Adverse metabolic response to regular exercise: is it a rare or common occurrence?

Abstract

Individuals differ in the response to regular exercise. Whether there are people who experience adverse changes in cardiovascular and diabetes risk factors has never been addressed.
An adverse response is defined as an exercise-induced change that worsens a risk factor beyond measurement error and expected day-to-day variation. Sixty subjects were measured three times over a period of three weeks, and variation in resting systolic blood pressure (SBP) and in fasting plasma HDL-cholesterol (HDL-C), triglycerides (TG), and insulin (FI) was quantified. The technical error (TE) defined as the within-subject standard deviation derived from these measurements was computed. An adverse response for a given risk factor was defined as a change that was at least two TEs away from no change but in an adverse direction. Thus an adverse response was recorded if an increase reached 10 mm Hg or more for SBP, 0.42 mmol/L or more for TG, or 24 pmol/L or more for FI or if a decrease reached 0.12 mmol/L or more for HDL-C. Completers from six exercise studies were used in the present analysis: Whites (N = 473) and Blacks (N = 250) from the HERITAGE Family Study; Whites and Blacks from DREW (N = 326), from INFLAME (N = 70), and from STRRIDE (N = 303); and Whites from a University of Maryland cohort (N = 160) and from a University of Jyvaskyla study (N = 105), for a total of 1,687 men and women. Using the above definitions, 126 subjects (8.4%) had an adverse change in FI. Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C. About 7% of participants experienced adverse responses in two or more risk factors.
Adverse responses to regular exercise in cardiovascular and diabetes risk factors occur. Identifying the predictors of such unwarranted responses and how to prevent them will provide the foundation for personalized exercise prescription.

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Adverse Metabolic Response to Regular Exercise: Is It a
Rare or Common Occurrence?
Claude Bouchard1*, Steven N. Blair2, Timothy S. Church3, Conrad P. Earnest3, James M. Hagberg4,
Keijo Ha ¨kkinen5, Nathan T. Jenkins4¤, Laura Karavirta5, William E. Kraus6, Arthur S. Leon7, D. C. Rao8,
Mark A. Sarzynski1, James S. Skinner9, Cris A. Slentz6, Tuomo Rankinen1
1Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States of America, 2Departments of Exercise Science and
Epidemiology/Biostatistics, University of South Carolina, Columbia, South Carolina, United States of America, 3Preventive Medicine Laboratory, Pennington Biomedical
Research Center, Baton Rouge, Louisiana, United States of America, 4Department of Kinesiology, University of Maryland, College Park, Maryland, United States of America,
5Department of Biology of Physical Activity, University of Jyva ¨skyla ¨, Jyva ¨skyla ¨, Finland, 6Department of Medicine, Duke University Medical Center, Durham, North
Carolina, United States of America, 7School of Kinesiology, University of Minnesota, Minneapolis, Minnesota, United States of America, 8Division of Biostatistics,
Washington University School of Medicine, St. Louis, Missouri, United States of America, 9Professor Emeritus of Kinesiology, Indiana University, Bloomington, Indiana,
United States of America
Abstract
Background: Individuals differ in the response to regular exercise. Whether there are people who experience adverse
changes in cardiovascular and diabetes risk factors has never been addressed.
Methodology/Principal Findings: An adverse response is defined as an exercise-induced change that worsens a risk factor
beyond measurement error and expected day-to-day variation. Sixty subjects were measured three times over a period of
three weeks, and variation in resting systolic blood pressure (SBP) and in fasting plasma HDL-cholesterol (HDL-C),
triglycerides (TG), and insulin (FI) was quantified. The technical error (TE) defined as the within-subject standard deviation
derived from these measurements was computed. An adverse response for a given risk factor was defined as a change that
was at least two TEs away from no change but in an adverse direction. Thus an adverse response was recorded if an increase
reached 10 mm Hg or more for SBP, 0.42 mmol/L or more for TG, or 24 pmol/L or more for FI or if a decrease reached
0.12 mmol/L or more for HDL-C. Completers from six exercise studies were used in the present analysis: Whites (N=473)
and Blacks (N=250) from the HERITAGE Family Study; Whites and Blacks from DREW (N=326), from INFLAME (N=70), and
from STRRIDE (N=303); and Whites from a University of Maryland cohort (N=160) and from a University of Jyvaskyla study
(N=105), for a total of 1,687 men and women. Using the above definitions, 126 subjects (8.4%) had an adverse change in FI.
Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C. About 7% of participants
experienced adverse responses in two or more risk factors.
Conclusions/Significance: Adverse responses to regular exercise in cardiovascular and diabetes risk factors occur.
Identifying the predictors of such unwarranted responses and how to prevent them will provide the foundation for
personalized exercise prescription.
Citation: Bouchard C, Blair SN, Church TS, Earnest CP, Hagberg JM, et al. (2012) Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common
Occurrence? PLoS ONE 7(5): e37887. doi:10.1371/journal.pone.0037887
Editor: Shengxu Li, Tulane School of Public Health and Tropical Medicine, United States of America
Received April 9, 2012; Accepted April 25, 2012; Published May 30, 2012
Copyright: ? 2012 Bouchard et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Studies used for this report were supported by multiple grants from the National Institutes of Health (NIH): HL-45670, HL-47323, HL-47317, HL-47327,
HL-47321, HL-66262, HL-57354, AG-17474, and AG-15389. C. Bouchard is partially supported by the John W. Barton, Sr. Chair in Genetics and Nutrition. T. Church is
partially supported by the John S. McIlhenny Chair in Health Wisdom. N.T. Jenkins was supported by NIH T32 AG00068 and NIH T32 AR048523. The funders had
no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: C. Bouchard is a member of the Science Advisory Board of Pathway Genomics. This does not alter the authors’ adherence to all the PLoS
ONE policies on sharing data and materials.
* E-mail: claude.bouchard@pbrc.edu
¤ Current address: Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, United States of America
Introduction
Physical activity level and cardiorespiratory fitness are strongly
and inversely associated with the risk of cardiovascular-, metabol-
ic-, and aging-related morbidities, as well as premature mortality
[1]. To alleviate the health burden associated with sedentary
behavior and poor fitness, public health recommendations are that
adults be physically active at a moderate intensity for 150 minutes
per week or at a vigorous intensity for 75 minutes per week [2].
However, there is considerable interindividual variability in the
ability to improve one’s cardiorespiratory fitness and cardiometa-
bolic and diabetes risk factor profile in response to regular
exercise. This clear finding of the HERITAGE Family Study has
been replicated [3,4,5,6]. A fundamental question is whether there
are individuals who experience one or several adverse responses
(ARs) in terms of exercise-induced changes in common risk factors.
This issue is addressed herein based on data from six exercise
intervention studies, with a focus on exercise-induced changes in
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resting systolic blood pressure (SBP), fasting insulin (FI), HDL-
cholesterol (HDL-C), and triglycerides (TG). The studies used for
this purpose are: HERITAGE Family Study (HERITAGE),
DREW, INFLAME, STRRIDE, University of Maryland Gene
Exercise Research Study (MARYLAND), and University of
Jyva ¨skyla ¨ study (JYVASKYLA).
Methods
Data on a maximum of 1687 adults from six studies were
available for analysis. These studies will be briefly described,
followed by the definition of AR and the statistical procedures
employed. More information on each study is available in
Information S1.
HERITAGE (Health, Risk Factors, Exercise Training And
Genetics) Family Study
The sample, study design, and exercise training protocol of
HERITAGE have been described elsewhere [7]. Briefly, 473
adults from 99 families of Caucasian descent and 250 Blacks from
105 families or sibships completed the 20-week endurance training
program. Parents were 65 years of age or less while offspring
ranged in age from 17 to 41 years.
Dose Response to Exercise in Women (DREW) Study
A complete description of the DREW design and methods and
details of the study participants have been published [8]. In brief, it
wasa randomized,dose-responseexercise trialwith sedentary, high-
normal blood pressure, postmenopausal, overweight or obese
women (N=326: 63% White) assigned to either a nonexercise
control group or to endurance exercise groups that expended 4, 8,
or 12 kcal/kg of body weight per week for a period of 6 months [6].
Inflammation and Exercise (INFLAME) Study
Sedentary men and women between the ages of 30 and 75 years
who had an elevated plasma C-reactive protein (CRP) concentra-
tion ($2.0 mg/L but ,10.0 mg/L) were randomized to an
endurance exercise or a control group [9]. Completers (70%
Whites) exercised a mean of 204 minutes per week.
Studies of a Targeted Risk Reduction Intervention
through Defined Exercise (STRRIDE)
STRRIDE (84% Whites) includes two complementary studies
[10,11]. STRRIDE was composed of 40- to 65-year-old, sedentary,
overweight or class 1 obese (BMI 25–35 kg/m2), dyslipidemic men
and women. They were assigned to one of three aerobic exercise
groups and exercisedfor 6 months.The STRRIDE aerobic training
Table 1. Reproducibility of Risk Factors from Measurements Repeated Over 3 Days on 60 Subjects.
VariableMean ± SD (at first test) CVICCTE
Stature, cm171.768.30.21.00 0.3
Body weight, kg 71.5612.8 0.91.000.7
Fasting insulin*, pmol/L65.8640.019–290.78–0.9413.2–19.8 (12)
HDL-C, mmol/L 1.0860.256.0 0.94 0.06
Triglycerides, mmol/L1.0460.4721.80.790.21
Systolic BP, mm Hg118.7610.3 4.10.76 4.9
ICC=intraclass correlation computed from the within-subject variance compared to the overall measurement variance.
TE=technical error defined by the within-subject standard deviation calculated from repeated measurements. It includes a combination of measurement error plus day-
to-day variation.
CV=Coefficients of variation is expressed as a percentage and is derived from the technical error and the measurement mean.
*Note on insulin: The values reported here are from the repeated measurements obtained at baseline (N=779) and after (N=624) the exercise program in HERITAGE
(Information S1). The TE used for this report is shown in parentheses.
To convert pmol/L of insulin to mU/L, divide by 6.945. To convert mmol/L of HDL-C to mg/dL, divide by 0.02586. To convert mmol/L of triglycerides to mg/dl, divide by
0.01129.
doi:10.1371/journal.pone.0037887.t001
Table 2. Descriptive Data, Including Baseline V ˙O2max and its Response to Training, for the Six Cohorts.
HERITAGE
Whites
HERITAGE
Blacks DREWINFLAMESTRRIDEMARYLANDJYVASKYLA
Maximum number of subjects473250 32670 303 160105
Age, yrs 35.8 (14.5)33.6 (11.5) 57.9 (6.5) 51.2 (10)51.0 (7.7)58.0 (5.8) 53.5 (7.6)
Baseline BMI, kg/m2
25.8 (4.9)27.8 (5.8)31.5 (3.9)31.1 (4.3) 29.9 (2.9)28.3 (4.6)25.4 (3.1)
Baseline
V ˙O2max, mL/min
2458 (740)2086 (629)1312 (240) 1629 (567)2466 (694) 2060 (536)2262 (616)
Baseline
V ˙O2max, mL/kg/min
33.2 (8.9) 27.3 (7.3)15.8 (2.5)19.0 (5.6)28.2 (6.0) 25.3 (4.6)29.8 (6.2)
V ˙O2max response, mL/min 395 (215)362 (171)108 (132)204 (213) 281 (273)250 (228)259 (223)
V ˙O2max response, % 16.9 (9.0)18.9 (10.3)8.7 (10.5)14.1 (13.5)12.0 (12.0) 12.3 (10.1) 13.0 (11.7)
Values are given as mean (SD). V ˙O2max response=post-training V ˙O2max minus baseline V ˙O2max (positive value represents improvement in V ˙O2max).
All gains in VO2max are significant at p,0.05.
doi:10.1371/journal.pone.0037887.t002
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versus resistance training (AT/RT) cohort was very similar to
STRRIDE, but only those who were enrolled in endurance exercise
programs are included in the present report.
University of Maryland Gene Exercise Research Study
(MARYLAND)
Briefly, 160 men and women (100% Whites) ages 50 to 75 years
who were sedentary, nondiabetic, and nonsmoking, with no prior
history of cardiovascular disease but with one National Cholesterol
Education Program lipid abnormality or blood pressure in the
prehypertensive range, exercised three times per week for a period
of 6 months [12].
University of Jyva ¨skyla ¨ Study (JYVASKYLA)
Healthy, sedentary 40- to 67-year-old men and women were
recruited [13]. A total of 206 subjects were randomized to one of
four groups. Here we used the data on 25 men and 26 women of
the endurance training group and on 30 men and 24 women (all
Whites) of the combined endurance and strength training group
who exercised for 21 weeks.
Definition of adverse responses
For the four traits studied, some subjects experienced changes in
an opposite, unfavorable direction compared to the expected
beneficial effects. This is analogous to an AR pattern. Defining an
AR for any given risk factor is a challenge. A robust definition
takes into account the measurement error of the trait, including
the variance among laboratories or laboratory technicians, and the
normal day-to-day biological variation of the trait. The parameter
that captures the totality of these sources of variance in a trait is
known as the technical error (TE), defined as the within-subject
standard deviation as derived from repeated measures (or assays)
over a given period of time, as used in the National Health and
Nutrition Examination Survey (NHANES) [14]. An ancillary
study designed to quantify TE for several biological traits was
undertaken in HERITAGE. Sixty subjects were measured three
times (except for FI) over a period of 3 weeks for each trait
[15,16,17,18,19]. TEs and other useful indicators of reproducibil-
ity are shown in Table 1. In the case of FI, the assays were
performed only twice, and we used other HERITAGE data plus
observations from the literature to develop an estimate of TE for
FI (Information S1). Here, we have conservatively defined an AR
as a response beyond 26TE in a direction indicating a worsening
of the risk factor. For the four traits in the present study, twice the
value of TE would mean that ARs would be reached if the exercise
training-inducedincreases are
$0.42 mmol/L for plasma TG, and $24 pmol/L for plasma FI
or if there is a decrease of #0.12 mmol/L for HDL-C. These AR
definitions are used in the remainder of this report.
$10 mmHgfor SBP,
Statistical procedures
Data are expressed as means and standard deviations or
standard errors as specified. Intraclass correlations were computed
from the within-subject variance relative to the overall measure-
ment variance. The coefficient of variation is expressed as a
percentage and is derived from the TE relative to the measure-
ment mean. The significance of the gains in VO2max and of the
mean changes in the four targeted risk factors within each cohort
was assessed with paired t tests. The comparisons of VO2max
gains between adverse responders and non-adverse responders for
each risk factor trait for each study was undertaken as follows: The
difference between the changes in VO2max with exercise training
expressed in ml O2per minute was tested with the general linear
Table 3. Baseline and training-induced changes in the four risk factors for the five cohorts (mean 6 SD).
HERITAGE
DREW
INFLAME
STRRIDE
Maryland
Jyvaskyla
Variable
Whites (n# #473)
Blacks (n# #250)
4 kcal/kg/wk
(n# #143)
8 kcal/kg/wk
(n# #89)
12 kcal/kg/wk
(n# #94)
(n# #70)
(n# #303)
(n# #160)
(n# #105)
Baseline fasting insulin, pmol/L
65.7640.0
79.7663.2
74641.24
75.85642.34
70.93641.08
82.30640.77
265.3641.8
83631
31.6616.7
Change in fasting insulin, pmol/L
25.2624.9{{{
210.8644.6{{{
22.02631.06
27.98627.59{
21.95629.54
25.58631.33
211.6629.1{{{
211621{{{
23.2614.0
Baseline HDL-C, mmol/L
1.0460.26
1.0960.32
1.5060.38
1.4960.40
1.5060.35
1.5060.39
1.1760.35
1.2460.41
1.2860.40
Change in HDL-C, mmol/L
0.0460.12{{{
0.0360.13{{{
20.0160.21
20.0160.21
20.0460.20
20.0560.14{{
0.0460.16
0.0860.21{{{
0.0160.21
Baseline Tg, mmol/L
1.3860.78
1.0460.62
1.4560.67
1.4760.68
1.4460.81
1.2860.56
1.7260.89
1.6761.08
1.1960.71
Change in Tg, mmol/L
20.0260.42
20.0360.41
20.0860.47
20.0260.50
0.0360.56
0.0060.46
20.2460.64{{
20.2160.74{{{
20.1160.54{
Baseline SBP, mm Hg
116.2610.9
122.8612.0
138.9613.4
139.9613.6
138.5612.7{
131.3620.4
N/A
133 + 16
131.7615.6
Change in SBP, mm Hg
0.266.2
21.267.8{
1612.7
21.6615.1
23.1611.8
24.3613.8{
N/A
1 + 13
23.7610.9{{
{p#0.05.
{{p,0.01.
{{{p,0.001 indicates significant change score within a group.
To convert pmol/L of insulin to mU/L, divide by 6.945. To convert mmol/L of HDL-C to mg/dL, divide by 0.02586. To convert mmol/L of triglycerides to mg/dl, divide by 0.01129.
doi:10.1371/journal.pone.0037887.t003
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model and is reported as least squares (LS) means with age, sex,
and baseline VO2max as covariates. The gain in VO2max % is
reported as LS means with age and sex as covariates.
Results
Subjects in DREW, INFLAME, STRRIDE, MARYLAND, and
JYVASKYLA were about 20 years older than HERITAGE Whites
and Blacks (Table 2).All cohorts had a mean BMIin the overweight
range (i.e., .25.0 but ,30.0 kg/m2), with the exception of DREW
and INFLAME, with mean values of about 31 kg/m2. Mean
baseline VO2max was considerably lower in DREW and
INFLAME compared to the other studies. The mean increase in
VO2max (ml O2per minute) ranged from 108 (DREW) to 395
(HERITAGE Whites). The percent increase of VO2max ranged
from 8.7% (DREW) to 18.9% (HERITAGE Blacks).
Baseline values and the mean (6SD) changes of the risk factors
in response to exercise programs are shown in Table 3 for each
Figure 1. Distribution of the response to the HERITAGE exercise program with adverse responders highlighted in red. To convert
pmol/L of insulin to mU/L, divide by 6.945. To convert mmol/L of HDL-C to mg/dL, divide by 0.02586. To convert mmol/L of triglycerides to mg/dl,
divide by 0.01129.
doi:10.1371/journal.pone.0037887.g001
Table 4. Prevalence of Adverse Responders in HERITAGE.
HERITAGE Whites (# #473)HERITAGE Blacks (# #250)
Risk factor26TEN%N%
D Fasting insulinN$24 pmol/L389 179
D HDL-CN#0.12 mmol/L28619 8
D TriglyceridesN$0.42 mmol/L378198
D Systolic BPN$10 mm Hg286167
To convert pmol/L of insulin to mU/L, divide by 6.945. To convert mmol/L of HDL-C to mg/dL, divide by 0.02586. To convert mmol/L of triglycerides to mg/dl, divide by
0.01129.
doi:10.1371/journal.pone.0037887.t004
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cohort. There was a wide range of baseline values for all risk
factors. For instance, mean baseline HDL-C levels ranged from
1.04 mmol/L (HERITAGE Whites) to about 1.50 mmol/L
(INFLAME and all DREW exercise groups). The mean changes
induced by the exercise programs were generally in the expected
direction (i.e., decreases in FI, TG, and SBP and increases in
HDL-C). There were, however, some statistically nonsignificant
exceptions to these general trends.
Using the definitions outlined in Table 1, the prevalence of ARs
for the four risk factors was first explored in the 473 Whites and
250 Blacks of HERITAGE who were all exposed to the same
standardized exercise programs and were all qualified as
completers. The results are depicted in Figure 1 and are
summarized in Table 4. Although HERITAGE subjects were
apparently healthy and not taking medication for blood pressure,
glucose, or lipid anomalies and were exposed to the same exercise
program, 6% to 9% of Blacks and Whites experienced ARs for
each of the four risk factors, with no substantive differences
between the two ethnic groups.
To gain a better understanding of the true prevalence of ARs
for each risk factor, we compared the data obtained in
HERITAGE with those of five other exercise training studies.
The results are summarized in Table 5. It is quite obvious that the
findings in HERITAGE are not unique to the HERITAGE
subjects and exercise protocol. Based on a maximum of 1687
subjects, the prevalence of an AR reached 8.3% for the changes in
FI, 13.3% for the changes in fasting HDL-C, 10.3% for TG, and
12.2% for resting SBP. The percentages of adverse responders for
each trait for each study are depicted in Figure 2. It is remarkable
that such cases were found in each study, even though the age and
health status of the subjects were widely divergent and the exercise
programs were quite heterogeneous.
Figure 2. Percentages of adverse responders for each risk factor trait by study, with number of adverse responder subjects in each
bar.
doi:10.1371/journal.pone.0037887.g002
Table 5. Prevalence of Adverse Responders to Regular Exercise in Six Studies.
HERITAGEDREW INFLAMESTRRIDEMARYLANDJYVASKYLATOTAL
%*
N subjects
#723
#326
#70
#303
#160
#105
#1687
D Fasting insulin55 36 1217421268.3
D HDL-C47 8721328 2722213.3
D Triglycerides565193411 1117210.3
D Systolic BP44 58 11 NA4310 166 12.2
*% represents the proportion of adverse responders in relation to the total number of subjects exercise trained for each of the four traits.
doi:10.1371/journal.pone.0037887.t005
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One important question to consider is whether those who
respond adversely for a given risk factor are also those who
experience the least improvement in cardiorespiratory fitness with
regular exercise. This question was addressed by comparing the
gains in VO2max between the subgroups of adverse responders and
non-adverse responders for a given risk factor. The results of these
analyses are shown in Table 6 for the gains in ml O2per minute and
the percentage increases in VO2max. A total of 56 differences were
tested with age, sex, and baseline VO2max as covariates for the gain
in ml O2per minute and age and sex for the percentage increase.
Only two suchdifferences reached the 0.05level of significance, and
they were far from reaching a multiple test Bonferroni adjusted P
value of 0.0009. These data indicate that AR traits are independent
of the improvement in cardiorespiratory fitness.
One couldhypothesize that the proportion of ARs should decrease
astheamountofexerciseincreases.Wetestedthishypothesiswiththe
Table 6. Comparison of the VO2max response to regular exercise between adverse responders and non-adverse responders for
each response trait in each study.
HERITAGE WhitesHERITAGE BlacksDREW INFLAME
Adverse
responders
Non-adverse
responders
Adverse
responders
Non-adverse
responders
Adverse
responders
Non-adverse
responders
Adverse
responders
Non-adverse
responders
D Fasting insulin
N subjects38 4111718436 2901258
D VO2max (ml/min) 382 (34)399 (10) 472 (43) 385 (14)76 (22)69 (7)99 (61) 226 (28)
D VO2max (%)16.1 (1.4) 17.0 (0.4)20.6 (2.5) 18.3 (0.8)6.0 (1.7)5.8 (0.6)8.0 (3.4) 14.5 (1.6)
D HDL-C
N subjects 2844319 220 87 2392149
D VO2max (ml/min)384 (40)400 (10)348 (39)388 (12)68 (14)71(8) 219 (48)196 (32)
D VO2max (%) 16.2 (1.7) 17.0 (0.4)15.5 (2.3)18.4 (0.7)5.4 (1.1) 6.0 (0.7)14.2 (2.7)12.9 (1.8)
D Triglycerides
N subjects3743419220 51275961
D VO2max (ml/min)424 (34)397 (10)332 (39) 392 (13)72 (18)70 (8)136 (72)213 (28)
D VO2max (%) 17.7 (1.4)16.9 (0.4)16.9 (2.3) 18.3 (0.7)6.1 (1.5)5.8 (0.6)8.6 (4.0) 14.0 (1.6)
D Systolic BP
N subjects 28 44216 22058268 11 59
D VO2max (ml/min) 348 (40)401 (10)396 (42)386 (12) 60 (17) 72 (8)140 (65)215 (28)
D VO2max (%) 14.8 (1.7) 17.0 (0.4) 16.7 (2.5)18.2 (0.7)4.9 (1.4)6.1 (0.6)7.5 (3.6)14.4 (1.6)
STRRIDEMARYLAND JYVASKYLA
Adverse
responders
Non-adverse
responders
Adverse
responders
Non-adverse
responders
Adverse
responders
Non-adverse
responders
D Fasting insulin
N subjects172864 922 57
D VO2max (ml/min)278 (102)278 (16)112 (102)306 (21)340 (158)277 (30)
D VO2max (%) 10.5 (3.6)11.7 (0.7)7.7 (5.0) 15.1 (1.0) 12.7 (8.8)14.2 (1.6)
D HDL-C
N subjects322718 142 2671
D VO2max (ml/min)231 (41) 281 (17)206 (72)274 (17) 183 (42){
287 (26)
D VO2max (%)11.4 (2.6) 11.6 (0.7)10.0 (3.4) 13.4 (0.8)8.1 (2.2){
14.7 (1.3)
D Triglycerides
N subjects34269 11141 1186
D VO2max (ml/min) 201 (46) 281 (17) 276 (62)272 (17)285 (67)256 (24)
D VO2max (%)8.3 (1.9) 12.1 (0.7)13.4 (3.0) 13.3 (0.8)12.3 (3.5) 13.0 (1.3)
D Systolic BP
N subjectsN/AN/A 43115 1087
D VO2max (ml/min) N/AN/A230 (31) 271 (19)244 (70) 261 (24)
D VO2max (%)N/AN/A12.3 (1.5) 13.1 (0.9)12.9 (3.7)13.0 (1.2)
Data expressed as means and standard deviations.
D VO2max expressed as the change with exercise training in ml O2 per minute, reported as LS means with age, sex, and baseline VO2max as covariates. D VO2max %
reported as LS means with age and sex as covariates.
{p#0.05 indicates significant difference in VO2max training response between adverse responders and non-adverse responders.
doi:10.1371/journal.pone.0037887.t006
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data of DREW, and the results are summarized in Table 7. No
substantive differences were observed in the prevalence of ARs
among the three levels of exercise energy expenditure, which ranged
from 4 to 12 kcal/kg of body weight per week.
Another important question is that of the proportion of subjects
who experienced ARs for more than one risk factor. We tabulated
the number of participants in the six studies who registered ARs
for two or more risk factors, and the results are shown in Table 8.
Approximately 7% of sedentary adults experienced ARs for at
least two common cardiometabolic and diabetes risk factors
following exposure to regular exercise. Only a small minority of
participants (,1%) exhibited ARs for three or more traits.
Discussion
The prevalence of ARs for select risk factors varied from 8.3%
for the exercise training-induced changes in FI to 13.3% for the
changes in HDL-C, with about 7% of participants experiencing
adverse changes in two or more risk factors. This subgroup should
receive urgent attention. The prevalence of ARs appears to be
similar at low and high doses of exercise. However, we do not
know whether some adverse responders would revert to a more
positive response pattern if exposed to different exercise doses or
exercise modalities.
It is important to differentiate between ARs for risk factors for
common chronic diseases, as referred to in the present study, from
other more acute ARs such as cardiac events related to exertion
during an exercise bout [20,21,22], sudden cardiac death during or
immediately after exercise typically associated with a cardiomyop-
athy or a congenital abnormality [23], or even exercise intolerance
due to abnormal skeletal muscle energy metabolism [24]. These
events are fortunately rare among physically active people. In
contrast, ARs as defined herein for common cardiometabolic and
diabetes risk factors are much more prevalent and become evident
with exposure to regular exercise. It is not known whether such ARs
can be detected after a single or a few bouts of exercise.
Even though the presence of ARs was first detected among
completers in Blacks and Whites of the HERITAGE Family Study,
in which subjects were confirmed to be sedentary at baseline, with a
rather healthy profile, the phenomenon was confirmed in five other
exercise intervention studies. The consistency in the prevalence of
ARs across heterogeneous studies in terms of health status of
subjects at baseline and of exercise training regimen is notable.
One question that may arise is whether ARs are the result of
unwarranted exercise-drug interaction effects. The question
cannot be answered with direct experimental data at the moment,
but based on our analysis of the results of the six studies, it is highly
unlikely that it is the case. For instance, HERITAGE and
JYVASKYLA subjects were healthy adults taking no medication
for high blood pressure, hypercholesterolemia, or hyperglycemia.
However, many subjects in DREW, INFLAME, MARYLAND,
and STRRIDE were taking medications for high blood pressure,
Table 7. Adverse and Excellent Responders to Regular Exercise in DREW*.
DREW
4 kcal/kg/wk
DREW
8 kcal/kg/wk
DREW
12 kcal/kg/wk
N subjects143 89 94
ADVERSE RESPONDERSN%N%N%
D Fasting insulinN$24 pmol/L 16119 1011 12
D HDL-CN#0.12 mmol/L35 25212431 33
D TriglyceridesN$0.42 mmol/L 191314 1618 19
D SBPN$10 mm Hg 3222 1416 12
*A postmenopausal woman who follows the 2008 Physical Activity Guidelines for Americans expends about 8 kcal/kg/week in her exercise program. The 4 kcal/kg/week
is about 50% the current recommendation whereas the 12 kcal/kg/week is about 50% above the recommended dose.
doi:10.1371/journal.pone.0037887.t007
Table 8. Percentage of Subjects in Each Study with 1, 2, or 3 and More Adverse Responses.
1 Adverse Response2 Adverse Responses 3 or 4 Adverse Responses
N%N%N%
HERITAGE
Blacks 51 20% 114%0 0%
Whites 9420% 174%3 1%
DREW 13140% 37 11%9 3%
INFLAME 3246%9 13%11%
STRRIDE7124%9 3%0 0%
MARYLAND 5434%53%0 0%
JYVASKYLA 3533%77%00%
TOTALS (mean %)468 31%95 6%130.8%
The four traits considered were the exercise training-induced changes in fasting insulin, HDL-cholesterol, triglycerides, and resting systolic blood pressure.
doi:10.1371/journal.pone.0037887.t008
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hyperglycemia, or dyslipoproteinemia. Yet substantial numbers of
subjects with or without medication in these cohorts experienced
one or more ARs.
The challenge is now to investigate whether baseline predictors
of ARs can be identified to screen individuals at risk so that they
can be offered alternative approaches to modifying cardiometa-
bolic risk factors. Research based on HERITAGE has amply
demonstrated that the response pattern to exercise training
aggregates in families [25,26,27,28]. In fact, the heritability of
the changes induced by the exercise program reached about 30%
for plasma HDL-C and TG [26] and about 20% to 25% for
indicators of insulin metabolism and resting SBP [29,30]. There
are strong indications from a baseline skeletal muscle gene
expression profile and from a genome-wide association study
performed on the Whites of HERITAGE that the genetic
component of a response trait can be defined in terms of RNA
abundance observed in the sedentary state or by specific genomic
variants [31,32,33]. This suggests that it may be possible with
further research to identify molecular predictors of the inability to
benefit from regular exercise and of adverse changes in specific
cardiometabolic and diabetes risk factors.
In summary, we did not find any evidence for differences in the
prevalence of ARs between Blacks and Whites or between men
and women. Moreover, the AR traits are not explained by prior
health status of subjects, age, amount of exercise imposed by the
program, or lack of improvement in cardiorespiratory fitness. No
evidence could be found for the hypothesis that ARs were the
result of drug-exercise interactions. Thus, some individuals
experience ARs when exposed to regular exercise, but the causes
of the phenomenon are unknown at this time. The observations
reported herein need to be extended to other cardiometabolic and
diabetes risk factors such as LDL-cholesterol, small, dense LDL
particles, markers of low-grade inflammation, adiposity traits, and
ectopic fat depots. We conclude that it is critical to search for
potential physiological and molecular predictors so that individuals
at risk for adverse response patterns can be identified and offered
proper guidance in an exercise medicine preventive or therapeutic
context.
Supporting Information
Information S1
and the background material used to determine the
technical error for fasting insulin.
(DOCX)
Detailed description of the six studies
Acknowledgments
The contribution of Dr. Jack Wilmore, Professor Emeritus, University of
Texas at Austin, to the HERITAGE Family Study is gratefully
acknowledged. The authors would also like to express their gratitude to
Allison Templet for her numerous contributions to the development of this
manuscript.
Author Contributions
Conceived and designed the experiments: CB TR TSC. Performed the
experiments: CB TR. Analyzed the data: CB TR. Contributed reagents/
materials/analysis tools: CB SNB TSC CPE JMH KH NTJ LK WEK
DCR ASL JSS CAS TR. Wrote the paper: CB. Reviewed and contributed
to the final version of the manuscript: CB SNB TSC CPE JMH KH NTJ
LK WEK ASL DCR MAS JSS CAS TR.
References
1.Physical Activity Guidelines Advisory Committee (2008) Physical Activity
Guidelines Advisory Committee report, 2008. Washington, DC: U.S. Depart-
ment of Health and Human Services.
U.S.DepartmentofHealth and Human Services(2008)2008activityguidelinesfor
Americans. Washington, DC: U.S. Department of Health and Human Services.
Bouchard C, Rankinen T (2001) Individual differences in response to regular
physical activity. Med Sci Sports Exerc 33: S446–S451.
Boule NG, Weisnagel SJ, Lakka TA, Tremblay A, Bergman RN, et al. (2005)
Effects of exercise training on glucose homeostasis: The HERITAGE Family
Study. Diabetes Care 28: 108–114.
Leon AS, Gaskill SE, Rice T, Bergeron J, Gagnon J, et al. (2002) Variability in
the response of HDL cholesterol to exercise training in the HERITAGE Family
Study. Int J Sports Med 23: 1–9.
Church TS, Earnest CP, Skinner JS, Blair SN (2007) Effects of different doses of
physical activity on cardiorespiratory fitness among sedentary, overweight or
obese postmenopausal women with elevated blood pressure: a randomized
controlled trial. JAMA 297: 2081–2091.
Bouchard C, Leon AS, Rao DC, Skinner JS, Wilmore JH, et al. (1995) The
HERITAGE family study. Aims, design, and measurement protocol. Med Sci
Sports Exerc 27: 721–729.
Morss GM, Jordan AN, Skinner JS, Dunn AL, Church TS, et al. (2004) Dose
Response to Exercise in Women aged 45–75 yr (DREW): Design and rationale.
Med Sci Sports Exerc 36: 336–344.
Thompson AM, Mikus CR, Rodarte RQ, Distefano B, Priest EL, et al. (2008)
Inflammation and exercise (INFLAME): study rationale, design, and methods.
Contemp Clin Trials 29: 418–427.
10. Kraus WE, Torgan CE, Duscha BD, Norris J, Brown SA, et al. (2001) Studies of
a targeted risk reduction intervention through defined exercise (STRRIDE).
Med Sci Sports Exerc 33: 1774–1784.
11. Bateman LA, Slentz CA, Willis LH, Shields AT, Piner LW, et al. (2011)
Comparison of aerobic versus resistance exercise training effects on metabolic
syndrome (from the Studies of a Targeted Risk Reduction Intervention Through
Defined Exercise - STRRIDE-AT/RT). Am J Cardiol 108: 838–844.
12. Wilund KR, Colvin PL, Phares D, Goldberg AP, Hagberg JM (2002) The effect
of endurance exercise training on plasma lipoprotein AI and lipoprotein AI:AII
concentrations in sedentary adults. Metabolism 51: 1053–1060.
13. Karavirta L, Hakkinen K, Kauhanen A, Arija-Blazquez A, Sillanpaa E, et al.
(2011) Individual responses to combined endurance and strength training in
older adults. Med Sci Sports Exerc 43: 484–490.
14. Malina RM, Hamill PVV, Lemeshow S (1973) Selected body measurements of
children 6–11 years. Rockville, MD: National Center for Health Statistics.
2.
3.
4.
5.
6.
7.
8.
9.
(DHEW publication no. (HSM) 73-1605.) (DHEW publication no. (HSM) 73-
1605.).
15. Gagnon J, Province MA, Bouchard C, Leon AS, Skinner JS, et al. (1996) The
HERITAGE Family Study: Quality assurance and quality control. Ann
Epidemiol 6: 520–529.
16. Wilmore JH, Stanforth PR, Domenick MA, Gagnon J, Daw EW, et al. (1997)
Reproducibility of anthropometric and body composition measurements: the
HERITAGE Family Study1. Int J Obes Relat Metab Disord 21: 297–303.
17. Wilmore JH, Stanforth PR, Turley KR, Gagnon J, Daw EW, et al. (1998)
Reproducibility of cardiovascular, respiratory, and metabolic responses to
submaximal exercise: the HERITAGE Family Study. Med Sci Sports Exerc 30:
259–265.
18. Despres JP, Gagnon J, Bergeron J, Couillard C, Leon AS, et al. (1999) Plasma
post-heparin lipase activities in the HERITAGE Family Study: the reproduc-
ibility, gender differences, and associations with lipoprotein levels. HEalth, RIsk
factors, exercise Training and GEnetics. Clin Biochem 32: 157–165.
19. Skinner JS, Wilmore KM, Jaskolska A, Jaskolski A, Daw EW, et al. (1999)
Reproducibility of maximal exercise test data in the HERITAGE family study.
Med Sci Sports Exerc 31: 1623–1628.
20. Siscovick DS, Weiss NS, Fletcher RH, Lasky T (1984) The incidence of primary
cardiac arrest during vigorous exercise. N Engl J Med 311: 874–877.
21. Thompson PD, Mitchell JH (1984) Exercise and sudden cardiac death:
protection or provocation. N Engl J Med 311: 914–915.
22. Kim JH, Malhotra R, Chiampas G, d’Hemecourt P, Troyanos C, et al. (2012)
Cardiac arrest during long-distance running races. N Engl J Med 366: 130–
140.
23. Thompson PD (1993) Athletes, athletics, and sudden cardiac death. Med Sci
Sports Exerc 25: 981–984.
24. Rankinen T, Perusse L, Rauramaa R, Rivera MA, Wolfarth B, et al. (2002) The
human gene map for performance and health-related fitness phenotypes: the
2001 update. Med Sci Sports Exerc 34: 1219–1233.
25. Bouchard C, An P, Rice T, Skinner JS, Wilmore JH, et al. (1999) Familial
aggregation of VO(2max) response to exercise training: results from the
HERITAGE Family Study. J Appl Physiol 87: 1003–1008.
26. Rice T, Despres JP, Perusse L, Hong Y, Province MA, et al. (2002) Familial
aggregation of blood lipid response to exercise training in the health, risk factors,
exercise training, and genetics (HERITAGE) Family Study. Circulation 105:
1904–1908.
27. Katzmarzyk PT, Perusse L, Rice T, Gagnon J, Skinner JS, et al. (2000) Familial
resemblance for coronary heart disease risk: the HERITAGE Family Study.
Ethn Dis 10: 138–147.
Adverse Metabolic Response to Regular Exercise
PLoS ONE | www.plosone.org8 May 2012 | Volume 7 | Issue 5 | e37887

Page 9

28. Hong Y, Rice T, Gagnon J, Perusse L, Province M, et al. (2000) Familiality of
triglyceride and LPL response to exercise training: the HERITAGE study. Med
Sci Sports Exerc 32: 1438–1444.
29. An P, Teran-Garcia M, Rice T, Rankinen T, Weisnagel SJ, et al. (2005)
Genome-wide linkage scans for prediabetes phenotypes in response to 20 weeks
of endurance exercise training in non-diabetic whites and blacks: the
HERITAGE Family Study. Diabetologia 48: 1142–1149.
30. Rice T, An P, Gagnon J, Leon AS, Skinner JS, et al. (2002) Heritability of HR
and BP response to exercise training in the HERITAGE Family Study. Med Sci
Sports Exerc 34: 972–979.
31. Bouchard C, Sarzynski MA, Rice TK, Kraus WE, Church TS, et al. (2011)
Genomic predictors of the maximal O uptake response to standardized exercise
training programs. J Appl Physiol 110: 1160–1170.
32. Timmons JA, Knudsen S, Rankinen T, Koch LG, Sarzynski M, et al. (2010)
Using molecular classification to predict gains in maximal aerobic capacity
following endurance exercise training in humans. J Appl Physiol 108:
1487–1496.
33. Rankinen T, Sung YJ, Sarzynski MA, Rice TK, Rao DC, et al. (2012) The
heritability of submaximal exercise heart rate response to exercise training is
accounted for by nine SNPs. J Appl Physiol 112: 892–897.
Adverse Metabolic Response to Regular Exercise
PLoS ONE | www.plosone.org9 May 2012 | Volume 7 | Issue 5 | e37887