Does Cardiorespiratory Fitness Modify the Association between Birth Weight and Insulin Resistance in Adult Life?
et al. (2013) Does Cardiorespiratory Fitness Modify the Association between Birth Weight and
Insulin Resistance in Adult Life? PLoS ONE 8(9): e73967. doi:10.1371/journal.pone.0073967
Does Cardiorespiratory Fitness Modify the Association between Birth Weight and Insulin Resistance in Adult Life?
Tomoko Aoyama 0
Kazuyo Tsushita 0
Nobuyuki Miyatake 0
Takeyuki Numata 0
Motohiko Miyachi 0
Izumi Tabata 0
Zhen-Bo Cao 0
Shizuo Sakamoto 0
Mitsuru Higuchi 0
Pratibha V. Nerurkar, College of Tropical Agriculture and Human Resources, University of Hawaii, United States of America
0 1 Graduate School of Sport Sciences, Waseda University , Tokorozawa, Saitama , Japan , 2 Japan Society for the Promotion of Science , Chiyoda, Tokyo , Japan , 3 Aichi Comprehensive Health Science Center , Chita, Aichi , Japan , 4 Department of Hygiene, Faculty of Medicine, Kagawa University , Kita, Kagawa , Japan , 5 Okayama Southern Institute of Health , Okayama Health Foundation, Kita, Okayama , Japan , 6 National Institute of Health and Nutrition, Shinjuku, Tokyo, Japan, 7 Faculty of Sport and Health Science, Ritsumeikan University , Kusatsu, Shiga , Japan , 8 Faculty of Sport Sciences, Waseda University , Tokorozawa, Saitama , Japan
Objective: Lower birth weight is associated with higher insulin resistance in later life. The aim of this study was to determine whether cardiorespiratory fitness modifies the association of birth weight with insulin resistance in adults. Methods: The subjects were 379 Japanese individuals (137 males, 242 females) aged 20-64 years born after 1943. Insulin resistance was assessed using a homeostasis model assessment of insulin resistance (HOMA-IR), which is calculated from fasting blood glucose and insulin levels. Cardiorespiratory fitness (maximal oxygen uptake, VO2max) was assessed by a maximal graded exercise test on a cycle ergometer. Birth weight was reported according to the Maternal and Child Health Handbook records or the subject's or his/her mother's memory. Results: The multiple linear regression analysis revealed that birth weight was inversely associated with HOMA-IR (b = 20.141, p = 0.003), even after adjustment for gender, age, current body mass index, mean blood pressure, triglycerides, HDL cholesterol, and smoking status. Further adjustments for VO2max made little difference in the relationship between birth weight and HOMA-IR (b = 20.148, p = 0.001), although VO2max (b = 20.376, p,0.001) was a stronger predictor of HOMA-IR than birth weight. Conclusions: The results showed that the association of lower birth weight with higher insulin resistance was little modified by cardiorespiratory fitness in adult life. However, cardiorespiratory fitness was found to be a stronger predictor of insulin resistance than was birth weight, suggesting that increasing cardiorespiratory fitness may have a much more important role in preventing insulin resistance than an individual's low birth weight.
Funding: This research was supported by a Research Grant for Comprehensive Research on Cardiovascular and Life-Style Related Diseases from the Ministry of
Health, Labor, and Welfare, Japan (19160101). This study was partly supported by a Grant-in-Aid for the Global COE Sport Science for the Promotion of Active
Life from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a Grant-in-Aid for Research Fellow of the Japan Society for the
Promotion of Science (no.23-4764). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Low birth weight, a proxy for fetal underdevelopment, is
associated with increased risk of insulin resistance [1,2,3,4,5], type
2 diabetes , and metabolic syndrome [1,5] in adults. Insulin
resistance is the major metabolic disorder that is a potentially
underlying physiological factor for type 2 diabetes and metabolic
syndrome . Type 2 diabetes as well as metabolic syndrome has
become a major health problem worldwide, and the identification
of lifestyle factors able to improve the insulin resistance
accompanied by low birth weight is important to achieve primary
prevention of these metabolic disorders.
Although a sedentary lifestyle and obesity, especially abdominal
obesity, are known to be important in the development of insulin
resistance , recently cardiorespiratory fitness (CRF) has been
recognized as an important predictor of insulin resistance [8,9].
However, only one study by Laaksonen et al. (2003) has
investigated whether CRF in adult life can improve insulin
resistance associated with low birth weight , and the
investigators demonstrated that higher levels of CRF modify the association
between low size at birth, as assessed by the ponderal index (kg/
m3), with insulin resistance, which was estimated using a validated
insulin sensitivity index (QUICKI) in middle-aged men. It remains
unclear whether CRF modifies the association of birth weight with
insulin resistance in other racial groups. Because mean birth
weight is lower in the Asian population  compared with
Westerners [11,12,13], the relative contributions of birth weight
and CRF to insulin resistance in Asians may differ from those
found in the previous study . The aim of this study was to
examine the association of birth weight with insulin resistance and
to assess how the association is influenced by CRF in Japanese
adults, whose birth weights are generally much lower than those of
The subjects were 379 Japanese individuals aged 2064 years
who had taken part in our previous research (the Physical Activity
and Fitness for Health Promotion Study) [15,16]. This
crosssectional study of CRF and health status was conducted between
2007 and 2009 in the following independent institutions in Japan:
Waseda University (WU), Aichi Comprehensive Health Science
Center (ACHSC), Okayama Southern Institute of Health (OSIH),
and the National Institute of Health and Nutrition (NIHN). None
of the participants had been diagnosed with diabetes mellitus or
were taking any medications that could affect the study variables
(i.e., antihypertensive, antilipemic, or diabetes drugs or drugs that
alter the energy metabolism).
The research project was approved by the Ethical Committee of
WU, ACHSC, OSIH, and NIHN, respectively. Written informed
consent was obtained from each participant.
The subjects birth weights were obtained using a
questionnaireby-mail-survey between 2010 and 2011. We sent questionnaires to
968 participants born after 1943 out of 1,020 participants who
enrolled in the above-described research. Data on their CRF,
obesity measures, insulin resistance, and confounding variables
were recorded in the above-described research, which had been
stored at each institution. The questionnaire along with a detailed
explanation of the project as described below was sent to 968
participants, using reply-paid envelopes. The subjects were asked
to provide their birth weights through the Maternal and Child Health
Handbook (including the Handbook of Mothers and Children and the
Pregnant Women and Nursing Mothers Notebook) records. The Maternal
and Child Health Handbook is a unique tool that is provided to
women in Japan who report their pregnancies to each municipal
office. In Japan, birth weights have been recorded since July 1942,
when the Pregnant Women and Nursing Mothers Notebook was
distributed. Starting in 1948, the Handbook of Mothers and Children
was distributed instead of the Notebook. In 1967, the Maternal and
Child Health Handbook had taken the place of the Handbook of Mothers
and Children. Those subjects who had lost the Handbook or Notebook
were asked to report their birth weights from memory if the subject
or his/her mother knew the subjects birth weight precisely. The
subjects reply rate was 41% (397/968). After excluding
questionnaires that were not answered completely (n = 18), the completed
questionnaires of 379 subjects (137 males and 242 females) were
selected for analysis. Of these subjects, 213 (71 males and 142
females) had Notebook or Handbook records of their birth weight, and
166 (66 males and 100 females) were able to recall their birth
weight or obtain it from their mother.
Body mass index (BMI) was calculated from measured height
and weight (kg/m2). Abdominal circumference was measured at
the umbilical region with an inelastic measuring tape at the end of
CRF was assessed by a maximal graded exercise test on a cycle
ergometer [Lode Excalibur (OSIH) and Lode Corival (ACHSC),
Lode BV, Groningen, Netherlands; Monark Ergomedic 828E
(WU, NIHN), Varberg, Sweden] and quantified in terms of
maximal oxygen uptake (VO2max). The initial work load was 30
60 W, and the work rate was increased thereafter by 15 W/min
until the subject could not maintain the required pedaling
frequency (60 rpm) . Heart rate and a rating of perceived
exertion (RPE) were monitored throughout the exercise. During
the progressive exercise test, the expired gas of the subjects was
collected, and the rates of oxygen consumption (VO2) and carbon
dioxide production (VCO2) were measured over 30-s intervals
using an automated breath-by-breath gas analyzing system
[Aeromonitor AE-280S (ACHSC, WU), Minato Medical Science,
Tokyo, Japan; Oxycon Alpha (OSIH), Mijnhardt b.v., The
Netherlands]. The expired air was collected in Douglas bags,
and an O2 and CO2 mass spectrometer (Arco-1000, Arco System,
Japan) was used to analyze the O2 and CO2 concentrations
(NIHN). The volume of expired air was determined using a dry
gas volume meter (DC-5, Shinagawa Seisakusyo, Japan) and
converted to standard temperature, pressure and dry gas. During
the latter stages of the test, each subject was verbally encouraged
by the test operators to give maximal effort. VO2max was
considered to have been achieved if at least two of the following
four criteria were achieved: the VO2 curve showed a leveling off,
the subjects maximal heart rate was .95% the age-predicted
maximal heart rate (220 2 age), the respiratory exchange ratio
exceeded 1.0, and the subject achieved an RPE of 19 or 20.
Insulin resistance was assessed using the homeostasis model
assessment of insulin resistance (HOMA-IR), calculated as fasting
blood glucose (mg/dL) 6 fasting insulin (mU/mL)/405. Fasting
venous blood samples were collected after a fast of 12 h or more,
and the concentrations of blood glucose and insulin were
Several confounding variables were included in the analyses. In
the general population insulin resistance is associated with
hypertension, higher concentration of plasma triglycerides, and
lower concentrations of high density lipoprotein (HDL) cholesterol
. Therefore, we included the following confounders in the
analyses: mean blood pressure [diastolic blood pressure+(systolic
blood pressure 2 diastolic blood pressure)/3], triglycerides, HDL
cholesterol . Number of cigarettes smoked per day assessed by
means of a questionnaire  was also included among the
confounders, because smoking may directly increase insulin
Measured and calculated values are presented as means 6 SD.
HOMA-IR was log-transformed due to non-normal distribution in
the analyses. Students t-test was used to determine the differences
between males and females. Partial correlation analysis was used to
test the associations between study variables controlled for gender
and age as covariates. Multiple linear regression analyses were
performed to assess the associations of birth weight and CRF with
insulin resistance. We first entered the birth weight as an
independent variable and HOMA-IR as a dependent variable.
We then added VO2max as an independent variable to examine
how the association is altered by CRF. All models were adjusted
for gender, age, one of two obesity measures (i.e., BMI or
abdominal circumference), study location, mean blood pressure,
triglycerides, HDL cholesterol, and smoking status. We also
included an interaction term of CRF 6 birth weight.
Multicollinearity in the regression model was assessed by examining the
variance inflation factor. All statistical analyses were completed
using SPSS 20.0J for Windows (IBM Japan Inc., Tokyo, Japan).
The statistical significance level was set at p,0.05.
The characteristics of the subjects are shown in Table 1. The
average age of the subjects was 40.0610.5 years in males and
41.7610.7 years in females. The average birth weight was
3.1760.42 kg in males and 3.1160.45 kg in females. Significant
differences between males and females were observed in most
variables, so all models were adjusted for gender, as well as age in
the subsequent analyses. Table 2 shows the partial correlation
matrix of birth weight and current height, weight, obesity
measures (BMI and abdominal circumference), VO2max, and
HOMA-IR controlled for gender and age as covariates. Birth
weight was correlated positively with current height (r = 0.28,
p,0.001) and weight (r = 0.13, p = 0.010) and inversely with
HOMA-IR (r = 20.15, p = 0.004). Both BMI and abdominal
circumference were significantly correlated with HOMA-IR
(r = 0.38, p,0.001, respectively). VO2max was inversely
correlated with HOMA-IR (r = 20.38, p,0.001).
Table 3 presents the results of multiple linear regression analyses
of HOMA-IR as a dependent variable. As shown in the model 1,
birth weight was inversely associated with HOMA-IR even after
adjusting for gender, age, BMI, study location, mean blood
pressure, triglycerides, HDL cholesterol, and smoking status
(b = 20.141, p = 0.003). Further adjustment for VO2max made
little difference in the relationship between birth weight and
HOMA-IR (b = 20.148, p = 0.001) (model 2). Adjusting for
abdominal circumference instead of BMI showed similar results
(b = 20.152, p = 0.001) (model 3). This association was largely
unaffected by further adjustment for VO2max (b = 20.159,
p,0.001) (model 4). In the final models (model 2 and 4), gender,
age, and obesity variables (BMI or abdominal circumference) were
Abdominal circumference (cm)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Mean blood pressure (mmHg)
HDL cholesterol (mg/dL)
Fasting blood glucose (mg/dL)
Fasting insulin (mU/mL)
Data are means 6 SD (Range).
BMI, body mass index; VO2max, maximal oxygen uptake.
All (n = 379)
found to be significant predictors of HOMA-IR (gender:
p = 0.004, age and BMI: p,0.001 in model 2, gender:
p = 0.009, age and abdominal circumference: p,0.001 in model
4). No significant associations were observed between an
interaction term (CRF 6 birth weight) and HOMA-IR
(p = 0.997 in model 2, p = 0.857 in model 4).
When we separately analyzed the subjects with recorded birth
weight data (n = 213) and those with recalled birth weight data
(n = 166), we found that the b-related birth weight and HOMA-IR
were almost the same between two groups in the model including
BMI and VO2max as covariates (recorded birth weight group:
b = 20.149, p = 0.016, recalled birth weight group: b = 20.164,
p = 0.021).
This study was performed to examine the association of birth
weight with insulin resistance, and how the association is
influenced by CRF in adults. Birth weight was found to be
significantly and inversely associated with HOMA-IR after
adjustment for gender, age, obesity measurement, and other
potential confounders (Table 3). This result is in line with previous
studies showing that birth weight is a significant predictor of
insulin resistance in adults [1,3,4,5]. Insulin resistance is a major
metabolic disorder in the early stages of development of type 2
diabetes and metabolic syndrome . As such, low birth weight
may be a cause of type 2 diabetes and metabolic syndrome later in
life, while genetic and early environmental factors are of
importance in the development of insulin resistance. Although
the detailed mechanisms by which low birth weight increases
insulin resistance are not completely understood, Hales and Barker
proposed the thrifty phenotype hypothesis . According to
this hypothesis, fetal malnutrition and the consequent low birth
weight set in motion mechanisms of fetal nutritional thrift and
result in the redistribution of blood flow, with selective protection
of brain growth . These changes in the mechanisms that
maintain glucose tolerance last permanently after birth, and lead
Males (n = 137)
Females (n = 242)
Abdominal circumference (cm)
to insulin resistance under the condition of a mismatch between
intrauterine constraint and a nutritionally rich postnatal
environment. The findings of this study provide further support for this
hypothesis and further evidence that low birth weight may be
linked to insulin resistance in Japanese adults .
The present study showed that the association of lower birth
weight with insulin resistance was not modified by CRF. This
finding is in contrast with the study by Laaksonen et al. . They
reported that higher CRF may moderate the association of lower
size at birth with insulin resistance in adult life . There are a
number of potential reasons for the differences between the
present studys findings and those of the Laaksonen study . We
examined the influence of CRF on the associations between birth
weight and insulin resistance in men and women aged 2064
years, whereas the Laaksonen study was performed in middle-aged
men aged 4260 years. However, there were no differences in the
HOMA-IR was log-transformed for analysis.
Model 1: adjusted for gender, age, study location, mean blood pressure,
triglycerides, HDL cholesterol, smoking status, and BMI.
Model 2: As model 1 plus CRF 6 birth weight.
Model 3: adjusted for gender, age, study location, mean blood pressure,
triglycerides, HDL cholesterol, smoking status, and abdominal circumference.
Model 4: As model 3 plus CRF 6 birth weight.
B, unstandardized regression coefficient; b, standardized regression coefficient;
R2, coefficient of determination; VO2max, maximal oxygen uptake.
association of birth weight and CRF with HOMA-IR between the
males and females or between the younger group and the
middleaged group in the present study (date are not shown). Thus the
lack of a modifying effect of CRF in the present study is not
explained by differences in gender or age. It is possible that the
effect of CRF on the association of birth weight with insulin
resistance may be overestimated by the lack of adjustment for
obesity in the Laaksonen study . We confirmed, however, that
CRF did not modify the association of birth weight with
HOMAIR (b = 20.158, p = 0.001) without adjusting for obesity in our
data. As such, the presence of the covariate of obesity is not likely
to be related to the lack of modifying effect of CRF.
The difference in race may be a potential reason for the
discrepancy between our findings and those of Laaksonen et al.
. Because type 2 diabetes occurs in Asians, who are less obese
than populations in Western countries , the association of birth
weight with insulin resistance may be stronger in Japanese, whose
birth weights are generally much lower than those of Westerners
. This might make it difficult to modify the association of birth
weight with insulin resistance by CRF in Japanese. The finding in
our study is consistent with that of Ridgway et al. (2011), in which
the association between low birth weight and HOMA-IR was not
modified by aerobic fitness (watts per kilogram FFM) in 9- and
15year-olds . As in children and adolescents, it is plausible that
the lifelong influence of low birth weight on insulin resistance
could not be offset by lifestyle modification such as increasing CRF
in Japanese adults.
However, it should be noted that CRF had a closer relationship
to HOMA-IR than did birth weight. The contribution of birth
weight to HOMA-IR (b = 20.148) was relatively small when
compared with that of VO2max (b = 20.376) in the model 2
(Table 3). CRF in adult life seems to be a more important
determinant of the occurrence of insulin resistance than birth
weight. Because exercise improves muscular insulin sensitivity
through a variety of mechanisms , high levels of CRF with
regular exercise may have a protective effect against insulin
resistance associated with low birth weight. Thus, increasing CRF
may have a much more important role in preventing insulin
resistance than does an individuals low birth weight.
Incidentally, macrosomia, defined as a birth weight of 4 kg or
more, is known to be attributed in part to a maternal history of
diabetes, which increases the risk of type 2 diabetes in adult
offspring . In this study, 14 subjects showed macrosomia.
Therefore, we also examined the influence of excluding
macrosomic participants on the strength of the contribution of birth
weight to HOMA-IR (data not shown). The exclusion of 14
participants with birth weights greater than 4 kg reduced the
brelated birth weight and HOMA-IR by a small amount, from
20.148 (p = 0.001) to 20.101 (p = 0.031). These data imply that
macrosomic participants in this study may strengthen the
association of lower birth weight with insulin resistance. The
number of babies with a maternal history of diabetes was thought
to be small in relation to the number of babies who were heavy
due to good fetal nutrition and for other reasons in the general
population . Therefore, the association between higher birth
weight and higher insulin resistance was regarded as negligible in
this Japanese cohort. Thus we did not exclude macrosomia
subjects in the analysis.
Recent trends in industrialized countries, such as the USA,
Canada , Sweden , and Norway , show that infants
are born heavier, with increased mean birth weight and a decline
in the prevalence of low birth weight infants (,2.5 kg). By
contrast, the mean birth weight of Japanese infants has steadily
declined since the 1980s. Mean birth weight has decreased from
3.19 kg in 1980 to 3 kg in 2010 . In line with this, the
incidence of low birth weight babies has increased from 5.2% in
1980 to 9.6% in 2010 in Japan . In these circumstances,
successful strategies are especially needed to promote physically
active lifestyle, which focus on aerobic exercise to increase CRF
for children born with a low birth weight. However, this recent
trend toward reduced fetal weight in Japan seems to be partially
attributable to changes in maternal health, such as an increase in
the prevalence of underweight (BMI ,18.5 kg/m2) in young
women  and of low dietary intake during pregnancy . The
present study showed that CRF in adult life did not modify the
association of birth weight with insulin resistance. In other words,
it would be difficult to disentangle the negative influence of low
birth weight after birth. Therefore, the Japanese population should
be aware of the public health problems associated with low birth
weight. Successful strategies are also needed to spread the
information among pregnant women that malnutrition of mothers
during pregnancy can result in their babies having a future risk of
The present study has several limitations. First, as it was a
retrospective study, larger sample sizes and long term follow-up
studies are needed to confirm the effects of birth weight and adult
CRF on insulin resistance. Second, data on gestational age were
not available. Nonetheless, adjustment for gestational age has not
attenuated the association of thinness at birth with insulin
resistance in the previous study . Third, we used both
recorded birth weight data and recalled birth weight data
(according to subjects or his/her mothers memory). However,
recalled and recorded birth weight measurements are known to be
highly correlated (r = 0.88) . In addition, the association of
birth weight and HOMA-IR was similar between the recorded
birth weight group and the recalled birth weight group. Fourth,
HOMA-IR reflects insulin resistance in the liver rather than in fat
and muscle , and it is a relatively indirect method of measuring
insulin resistance compared with the oral glucose tolerance test
(OGTT) and the euglycemic insulin clamp test. Further studies are
needed to assess whether birth weight and CRF influence insulin
resistance in the whole body, as estimated by the OGTT and
euglycemic clamp test. While this remains to be investigated, this
study has contributed valuable information pertaining to the
In summary, the present study showed that the association of
lower birth weight with higher insulin resistance was little modified
by CRF in adult life. However, CRF was a stronger predictor of
insulin resistance than was birth weight. These results suggest a
lifelong adverse effect of low birth weight on glucose metabolism,
as well as an importance of lifestyle factors that can improve
insulin resistance. Our data demonstrate that higher levels of CRF
would not offset the adverse effects of low birth weight on insulin
resistance; however, increasing CRF may have a much more
important role in preventing insulin resistance than does an
individuals low birth weight.
The authors would like to thank the staff members of the WU, ACHSC,
OSIH, and NIHN who were involved with the birth weight survey.
Conceived and designed the experiments: TA MH IT. Performed the
experiments: TA KT NM TN MM SS. Analyzed the data: TA Z-BC.
Wrote the paper: TA Z-BC MH. Critically revised the manuscript: KT
NM TN MM IT SS.
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