-treat principle, with missing values carried forward. Following intention-to-treat

analyses, sub-group analyses were conducted comparing both training groups combined with

controls. All statistical analyses were conducted using SAS software version 9.3 and SPSS

version 22. A p-value of < 0.05 was considered statistically significant.

8|Page © 2015 Macmillan Publishers Limited. All rights reserved.

RESULTS

Study flow of participants through the trial is provided in Figure 1. Baseline

characteristics of the 106 randomized youth who were included in the final intention to treat

analysis are presented in Table 1. Youth were on average 15.2 ± 1.7 years of age, 76% were

female, 62% were Caucasian, BMI-Z was 2.01 ± 0.4 and 33% presented with hepatic steatosis.

Exercise training information is provided in Table 2. Youth attended ~60% of prescribed

exercise sessions with rates declining between the first and sixth month of training. As per the

study design, youth randomized to the high intensity arm trained at a greater percentage of heart

rate reserve compared to youth randomized to the moderate intensity arm (67% vs. 55%, p <

0.001). Despite the differences in mean exercise intensity, the average energy expenditure per

session was similar between intervention arms (329 ± 60 kcals/session in the high intensity arm

vs. 316 ±78 kcals/session in the moderate intensity arm, p= 0.43) as youth in the moderate

intensity arm exercised ~15% longer (6.1 minutes/session) during each exercise session than

youth in the high intensity arm.

In the intention-to-treat analyses, no significant group wise differences were observed in

either insulin sensitivity, or hepatic triglyceride content at the end of the trial (Table 3). No

significant group wise differences were observed in any measure of adiposity (Table 3), however

there was a trend for reductions in most measures in the two intervention arms (Figure 2).

Cardiorespiratory fitness expressed relative to fat free mass increased significantly in both the

moderate intensity arm (+4.4 ± 1.4 ml/kg-FFM/min, p = 0.004) and the high intensity arm (+4.4

± 1.4 ml/kg-FFM/min, p = 0.003) relative to the control arm. There was also a trend for

increased physical activity levels in both intervention arms (+1552 ± 715 steps/day in the high

intensity, and +616 ± 770 in the moderate ET arm, p 0.09), relative to the control arm. No

9|Page © 2015 Macmillan Publishers Limited. All rights reserved.

differences in the change in fitness or physical activity levels were observed between the

moderate and high intensity exercise arms.

In sub-group analyses with both training groups combined, no statistically significant

group-wise differences were observed for main outcome measures (Table 4). Within efficacy

analyses, with outcomes restricted to adolescents that completed more than 70% of the

prescribed exercise both high and moderate intensity exercise training yielded improvements in

cardiorespiratory fitness relative to body mass and fat free mass in trained individuals compared

with the controls (Appendix 1), however there were no differences in measures of insulin

sensitivity or adiposity between the groups. The study was underpowered to examine the effect

of sex and ethnicity on outcome measures. No adverse events were reported throughout the trial.

DISCUSSION

This effectiveness trial of high intensity ET on risk factors for type 2 diabetes remains

inconclusive as adherence to the intervention over 6 months was low. Based on exploratory

analyses of those who adhered to the prescribed exercise sessions, the current trial does not

support findings from shorter efficacy trials in overweight adolescents and adults as insulin

sensitivity and hepatic triglyceride content were not improved with high intensity ET. Similar to

previous trials of overweight adolescents2 3, this experimental trial suffered from low rates of

adherence to the study intervention. Additionally, it was difficult achieving the target exercise

intensity in the high intensity arm. These two factors likely explain the disparate results between

the current effectiveness trial and previous efficacy trials of ET in obese adolescents.

Endurance exercise is a cornerstone in the prevention of type 2 diabetes in adults33 34.

Randomized trials in overweight youth and adults reveal that structured ET lasting less than 6

10 | P a g e © 2015 Macmillan Publishers Limited. All rights reserved.

months significantly improves insulin sensitivity7 35
, an established risk factor for type 2

diabetes. In contrast to these trials, the current 6-month intervention did not alter insulin

sensitivity in overweight and obese adolescents. Several factors may explain this negative

finding. First, insulin sensitivity was measured at least 72 hours after the final exercise session,

to distinguish between the acute effects of exercise from the chronic adaptations with exercise

training. Second, the majority of adolescents gained weight during the trial (+0.8 kg, 95% CI: -

0.7, +1.9kg) and weight status is an important determinant of insulin sensitivity8 10

. Finally,

lower attendance in the final month of training may have led to a wash-out of any chronic effects

observed in the first months of training. While endurance ET is efficacious for improving insulin

sensitivity in short term trials7 35, the data presented here indicate that it may be less effective in

obese and overweight adolescents when delivered over a prolonged period of time and

performed less than 3 days weekly, due to difficulties with adherence and concurrent weight

gain.

Studies by our group and others clearly demonstrate that ectopic lipid accumulation in the

liver is a robust predictor of type 2 diabetes in youth8-10. A very limited number of randomized

trials have tested the effect of ET on ectopic lipid deposition7 11. Trials that include exercise and

dietary components reveal that weight loss is associated with significant, clinically meaningful

reductions in both muscle and hepatic lipid content11 36. The only other trial published to date in

obese adolescents reported 60-100% reductions in hepatic triglyceride content after four weeks

of either high intensity endurance ET or resistance ET, performed at a dose equiavlant to current

physical activity guidelines: 5 days per week, for >60 minutes daily7. The data presented here

suggest that ET it is less effective for reducing ectopic lipid among obese adolescents if it is

11 | P a g e © 2015 Macmillan Publishers Limited. All rights reserved.

performed at frequency (3 vs. 5 days/week) or duration (~40 minutes daily) below the current

guidelines for physical activity.

Supervised chronic endurance ET (3-7 days/week of 30-60 minutes duration)

significantly reduces visceral adipose tissue in adults and youth independent of weight change35
37 38
. In obese children, doubling the duration of ET from 20 to 40 minutes daily, doubled the

reduction in measures of central adiposity35. The role of exercise intensity on measures of fat

mass is a topic of considerable interest39. We were unable to expand on this work and provide

evidence for the role of vigorous intensity exercise on visceral fat among obese adolescents, due

to the poor adherence with the intervention. Therefore, it remains unclear if higher intensity ET

can elicit greater reductions in measures of adiposity, among obese adolescents, in a manner

similar to that observed in obese adults40.

The current study has several limitations which should be acknowledged. First, the daily

exercise sessions and the weekly frequency of training were shorter than previous trials and may

have contributed to the small effect sizes presented here. Previous intervention studies suggest

that meaningful improvements in diabetes risk factors are achieved when exercise sessions last

greater than 60 minutes daily41 and when delivered 5 days/week1. Second, the sample consisted

mainly of female and Caucasian adolescents, limiting the generalizability of our findings. Third,

the variability in response to training for all measures of diabetes risk was significantly greater

than originally anticipated, limiting our ability to detect treatment effects. Finally, as the

adolescents in this trial did not achieve the intensities of exercise that we had originally

proposed, the role of high intensity on diabetes risk in overweight and obese adolescents at risk

of type 2 diabetes remains unknown.

12 | P a g e © 2015 Macmillan Publishers Limited. All rights reserved.

 In conclusion, endurance training offered 2 days weekly for 40 minutes at either

moderate or vigorous intensity improves fitness among obese adolescents. However, due to lack

of compliance to the trial (both attendance and intensity) the influence of exercise intensity on

insulin sensitivity and hepatic triglyceride content in this population remains unclear.

13 | P a g e © 2015 Macmillan Publishers Limited. All rights reserved.

Financial Disclosures: All authors have no financial disclosures to declare.

Conflicts of Interest: All authors have no conflicts of interest to declare.

ACKNOWLEDGEMENTS

Author Contributions:

J.M. conceptualized and designed the research project, carried out analyses and wrote the

manuscript. J.H. collected data, carried out analyses, reviewed and revised the manuscript.

K.W. conceptualized and designed the study, collected data, reviewed and revised the

manuscript. A.M. collected data, reviewed and revised the manuscript. T.D. collected data,

reviewed and revised the manuscript. E.S. participated in study design, collected data, reviewed

and revised the manuscript. H.D. participated in study design, collected data, reviewed and

revised the manuscript. E.R. participated in study design, collected data, reviewed and revised

the manuscript. L.B. collected data, reviewed and revised the manuscript. D.K. participated in

study design, reviewed and revised the manuscript. P.G. participated in study design, reviewed

and revised the manuscript. B.W. conceptualized and designed the study, collected data,

reviewed and revised the manuscript.

We are indebted and extremely grateful to the adolescents that participated in the

POWER trial and their parents for supporting them. We would also like to acknowledge the help

and support of the following individuals, without whom the project could not have been

completed: Mr. Paul McArthur, Ms. Catherine MacDonald, Maureen McKay RN, Ms. Jackie

Dumontet, Ms, Angella Griffith, Dr. Lawrence Ryner, Dr. Patricia Gervai, Ms. Quan Van

Uytven, and the nurses of both the Clinical Research Unit of the Manitoba Institute of Child

Health, and the Diabetes Research Group for their contributions towards data collection and

14 | P a g e © 2015 Macmillan Publishers Limited. All rights reserved.

delivery of the intervention. Dr. Jonathan McGavock had full access to all of the data in the

study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Sources: This study was supported by grants from the Canadian Institutes of Health

Research, the Lawson Foundation, the Cosmopolitan Foundation, and the Children’s Hospital

Foundation of Manitoba. Salary support for the project was provided by The Manitoba Health

Research Council (JH, BW) and Manitoba Institute of Child Health (JH), the Canadian Diabetes

Association (JM) and the Canadian Institutes of Health Research (JM, KW). The funding

agencies had no role in the design and conduct of the study; collection, management, analysis,

and interpretation of the data; and preparation, review, or approval of the manuscript. The

authors report no conflicts of interest.

15 | P a g e © 2015 Macmillan Publishers Limited. All rights reserved.

REFERENCES

1. Davis CL, Pollock NK, Waller JL, Allison JD, Dennis BA, Bassali R, et al. Exercise dose and
diabetes risk in overweight and obese children: a randomized controlled trial. Jama
2012;308(11):1103-12.
2. Ho M, Garnett SP, Baur LA, Burrows T, Stewart L, Neve M, et al. Impact of Dietary and
Exercise Interventions on Weight Change and Metabolic Outcomes in Obese Children
and Adolescents: A Systematic Review and Meta-analysis of Randomized Trials. JAMA
Pediatr 2013;167(8):759-68.
3. Gutin B, Barbeau P, Owens S, Lemmon CR, Bauman M, Allison J, et al. Effects of exercise
intensity on cardiovascular fitness, total body composition, and visceral adiposity of
obese adolescents. Am J Clin Nutr 2002;75(5):818-26.
4. Gibala MJ, Little JP, Macdonald MJ, Hawley JA. Physiological adaptations to low-volume,
high-intensity interval training in health and disease. J Physiol 2012;590(Pt 5):1077-84.
5. Little JP, Gillen JB, Percival ME, Safdar A, Tarnopolsky MA, Punthakee Z, et al. Low-
volume high-intensity interval training reduces hyperglycemia and increases muscle
mitochondrial capacity in patients with type 2 diabetes. J Appl Physiol 2011;111(6):1554-
60.
6. Tjonna AE, Lee SJ, Rognmo O, Stolen TO, Bye A, Haram PM, et al. Aerobic interval training
versus continuous moderate exercise as a treatment for the metabolic syndrome: a pilot
study. Circulation 2008;118(4):346-54.
7. 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):2787-95.
8. Wicklow BA, Wittmeier KD, MacIntosh AC, Sellers EA, Ryner L, Serrai H, et al. Metabolic
consequences of hepatic steatosis in overweight and obese adolescents. Diabetes Care
2012;35(4):905-10.
9. Schwimmer JB, Pardee PE, Lavine JE, Blumkin AK, Cook S. Cardiovascular risk factors and
the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation
2008;118(3):277-83.
10. Wittmeier KD, Wicklow BA, MacIntosh AC, Sellers EA, Ryner LN, Serrai H, et al. Hepatic
steatosis and low cardiorespiratory fitness in youth with type 2 diabetes. Obesity (Silver
Spring) 2012;20(5):1034-40.
11. Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, Rood J, et al. Effect
of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and
oxidative stress in overweight individuals: a randomized controlled trial. JAMA
2006;295(13):1539-48.
12. Kang HS, Gutin B, Barbeau P, Owens S, Lemmon CR, Allison J, et al. Physical training
improves insulin resistance syndrome markers in obese adolescents. Med Sci Sports
Exerc 2002;34(12):1920-7.
13. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing A Standard Definition For Child
Overweight And Obesity Worldwide: International Survey. BMJ: British Medical
Journal 2000;320(7244):pp. 1240-43.

16 | P a g e © 2015 Macmillan Publishers Limited. All rights reserved.

14. Canadian Diabetes Association Clinical Practice Guidelines Expert C. Canadian Diabetes
Association Clinical Practice Guidelines 2008, 2008:December 7 2010.
15. Young TK, Martens PJ, Taback SP, Sellers EA, Dean HJ, Cheang M, et al. Type 2 diabetes
mellitus in children: prenatal and early infancy risk factors among native canadians. Arch
Pediatr Adolesc Med 2002;156(7):651-5.
16. Garber CE, Blissmer B, Deschenes MR, Franklin B, Lamonte MJ, Lee I-M, et al. American
College of Sports Medicine position stand. Quantity and quality of exercise for
developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in
apparently healthy adults: guidance for prescribing exercise. Medicine and science in
sports and exercise 2011;43(7):1334-59.
17. Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, et al. Coordinated reduction
of genes of oxidative metabolism in humans with insulin resistance and diabetes:
Potential role of PGC1 and NRF1. Proceedings of the National Academy of Sciences
2003;100(14):8466-71.
18. Ukropcova B, Sereda O, de Jonge L, Bogacka I, Nguyen T, Xie H, et al. Family history of
diabetes links impaired substrate switching and reduced mitochondrial content in skeletal
muscle. Diabetes 2007;56(3):720-27.
19. Musi N, Fujii N, Hirshman MF, Ekberg I, Fröberg S, Ljungqvist O, et al. AMP-activated
protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during
exercise. Diabetes 2001;50(5):921-27.
20. Nielsen JN, Mustard KJ, Graham DA, Yu H, MacDonald CS, Pilegaard H, et al. 5′-AMP-
activated protein kinase activity and subunit expression in exercise-trained human
skeletal muscle. Journal of Applied Physiology 2003;94(2):631-41.
21. Chen Z-P, Stephens TJ, Murthy S, Canny BJ, Hargreaves M, Witters LA, et al. Effect of
exercise intensity on skeletal muscle AMPK signaling in humans. Diabetes
2003;52(9):2205-12.
22. Kuhl JE, Ruderman NB, Musi N, Goodyear LJ, Patti ME, Crunkhorn S, et al. Exercise
training decreases the concentration of malonyl-CoA and increases the expression and
activity of malonyl-CoA decarboxylase in human muscle. American Journal of
Physiology-Endocrinology and Metabolism 2006;290(6):E1296-E303.
23. Roepstorff C, Halberg N, Hillig T, Saha AK, Ruderman NB, Wojtaszewski JF, et al.
Malonyl-CoA and carnitine in regulation of fat oxidation in human skeletal muscle
during exercise. American Journal of Physiology-Endocrinology and Metabolism
2005;288(1):E133-E42.
24. Slentz CA, Aiken LB, Houmard JA, Bales CW, Johnson JL, Tanner CJ, et al. Inactivity,
exercise, and visceral fat. STRRIDE: a randomized, controlled study of exercise intensity
and amount. Journal of applied physiology (Bethesda, Md.: 1985) 2005;99(4):1613-18.
25. Gutin B, Barbeau P, Owens S, Lemmon CR, Bauman M, Allison J, et al. Effects of exercise
intensity on cardiovascular fitness, total body composition, and visceral adiposity of
obese adolescents. The American Journal of Clinical Nutrition 2002;75(5):818-26.
26. Boston RC, Stefanovski D, Moate PJ, Sumner AE, Watanabe RM, Bergman RN. MINMOD
Millennium: a computer program to calculate glucose effectiveness and insulin sensitivity
from the frequently sampled intravenous glucose tolerance test. Diabetes Technol Ther
2003;5(6):1003-15.

17 | P a g e © 2015 Macmillan Publishers Limited. All rights reserved.

27. Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM. Relationships of
Generalized and Regional Adiposity to Insulin Sensitivityin Men. The Journal of Clinical
Investigation 1995;96(1):88-98.
28. Levine BD, Zib I, Tillery T, Unger R, Victor RG, Raskin P, et al. Cardiac steatosis in
diabetes mellitus: A 1H-magnetic resonance spectroscopy study. Circulation
2007;116(10):1170-75.
29. McGuire KA, Ross R. The Revision of the Measurement of Waist Circumference in the
CPAFLA, 2008.
30. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr., et al. The
Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure: the JNC 7 report. Jama 2003;289(19):2560-72.
31. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of
Disease in Childhood 1969;44(235):291-303.
32. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of
Disease in Childhood 1970;45(239):13-23.
33. Lachin JM, Knowler WC, Barrett-Connor E, Walker EA, Hamman RF, Nathan DM, et al.
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
NEW ENGLAND JOURNAL OF MEDICINE 2002;346(6):393-403.
34. Lindström J, Louheranta A, Mannelin M, Rastas M, Salminen V, Eriksson J, et al. The
Finnish Diabetes Prevention Study (DPS) Lifestyle intervention and 3-year results on diet
and physical activity. Diabetes care 2003;26(12):3230-36.
35. Ross R, Dagnone D, Jones PJ, Smith H, Paddags A, Hudson R, et al. Reduction in obesity
and related comorbid conditions after diet-induced weight loss or exercise-induced
weight loss in men. A randomized, controlled trial. Ann Intern Med 2000;133(2):92-103.
36. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of
nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate
weight reduction in patients with type 2 diabetes. Diabetes 2005;54(3):603-8.
37. Ross R, Janssen I, Dawson J, Kungl A-M, Kuk JL, Wong SL, et al. Exercise-Induced
Reduction in Obesity and Insulin Resistance in Women: a Randomized Controlled Trial.
Obesity 2004;12(5):789-98.
38. Lee S, Kuk JL, Davidson LE, Hudson R, Kilpatrick K, Graham TE, et al. Exercise without
weight loss is an effective strategy for obesity reduction in obese individuals with and
without Type 2 diabetes. Journal of applied physiology 2005;99(3):1220-25.
39. Ross R, Bradshaw AJ. The future of obesity reduction: beyond weight loss. Nat Rev
Endocrinol 2009;5(6):319-25.
40. Slentz CA, Duscha BD, Johnson JL, Ketchum K, Aiken LB, Samsa GP, et al. Effects of the
amount of exercise on body weight, body composition, and measures of central obesity:
STRRIDE--a randomized controlled study. Arch Intern Med 2004;164(1):31-9.
41. Barbeau P, Johnson MH, Howe CA, Allison J, Davis CL, Gutin B, et al. Ten months of
exercise improves general and visceral adiposity, bone, and fitness in black girls. Obesity
(Silver Spring) 2007;15(8):2077-85.

18 | P a g e © 2015 Macmillan Publishers Limited. All rights reserved.

Table and Figure Legends

Tables

Table 1. Baseline study participant characteristics

Legend: Data presented as mean (standard deviation). BMI = Body mass index; VAT= visceral
adipose tissue Si = insulin sensitivity, HOMA= homeostatic model of assessment- insulin
resistance; BP = blood pressure; VO2peak = peak oxygen uptake; FFM=fat free mass.

Table 2. Exercise training data for the two study arms.

Legend: E.E. = energy expenditure. HR = Heart rate; †= p < 0.01 between the vigorous and
moderate intensity arms.

Table 3. Intention-to-treat analyses on post data.

Legend: Effect sizes are presented as means and standard error (SE); Si = insulin sensitivity:
TG=triglycerides; VAT=visceral adipose tissue; BP = blood pressure; VO2peak = peak oxygen
uptake; FFM=fat free mass; *=post-hoc significantly different compared with controls.

Table 4. Training vs. control for outcome measures

Legend: Effect sizes are presented as means and standard error (SE); Si = insulin sensitivity;
TG=triglycerides; VAT=visceral adipose tissue; BP = blood pressure; VO2peak = peak oxygen
uptake; FFM=fat free mass.

Figures

Figure 1. CONSORT Flow chart of participants through the trial.

Figure 2. Changes in measures of adiposity with exercise training in overweight adolescents

19 | P a g e © 2015 Macmillan Publishers Limited. All rights reserved.

Table 1. Baseline study participant characteristics.

High Intensity Moderate Intensity Control

Demographics (n=38) (n=32) (n=36)
Age 15.3 (1.7) 15.1 (1.8) 15.2 (1.7)
Girls, No. (%) 33 (87) 25 (78) 23 (64)
Race/ethnicity, No.
(%))Caucasian 27 20 19
Aboriginal 11 4 9
Other 0 8 8
Pubertal Stage (%)
Tanner 2-3 32% 24% 40%
Tanner 4-5 68% 76% 60%
Anthropometric Variables
Weight (kg) 89.1 (15.7) 86.8 (15.8) 92.9 (17.4)
2
BMI (kg/m ) 32.6 (4.8) 31.9 (4.8) 32.9 (5.4)
BMI z score 2.00 (0.42) 1.97 (0.44) 2.08 (0.43)
Body fat (%) 40.1 (4.6) 38.8 (5.2) 39.1 (5.3)
Trunk fat (%) 17.2 (5.2) 16.7 (6.0) 17.1 (5.4)
Waist (cm) 106.0 (12.6) 101.2 (13.0) 107.6 (13.6)
2
VAT (cm ) 80.1 (30) 75.6 (39) 84.4 (36)
Cardiometabolic Variables
Si (mU/kg/min) 3.9 (3.6) 4.0 (3.1) 3.1 (1.6)
Hepatic TG (%) 6.4 (7.0) 5.8 (7.0) 5.7 (4.5)
Systolic BP (mmHg) 116 (7) 115 (10) 116 (13)
Diastolic BP (mmHg) 65 (6) 64 (6) 63 (8)
Fitness and Physical Activity Variables
VO2peak (ml/kg/min) 24.2 (3.6) 25.3 (4.4) 23.8 (4.5)
VO2peak (ml/kg-FFM/min) 42.2 (4.6) 42.8 (5.5) 40.7 (5.9)
Total Steps (per/day) 6415 (2571) 6162 (1916) 6973 (3374)

1|Page © 2015 Macmillan Publishers Limited. All rights reserved.

Table 2. Exercise training data for the two training arms
Average/Session High Intensity Arm
Month 1 2 3 4 5 6 Average
Average HR (bpm) 152 (12) † 151 (10) † 151 (12) † 153 (11) 153 (11) 152 (13) 152 (9) †
Intensity (HRR%) 68 (10) † 68 (8) † † † 69 (8)
67 (9) † 69 (8) † † 68 †(10) 68 (6) †
E.E. (Kcals) 347 (71) 333 (66) 320 (64) 322 (64) 345 (89) 320†(74) 333 (59)
Duration (mins) 39 (7) † 38 (8) † 37 (6) † 36 (7) † 38 (8) † 36 (6) † 38 (6) †
Attendance (%) 77 (18) 66 (26) 61 (28) 61 (29) † 60 (32) † 50 (33) 61 (22)
Average/Session Moderate Intensity Arm
Month 1 2 3 4 5 6 Average
Average HR (bpm) 137 (10) 137 (10) 136 (10) 139 (13) 136 (12) 134 (13) 138 (9)
Intensity (HRR%) 55 (9) 55 (9) 54 (10) 58 (11) 55 (10) 53 (11) 56 (8)
E.E. (Kcals) 312 (90) 323 (96) 311 (84) 326 (80) 307 (73) 294 (51) 318 (76)
Duration (mins) 43 (8) 45 (7) 44 (7) 46 (9) 45 (8) 44 (8) 45 (6)
Attendance (%) 68 (29) 59 (30) 56 (32) 47 (33) 44 (38) 44 (36) 52 (27)

Data presented as mean (SD) for participants within each study arm. E.E. = energy expenditure.
HR = Heart rate;

†= p < 0.01 between the vigorous (top rows) and moderate intensity arms (bottom rows).

1|Page © 2015 Macmillan Publishers Limited. All rights reserved.

Table 3. Intention-to-treat for outcome measures on post outcomes.

Variables Group N Pre Post p-value

Control 33 3.1 (0.3) 3.5 (0.4)
Si (mU/kg/min) Moderate 32 4.0 (0.5) 3.8 (0.5) 0.97
High 38 3.9 (0.6) 3.8 (0.5)
Control 29 5.7 (0.8) 7.4 (1.7)
Hepatic TG (%F/W) Moderate 31 5.8 (1.3) 7.3 (2.0) 0.11
High 35 6.4 (1.2) 6.1 (0.7)
Control 35 84.4 (6.0) 84.4 (7.1)
VAT (cm2) Moderate 32 75.6 (7.0) 67.5 (5.6) 0.28
High 37 80.1 (5.0) 72.5 (4.7)
Control 36 107.6 (2.3) 108.7 (2.5)
Waist (cm) Moderate 32 101.2 (2.3) 103.1 (2.3) 0.22
High 38 106.0 (2.0) 104.8 (2.1)
Control 36 92.9 (2.9) 95.0 (3.1)
Body Weight (kg) Moderate 32 86.8 (2.8) 87.2 (2.9) 0.16
High 38 89.1 (2.5) 89.9 (2.6)
Control 34 39.1 (0.9) 39.1 (1.0)
Body Fat (%) Moderate 32 38.8 (0.9) 37.9 (0.9) 0.45
High 37 40.1 (0.8) 39.5 (0.8)
Control 34 17.1 (0.9) 17.8 (1.0)
Trunk Fat (%) Moderate 32 16.7 (1.1) 15.9 (0.9) 0.35
High 37 17.2 (0.9) 17.3 (0.9)
Control 36 2.2 (0.4) 2.2 (0.4)
VO2 (L/min) Moderate 32 2.2 (0.4) 2.3 (0.4) 0.41
High 38 2.1 (0.3) 2.7 (0.4)
Control 36 23.8 (0.7) 23.3 (0.8)
VO2peak (ml/kg/min) Moderate 32 25.3 (0.8) 26.5 (0.9)* 0.02
High 38 24.2 (0.6) 25.5 (0.8)
Control 36 40.7 (1.0) 39.7 (1.0)
VO2peak (ml/kg-FFM/min) Moderate 32 42.8 (1.0) 44.1 (0.9)* 0.002
High 37 42.2 (0.7) 44.1 (1.0)*
Control 33 6973 (616) 5841 (534)
Activity (steps/day) Moderate 25 6162 (391) 6458 (559) 0.09
High 35 6415 (441) 73936)
Data are presented as mean (SE)
* = p < 0.05 vs control. No differences were observed between the two exercise training
arms

1|Page © 2015 Macmillan Publishers Limited. All rights reserved.

Table 4. Training vs. Control for outcome measures

Variables Group N Pre Post p-value

Control 33 3.1 (0.3) 3.5 (0.4)
Si (mU/kg/min) 0.90
Training 70 4.0 (0.4) 3.8 (0.3)
Control 29 5.7 (0.8) 7.4 (1.7)
Hepatic TG (%F/W) 0.32
Training 66 6.2 (0.9) 6.7 (1.0)
Control 35 84.4 (6.0) 84.4 (7.1)
VAT (cm2) 0.17
Training 69 78.1 (4.2) 70.2 (3.6)
Control 36 107.6 (2.3) 108.7 (2.5)
Waist (cm) 0.09
Training 70 103.8 (1.5) 104.0 (1.5)
Control 36 92.9 (2.9) 95.0 (3.1)
Body Weight (kg) 0.08
Training 70 88.1 (1.9) 88.7 (1.9)
Control 34 39.1 (0.9) 39.1 (1.0)
Body Fat (%) 0.80
Training 69 39.5 (0.6) 38.8 (0.6)
Control 34 17.1 (0.9) 17.8 (1.0)
Trunk Fat (%) 0.30
Training 69 17.0 (0.7) 16.6 (0.6)
Control 36 23.8 (0.7) 23.3 (0.8)
VO2peak (ml/kg/min) 0.01
Training 70 24.7 (0.5) 25.9 (0.6)
Control 34 40.7 (1.0) 39.7 (1.0)
VO2peak (ml/kg-FFM/min) <0.001
Training 69 42.5 (0.6) 44.1 (0.7)
Control 33 6973 (616) 5841 (534)
Activity (steps/day) 0.07
Training 60 6310 (303) 7003 (365)

1|Page © 2015 Macmillan Publishers Limited. All rights reserved.

Appendix - Table 1. Efficacy analysis for youth that completed 70% of prescribed training.

Variables Group N Pre Post p-value

Control 33 3.1 (1.5) 3.5 (2.4)
Si (mU/kg/min) Moderate 32 3.2 (1.4) 2.4 (1.1) NS
High 38 4.1 (5.1) 4.2 (4.2)
Control 29 5.2 (5.4) 7.0 (9.0)
Hepatic TG (%F/W) Moderate 31 5.8 (3.3) 8.4 (13.3) NS
High 35 3.7 (4.7) 3.9 (3.0)
Control 35 84.3 (35.7) 84.4 (7.1)
VAT (cm2) Moderate 32 93.2 (45.1) 74.5 (30.1) NS
High 37 84.4 (27.9) 77.1 (32.1)
Control 36 108 (14) 109 (15)
Waist (cm) Moderate 32 106 (11) 106 (8.9) NS
High 38 105 (14) 102 (15)
Control 34 39.1 (5.2) 39.4 (4.8)
Body Fat (%) Moderate 32 38.8 (6.2) 37.9 (5.2) NS
High 37 40.4 (4.2) 39.5 (4.3)
Control 36 23.8 (4.5) 23.3 (4.8)
VO2peak (ml/kg/min) Moderate 32 24.7 (4.2) 26.0 (5.9) 0.04
High 38 24.8 (3.4) 26.6 (4.0)*
Control 36 40.7 (5.9) 39.7 (5.8)
VO2peak (ml/kg-FFM/min) Moderate 32 41.7 (5.9) 43.1 (6.3)* 0.004
High 37 43.2 (4.5) 45.5 (4.7)*
Control 33 6973 (3374) 5841 (3064)
Activity (steps/day) Moderate 25 6298 (2157) 6940 (3596) NS
High 35 6190 (2395) 6899 (3261)
* - p< 0.05 vs control Data displayed as Mean (SD)

© 2015 Macmillan Publishers Limited. All rights reserved.

© 2015 Macmillan Publishers Limited. All rights reserved.
Figure 2 Changes in adiposity with exercise training in obese adolescents.

A B
3.0 0

2.5
-2

Visceral Adipose Area (cm )

Hepatic Triglyceride (F/W%)

2
2.0
-4
1.5

1.0 -6

0.5
-8

0.0
-10
-0.5

-1.0 -12
High Moderate Control High Moderate Control

C D
1.2 0.0

1.0
-0.2

0.8
-0.4
0.6
Trunk Fat (kg)

Body Fat (%)

0.4 -0.6

0.2 -0.8

0.0
-1.0
-0.2

-1.2
-0.4

-0.6 -1.4
High Moderate Control High Moderate Control

E
1.0

0.8

0.6

0.4
BMI (kg/m )
2

0.2

0.0

-0.2

-0.4

-0.6
High Moderate Control

© 2015 Macmillan Publishers Limited. All rights reserved.