Context Physical inactivity and body mass index (BMI) are established independent
risk factors in the development of type 2 diabetes; however, their comparative
importance and joint relationship with diabetes are unclear.
Objective To examine the relative contributions and joint association of physical
activity and BMI with diabetes.
Design, Setting, and Participants Prospective cohort study of 37 878 women free of cardiovascular
disease, cancer, and diabetes with 6.9 years of mean follow-up. Weight, height,
and recreational activities were reported at study entry. Normal weight was
defined as a BMI of less than 25; overweight, 25 to less than 30; and obese,
30 or higher. Active was defined as expending more than 1000 kcal on recreational
activities per week.
Main Outcome Measure Incident type 2 diabetes, defined as a new self-reported diagnosis of
diabetes.
Results During the follow-up, 1361 cases of incident diabetes occurred. Individually,
BMI and physical activity were significant predictors of incident diabetes.
Compared with normal-weight individuals, the multivariate-adjusted hazard
ratio (HR) was 3.22 (95% confidence interval [CI], 2.69-3.87) for overweight
individuals and 9.09 (95% CI, 7.62-10.8) for obese individuals. For overall
activity (kilocalories expended per week), compared with the least active
first quartile, the multivariate-adjusted HRs were 0.91 (95% CI, 0.79-1.06)
for the second quartile, 0.86 (95% CI, 0.74-1.01) for the third, and 0.82
(95% CI, 0.70-0.97) for the fourth (P for trend =
.01). In the combined analyses, overweight and obese participants, whether
active or inactive, had significantly elevated risks, compared with normal-weight
active individuals. The multivariate-adjusted HRs were 1.15 (95% CI, 0.83-1.59)
for normal-weight inactive, 3.68 (95% CI, 2.63-5.15) for overweight active,
4.16 (95% CI, 3.05-5.66) for overweight inactive, 11.5 (95% CI, 8.34-15.9)
for obese active, and 11.8 (95% CI, 8.75-16.0) for obese inactive participants.
Conclusions Although BMI and physical inactivity are independent predictors of incident
diabetes, the magnitude of the association with BMI was greater than with
physical activity in combined analyses. These findings underscore the critical
importance of adiposity as a determinant of diabetes.
Physical inactivity and body mass index (BMI) are established independent
risk factors in the development of type 2 diabetes mellitus; however, the
comparative importance and joint relationship of these factors on diabetes
is unclear.1-4 In
the 1990s, the prevalence of both obesity and diabetes nearly doubled, demonstrating
the significance of each as a major public health issue.5
Data on the interrelationship between BMI and physical activity and
the risk of diabetes are limited. Some large clinical trials have investigated
the effect of diet and exercise interventions on high-risk individuals; however,
most did not distinguish between the effects of weight vs exercise, and all
were performed on participants with impaired glucose tolerance.6-8 There
are few observational studies that directly evaluate the joint relationship
between BMI and physical activity with diabetes in a population of healthy
women.9
A clearer understanding of the combined effect of BMI and physical activity
is needed to stratify patients by risk and in turn target those at highest
risk of developing diabetes. Therefore, we investigated the combined relationship
of BMI and physical activity with diabetes to understand whether increasing
physical activity levels reduce the elevated risk of diabetes from obesity.
In addition, because walking is the most common form of exercise in women,
we also considered walking in our analysis of physical activity.10-12
Participants were from the Women's Health Study (WHS), an ongoing randomized
double-blinded clinical trial of low-dose aspirin and vitamin E in the primary
prevention of cardiovascular disease (CVD) and cancer. Beginning in 1992,
39 876 US female health care professionals aged 45 years and older, free
of CVD, cerebrovascular disease, and cancer were recruited and randomized
into the study.13,14 Data were
collected on sociodemographics, health habits, and medical history. For this
study, 1998 women were excluded due to missing data on physical activity or
BMI or because of a preexisting diagnosis of diabetes, which left 37 878
women as the baseline population. The protocols of the WHS, including obtaining
informed consent, have been approved by the Brigham and Women's Hospital institutional
review board.
Assessment of BMI, Physical Activity, and Other Covariates
Using self-reported height and weight from the baseline questionnaire,
BMI was calculated by dividing weight in kilograms by height in meters squared.
Women were also asked to estimate the average time (0, 1-19 min/wk,
20-59 min/wk, 1 h/wk, 1.5 h/wk, 2-3 h/wk, 4-6 h/wk, or ≥7 h/wk) they spent
on 8 groups of recreational activities during the past year: walking or hiking;
jogging (>10-minute mile); running (≤10-minute mile); bicycling; aerobic
exercise, aerobic dance, or the use of exercise machines; lap swimming; tennis,
squash, or racquetball; and lower-intensity exercise (including yoga, stretching,
and toning).15 Additionally, the number of
flights of stairs climbed daily (0, 1-2, 3-4, 5-9, 10-14, or ≥15) was assessed.
A metabolic equivalent task (MET) score was assigned based on the energy cost
of each activity. Since 1 MET is approximately 1 kcal/kg of body weight per
hour, we were able to estimate energy expenditure in kilocalories per week
by multiplying the MET score by body weight and hours per week (using the
mid point of the time category). This measurement of physical activity has
been shown to be valid and reliable. The test-retest correlation over 2 years
in a random sample of nurses was 0.59. When questionnaire estimates were compared
with 4 past-week physical activity recalls collected the year before the questionnaire
was administered, the correlation was 0.79 and when compared with activity
diaries during the same year for 4 separate weeks, the correlation was 0.62.16
Participants also reported age (years), family history of diabetes in
a first-degree relative (yes, no), alcohol use (rare, 1-3 drinks per month,
1-6 drinks per week, ≥1 drink per day), smoking status (never, past, current),
use of hormone therapy (never, past, current), history of hypertension (yes,
no), and history of high cholesterol (yes, no). Women completed semiquantitative
food frequency questionnaires from which folate, saturated fat, vitamin E,
fiber, and fruit and vegetable intake was calculated.17 Hypertension
was defined as self-reported high blood pressure diagnosed by a physician,
a self-reported systolic blood pressure of 140 mm Hg or higher, or diastolic
blood pressure of 90 mm Hg or higher. High cholesterol was defined as self-reported
high cholesterol diagnosed by a physician, self-reported total cholesterol
level of 240 mg/dL (≥6.6 mmol/L) or higher, or use of cholesterol-lowering
medications.
Ascertainment of Diabetes Mellitus
Self-reported diabetes status was evaluated at baseline, and women with
a history of diagnosed diabetes were excluded. Since participants were aged
at least 45 years at baseline, incident diabetes mellitus was classified as
type 2 diabetes. Thereafter, all of the participants provided annual self-reports
whether and when they had been diagnosed with type 2 diabetes since completing
their previous questionnaire.
Two complementary approaches have been used to confirm self-reported
type 2 diabetes in the WHS. First, we attempted to contact 473 women with
self-reported diabetes who provided a blood sample as part of a nested case-control
study of diabetes to verify the self-reported diagnosis. Based on the American
Diabetes Association (ADA) diagnostic criteria, diabetes cases were confirmed
if 1 or more of the following were present: (1) 1 or more symptom of hyperglycemia
in conjunction with either a fasting plasma glucose level of at least 126
mg/dL or a random plasma glucose level of at least 200 mg/dL; (2) in the absence
of symptoms, 2 or more elevated plasma glucose measurements (fasting plasma
glucose of ≥126 mg/dL, random plasma glucose of ≥200 mg/dL, or plasma
glucose of ≥200 mg/dL at ≥2 hours during oral glucose tolerance testing);
(3) use of insulin or an oral hypoglycemic agent.18 Using
the ADA criteria, the self-reported diagnosis of diabetes was confirmed in
406 (91%) of 446 women who responded via telephone interview.19 Second,
a random sample of 147 women with self-reported diabetes was mailed a supplemental
diabetes questionnaire, also using the ADA criteria to parallel the telephone
interview. Among 136 respondents, 124 (91%) women were identified as having
diabetes by the supplemental questionnaire. In addition, 113 of the 124 women
gave permission to contact their primary care physician. Ninety-seven of the
113 physicians responded, of whom 90 provided adequate information to apply
the ADA criteria. For these 90 women, 89 (99%) were confirmed to have type
2 diabetes. Thus, we believe that self-reported type 2 diabetes is valid in
the WHS.
All analyses were conducted using SAS statistical software version 8
(SAS Institute, Cary, NC). Based on the current World Health Organization
guidelines, BMI was divided into 3 categories: normal weight, less than <25;
overweight, 25 to less than 30; and obese, 30 or higher.20 Mean
(SDs) were calculated for all continuous variables and the percentage of participants
in each category was determined for all categorical variables. Analyses of
covariance were run for continuous variables and χ2 tests for
trend were run for categorical variables to determine if statistically significant
differences were present.
Physical activity was categorized in 3 ways: (1) by categories of energy
expenditure: inactive, fewer than 1000 kcal/wk or active, more than 1000 kcal/wk
since 1000 kcal/wk satisfies current recommendations for physical activity;
ie, either 30 minutes of moderate-intense activity on 5 days of the week or
20 minutes of vigorous-intense activity on 3 days of the week10,21;
(2) by quartiles of energy expenditure: fewer than 200, 200 to 599, 600 to
1499, and 1500 or more kcal/wk; and (3) by time spent walking per week (no
walking, <1, 1-1.5, 2-3, and ≥4 h/wk). Cox proportional hazards models
examined the independent effects of both BMI and physical activity on diabetes.
Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated
using age- and multivariate-adjusted models, which included the previously
described covariates and randomized WHS treatments. Additional multivariate-adjusted
models controlled for all previously mentioned covariates, plus total kilocalories
per week in the BMI analysis and BMI in the physical activity analyses. To
test for overall effect modification, we created an interaction term with
the continuous BMI and physical activity (kilocalories per week) variables,
which was included in both age- and multivariate-adjusted models that included
the independent continuous variables.
To investigate the combined effect of BMI and physical activity on the
development of diabetes, joint BMI and physical activity variables were created.
That is, participants were divided into groups based on both their BMI and
physical activity level. Joint variables were created for each of the 3 different
classifications of physical activity described previously with the 3-level
BMI variable. For example, 6 groups of women were represented for the BMI
and dichotomous physical activity combined analysis: normal-weight active,
normal-weight inactive, overweight active, overweight inactive, obese active,
and obese inactive. The normal-weight, most active individuals were always
the referent group. Age- and multivariate-adjusted models were generated with
the joint variables using Cox proportional hazards regression. Cox proportional
hazards assumptions were tested using time-varying variables. Analyses of
time spent walking also adjusted for total energy expenditure in kilocalories
per week. To test for effect modification in each joint analysis, an interaction
term was defined by multiplying the categorical physical activity variable
and the 3-level BMI variable, which was individually entered into each age-
and multivariate-adjusted Cox proportional hazards model to generate HRs and
their 95% CIs.
Of the 37 878 women, 1361 developed type 2 diabetes during 6.9
mean years of follow-up. At baseline, 19 630 participants (52%) were
normal weight, 11 700 (31%) were overweight, and 6548 (17%) were obese.
The mean (SD) BMI was 25.9 (5.0). In all, 12 936 participants (34%) were
considered active based on the current recommendations (≥1000 kcal/wk)
and the median (interquartile range) energy expenditure was 581 (1148) kcal/wk.
The baseline characteristics of the participants by BMI category are
shown in Table 1. Women who were
overweight or obese were more likely to have a family history of diabetes,
hypertension, and high cholesterol. Body mass index was inversely associated
with energy expenditure per week, hormone therapy use, smoking status, and
regular alcohol consumption.
The independent effects of BMI and physical activity on diabetes in
both age and multivariate-adjusted models are presented in Table 2, Table 3, Table 4, and Table 5. Overweight participants had an increased risk of diabetes
with a multivariate HR of 3.22, and obese participants had an even greater
HR of 9.09 (Table 2).
Those who met the physical activity guidelines had a lower risk of incident
diabetes with an age-adjusted HR of 0.73 (Table 3). Although adjustment for confounders attenuated the association
with physical activity, the relationship remained significant. Additional
adjustment for BMI further attenuated the HR. Further analysis of physical
activity as energy expenditure in quartiles and time spent walking (Table 3) revealed a reduction in the HR
of diabetes as activity increased. There was no significant overall effect
modification of physical activity (kilocalorie per week) by BMI when the interaction
between the continuous BMI and physical activity variables was analyzed (P = .46).
Examination of the combined effect of BMI and physical activity is shown
in Table 6. With the exception
of the normal-weight inactive group, each group had a statistically significant
increased risk of diabetes compared with the normal-weight active reference
group. When the inactive group and active group within the same BMI strata
were compared, the HR decreased from 4.16 to 3.68 (P =
.28) for overweight participants and from 11.8 to 11.5 (P = .73) for obese participants. These decreases in risk were small
and nonsignificant. However, within the same activity level, when the overweight
and obese groups were compared with the normal-weight group, there were large
increases in the HRs (P<.01). Tests of proportional
hazards revealed changes over time in physical activity and in the obese-active
and obese-inactive groups. However, taking into account updated information
on BMI at 24, 36, and 72 months and updated information on physical activity
at 36 and 72 months, the HRs did not change appreciably. Although hypertension
and high cholesterol may be correlated with diabetes, multivariate models
that individually excluded these covariates did not alter the interpretation
of the results.
Further analysis of the joint effect of BMI and physical activity, as
energy expenditure per week in quartiles, in the multivariate model is displayed
in Figure 1. As before, as physical
activity level increased, there was a small reduction in the relative risk
of incident diabetes within each BMI group. However, as BMI increased the
magnitude of the HRs increased dramatically. For example, in obese participants,
the HR decreased from 14.6 for the least active to 14.0 for the most active
quartile (P = .68). In contrast, when comparing those
in the highest physical activity quartile, the obese group's risk of diabetes
was 14-fold that of the normal weight group (P<.01).
The relation between energy expenditure and diabetes risk was not influenced
by BMI level (P>.05).
Next, the relationship of BMI and time spent walking on diabetes is
shown in Figure 2. Body mass index
continued to have a greater influence on the development of incident diabetes
than physical activity in these analyses. When we considered the 1877 women
who walked at least 7 hours per week, results were identical to women who
walked at least 4 hours per week. The relation between time spent walking
and risk of diabetes was not influenced by BMI level (P>.05). The combination of BMI and intensity level was also examined
and demonstrated similar results as the models described previously.
Consistent with previous studies, we demonstrated that BMI and physical
inactivity are significant predictors of type 2 diabetes.1-4 This
study further revealed that the magnitude of the association with BMI is much
greater than with physical activity, when examining the combined relationship
of BMI and physical activity. We observed a modest reduction in the risk of
diabetes with increasing physical activity level compared with a large increase
in the risk with increasing BMI. In this study, joint analyses broaden our
understanding of risk factors' relative influence on diabetes.
These findings parallel the limited data on the combined effects of
physical activity and BMI. In one observational analysis examining multiple
risk factors for diabetes, being overweight or obese was also found to be
the strongest predictor in women in the Nurses' Health Study.9
Our results are also consistent with several randomized clinical trials
in diabetes prevention among participants with impaired glucose tolerance.
The Diabetes Prevention Program found that lifestyle modification, including
physical activity, diet modification, and weight loss, was more beneficial
than metformin therapy in reducing the development of diabetes.6 The
Da Qing Impaired Glucose Tolerance and Diabetes Study compared diet and exercise
interventions and found similar reductions in the risk of diabetes while controlling
for BMI.7 In both studies, the precise contribution
of weight and physical activity is unclear. Tuomilehto et al8 found
that improvement in diet and exercise reduced the risk of diabetes even when
participants did not attain their targeted weight loss; however, this study
did not examine the effect of exercise on diabetes risk based on BMI category.8 Each of these studies involved high-risk individuals,
whereas our cohort included apparently healthy women free of baseline diabetes.
Blumenthal et al,22 in their trial of
participants with hypertension, found that weight loss had a significantly
greater effect on the reduction of fasting glucose and insulin levels than
physical activity. Elevated glucose and insulin levels are precursors to the
development of diabetes. Thus, if glucose and insulin levels decrease, the
rate of diabetes may also decrease, consistent with our results.
Why does physical activity appear to have a stronger effect overall
than when explored by BMI strata? Although BMI and physical inactivity are
viewed as 2 independent variables, they may be influencing each other and
contributing to the same causal pathway leading to the development of diabetes.
This is suggested by the attenuation of the effects of physical activity by
adjusting for BMI in our analyses.
Although there are many theories, the mechanism by which obesity affects
insulin resistance and in turn leads to diabetes remains poorly understood.
Obesity is known to increase peripheral insulin resistance and reduces beta
cell sensitivity to glucose.23,24 Although
physical activity increases insulin sensitivity and has complex effects that
can improve glucose metabolism, such as insulin-receptor upregulation in muscle
and increased insulin and glucose delivery to muscle, it may not fully reverse
the effects of obesity.25 It has also been
postulated that adipose tissue affects insulin metabolism by releasing free
fatty acids and cytokines.23,26 Weight
loss may therefore be a key mechanism to reduce the secretion of these factors
by decreasing adipose tissue volume and subsequently reducing the risk of
diabetes.
Limitations of our study include the use of self-reported diabetes.
However, a validation study comparing self-reports with additional medical
information resulted in confirmation of at least 91% of the self-reported
cases, consistent with findings from the Nurses' Health Study.4 Since
diabetes is self-reported, we may be missing cases that are not yet diagnosed.
If anything, this would result in an underestimate of the true effect. The
physical activity variables may also be subject to measurement error. However,
studies have shown that the self-reported physical activity questionnaire
used in this study is both valid and reliable.16 Only
recreational, and not occupational activity, was reported, but all women are
health care professionals who tend to perform little occupational physical
activity. Even though activity may be somewhat underestimated, we do not expect
this to bias our findings. Although the women in this cohort tend to be healthier
than the general population,27 the biological
mechanisms that affect the development of diabetes are unlikely to be different
compared with the general population. Future studies should incorporate the
role of race or ethnicity, which we were underpowered to study. Finally, residual
confounding by variables such as carbohydrate intake and baseline impaired
fasting glucose level is always an issue in an observational study; however,
major confounders have been controlled for in our multivariate models.
In conclusion, this study demonstrates that both physical activity and
BMI play important roles in the development of type 2 diabetes. As opposed
to our original hypothesis, physical activity only modestly affected the influence
of BMI on diabetes risk, and rather the combination of risk factors attenuated
the individual influence of physical activity. The magnitude of the association
with diabetes risk was much greater for BMI than for physical activity. These
findings underscore the critical importance of adiposity as a determinant
of type 2 diabetes. Because physical activity is a significant individual
predictor and has a beneficial effect on BMI, it remains an important intervention
for diabetes prevention. Our study suggests that to further reduce the risk
of diabetes with physical activity, it should be performed in conjunction
with achieving weight loss. By furthering our understanding of the relative
influence of BMI and activity on diabetes, we may improve our ability to risk
stratify patients and in turn may reduce the incidence of diabetes.
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