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he increasing prevalence of obesity and associated risk factors for cardiovascular disease (CVD) constitute a major global
health problem, affecting both children and adults.1 Currently, however, the effects of weight gain on CVD morbidity
and mortality in patients with type 1 diabetes mellitus (T1DM) have been studied less extensively.2 Although intensive
insulin therapy has been shown to lower the development of microvascular,3 and ultimately macrovascular complications in
people with T1DM,4 its beneficial effects may be partially off-set by its weight gainpromoting properties, which are paralleled
by the occurrence of obesity-associated cardiometabolic risk factors.5
CVD has become the leading cause of mortality in patients with T1DM, with a 4- to 8-fold increase in mortality compared
with nondiabetic age-matched individuals.6 In these patients, CVD risk factors may have their onset in childhood and persist
throughout adulthood, leading to the early development of atherosclerotic lesions and accelerated progression to CVD.7 Previous studies have shown more severe atherosclerotic lesions in children with T1DM occurring at a younger age as compared
with healthy control subjects.8 In addition, two studies reported a high prevalence of risk factors and a positive family history in
Norwegian and German children with T1DM.9,10 Most studies evaluating the occurrence of these risk factors in pediatric populations with T1DM, however, did not address the role of overweight or obesity on the prevalence of these factors. Finally, the
prevalence of the metabolic syndrome (MetS), a clustering of cardiometabolic risk factors (including obesity, dyslipidemia and
hypertension), which encompasses increased risk for CVD in both obese adult and pediatric populations, was also not determined in these studies.11,12
The present study determined the prevalence of cardiometabolic risk factors in a cohort of children with T1DM. We also
assessed the occurrence of MetS, according to an adjusted pediatric definition, and assessed the influence of overweight and
obesity on the prevalence of these CVD risk factors.
ACR
ADA
ALT
BMI
CVD
MetS
T1DM
WC
Albumin-to-creatinine ratio
American Diabetes Association
Alanine aminotransferase
Body mass index
Cardiovascular disease
Metabolic syndrome
Type 1 diabetes mellitus
Waist circumference
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Methods
We studied a cohort of consecutive children (age 3 to 18
years) with T1DM who attended a Dutch specialized Pediatric Diabetes Center in Rotterdam in the period 2007 to 2008.
Data were collected according to a standardized treatment
protocol and cross-sectional analyses were performed to assess cardiometabolic risk factors within this cohort.
T1DM was diagnosed according to criteria of the American Diabetes Association (ADA), including measurements
of autoantibodies (islet cell antibodies [ICA], glutamic acid
decarboxylase [GAD], tyrosine phosphatase-like insulinoma
antigen 2 [IA-2]) and C-peptide at diagnosis.13 Children with
incomplete data sets (n = 157), except for ALT (n = 153),
were excluded from the study . In addition, to prevent bias,
children with only clinical diagnosis of T1DM (n = 87), maturity-onset diabetes of youth, or secondary causes of T1DM
(n = 24) and type 2 diabetes mellitus (n = 2) were excluded
from the study. Therefore, a sample of 283 was included in
this study. Children who were excluded due to incomplete
data sets were not different with respect to baseline characteristics (sex, age, ethnicity, z-body mass index [BMI], and diabetes duration).
During visits to the outpatient clinic, a detailed history, including glycemic control and insulin regimen, was collected.
A family history of type 2 diabetes and CVD was assessed
yearly by questionnaire. Measurements of height and weight
to calculate BMI, waist circumference (according to a previously described method),14 and blood pressure were performed every visit. Three consecutive blood pressure
measurements were performed in the nondominant arm,
with at least a 1-minute interval, in the seated position and
after 10 minutes of rest, using a validated oscillometric device
(Omron705 IT). Blood samples for nonfasting lipid levels
and HbA1c were drawn and urinary albumin and creatinine
in spot urine were determined to calculate the albumin-tocreatinine ratio (ACR).
Cardiometabolic risk factors (smoking, obesity, glycemic
control, elevated level of LDL-cholesterol, elevated level of
triglycerides, decreased level of HDL-cholesterol, and microalbuminuria) and a positive family history for premature
CVD and type 2 diabetes were identified according to the
ADA guidelines for children and adolescents with T1DM.15
BMI and waist circumference (WC) were standardized using
Z-scores (Z-BMI and Z-WC, respectively) according to
Dutch reference values, with a cutoff value for overweight defined as a Z-BMI $1.1.16,17 Lipid levels were evaluated according to the reference values recently proposed by the
ADA (LDL-cholesterol <2.6 mmol/L, HDL-cholesterol >1.1
mmol/L, and triglycerides <1.7),15 and blood pressure values
were considered abnormal when values were above the 95th
percentile according to European reference values for height
and sex.18 Target levels for HbA1c were defined as HbA1c
<7.5%.18 Microalbuminuria was diagnosed when ACR determined in spot urine were $2.5 mg/mmol for boys and $3.5
mg/mmol for girls.19 A positive family history was defined as
924
ORIGINAL ARTICLES
June 2010
Normal-weight
P value
174 (61.5%)
90 (51.7%)
108 (62.1%)
12.3 (9.7-15.7)
6.4 (3.7-9.4)
5.6 (3.0-9.1)
18.5 2.4
0.4 (-0.2-0.8)
66 8.7
0.7 (0.2-1.1)
112 14
63 9
8.1 (7.3-9.3)
4.3 0.7
1.4 (1.2-1.7)
2.3 0.6
1.0 (0.8-1.4)
1.0 0.5
119 (68.5%)
1.3 (0.8-2.4)
17 (14-20)
109 (38.5%)
48 (44.0%)
83 (76.1%)
13.4 (11.2-16.8)
3.7 (2.5-6.6)
7.7 (3.8-11.2)
24.1 3.8
1.8 (1.3-2.0)
80 11.4
1.9 (1.5-2.2)
122 15
70 10
8.4 (7.6-10.2)
4.3 0.9
1.4 (1.1-1.6)
2.4 0.6
1.1 (0.8-1.6)
1.0 0.5
71 (65.1%)
1.0 (0.7-2.0)
19 (15-27)
.21
.015
.014
<.001
.001
<.001
<.001
<.001
<.001
<.001
<.001
.038
.87
.22
.39
.096
.80
.99
.077
.005
*n = 153.
Results
The baseline characteristics are shown in Table I. The majority (77.0%) of children was Dutch native 3.5% was Turkish
and 7.1% Moroccan. The remaining group (12.4%) consisted
of children with other ethnic backgrounds or children of parents with 2 different origins. In the present cohort, 38.5% of
the children were classified as overweight/obese, and 9.2%
were obese (Z-BMI $2 ). Overweight/obese children differed
with respect to their normal-weight counterparts for age,
diabetes duration, age of onset, WC, HbA1c, blood pressure,
and ALT. Of the 283 children included in the study, 48.8%
were male, and 67.5% were $11 years of age (median age,
12.8 years; IQR, 9.9 to 16.0). Median diabetes duration was
5.3 years (IQR, 2.9 to 8.6). Most patients were receiving intensive insulin treatment consisting of multiple insulin injection therapy (27.9%) or continuous subcutaneous insulin
infusion (67.1%), and 5.0% of the children were treated
with 2 or fewer injections a day. When comparing the normal-weight and overweight group, no difference was found
in median ratio short/rapid acting insulin:intermediate/
long-acting insulin (0.57; IQR, 0.43-1.57 vs 0.51; IQR, 0.38
to 1.34; P = .24).
The 3 most prevalent cardiometabolic risk factors were
a suboptimal HbA1c (73.9%), a positive family history for
T2DM or CVD (64.0%), and high LDL-cholesterol
(28.6%). Regarding the risk factors that are not included in
the definition of MetS, high ALT was present in 9.3%, microalbuminuria was found in 17.7%, and 3.9% of the children
smoked. The prevalence of a positive family of hypertension
in first- or second-degree relatives was 37.4%.
All children fulfilled 1 component of MetS (namely
T1DM), 57.7% had 2, 28.6% had exactly 3, and 13.8% had
more than 3 components. Of the components comprising
MetS, low HDL-cholesterol was present in 21.2%, high triglycerides in 17.3%, and hypertension in 13.1%. There
were no differences according to sex for the different cardiometabolic risk factors, except for median ALT, which was
higher in boys than in girls (19; IQR, 17 to 26 IU/L vs 16;
IQR, 13 to 20 IU/L; P<.001).
Table II shows the overall prevalence of cardiometabolic
risk factors in the cohort, according to weight status. Hypertension, MetS, and high ALT were significantly more common in overweight/obese children, relative to their normalweight peers (23.9% vs 5.7%, P < .001, 25.7% vs 6.3%,
P<.001, and 15.6% vs 4.5%, P = .028, respectively). The prevalence of dyslipidemia and microalbuminuria did not differ
between the overweight/obese versus the normal-weight
group. However, in children who were obese (Z-BMI $2),
high triglycerides and low HDL-cholesterol were more common than in lean children (30.7% vs 14.7%, P = .086 and
36.4% vs 20.1%, P = .028, respectively).
In the normal-weight group, the percentage of pubertal
children was significantly higher compared with the overweight/obese group (76.1% vs 62.1%, P = .015), and pubertal
relative to prepubertal children had a higher prevalence of
high LDL-cholesterol (33.0% vs 19.6% P = .038), hypertension (17.8% vs 3%, P < .001), and HbA1c >7.5% (71.3% vs
56.8%, P = .03). High triglycerides, low HDL-cholesterol,
MetS, high ALT, and microalbuminuria did not differ significantly according to pubertal status.
Moreover, the presence of a suboptimal HbA1c was not
different after stratification for weight status, and, subsequently, within the overweight/obese group, children who
had a suboptimal HbA1c did not have an additional higher
prevalence of cardiometabolic risk factors. However, in the
normal-weight group, children with suboptimal glycemic
control more often had high LDL-cholesterol and high
Overweight Is Highly Prevalent In Children with Type 1 Diabetes And Associates with Cardiometabolic Risk
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Table II. Prevalence of cardiometabolic risk factors and the metabolic syndrome, stratified for weight status
n
HbA1c above $7.5%
High LDL-cholesterol (>2.6 mmol/L)
Low HDL-cholesterol (<1.1 mmol/L)
High triglycerides (>1.7 mmol/L)
Hypertension
-Systolic hypertension
-Diastolic hypertension
Smoking
Family history (total)
-Type 2 diabetes
-CVD
Microalbuminuria
The metabolic syndrome
ALT >30 IU/L*
Normal-weight
P value
174 (61.5%)
51 (70.7%)
46 (26.4%)
35 (20.1%)
26 (14.9%)
10 (5.7%)
9 (5.2%)
3 (1.7%)
8 (4.6%)
106 (60.9%)
91 (52.3%)
31 (17.8%)
33 (19.0%)
11 (6.3%)
4 (4.5%)
109 (38.5%)
23 (78.9%)
35 (32.1%)
25 (22.9%)
23 (21.1%)
26 (23.9%)
25 (22.9%)
6 (5.5%)
3 (2.8%)
75 (68.8%)
65 (59.6%)
24 (22.0%)
17 (15.6%)
28 (25.7%)
10 (15.6%)
.22
.69
.47
.23
<.001
<.001
.085
.34
.27
.49
.51
.38
<.001
.028
*n = 153.
Discussion
In our study, the proportion of obese children with T1DM
(Z-BMI $2) was twice as high as recently described in
a comparable Norwegian cohort, whereas the prevalence of
BMI >90th percentile was similar to that found in a German
pediatric T1DM cohort.9,10 In a multi-ethnic cohort with diabetes (mainly type 1) in the United States, the proportion of
obese children (as determined by high waist circumference)
ranged from 15% of non-Hispanic white children, to 56%
in Native American children.23
The prognostic value of MetS in both healthy individuals and patients with T1DM is under debate since studies
in both children and adults indicate that it may have a limited
independent prognostic value for CVD, and individual risk
factors may better predict adverse CVD outcomes.24-26
Moreover, a validated definition of MetS in children, based
on prognostic significance, is still eagerly awaited. Finally, despite the fact that a similar prevalence of MetS in nondiabetic
individuals and patients with T1DM is reported,27,28 patients
with T1DM are at greater risk for developing CVD,29 which
may partly be due to microvascular abnormalities and
a more atherogenic lipid profile in these patients.30
One may debate on the use of MetS in patients with T1DM
because T1DM has no role in the development of MetS. Although insulin resistance (in nondiabetic individuals) and
T1DM have different pathophysiological mechanisms, one
of the consequences of both conditions is the same, namely
van Vliet et al
ORIGINAL ARTICLES
June 2010
Table III. Difference in cardiometabolic risk factors and the metabolic syndrome, stratified for body shape in children
with Z-BMI $1.1
n
Boys
Age (y)
Age >11 y
HbA1c $7.5%
High LDL-cholesterol (>2.6 mmol/L)
Low HDL-cholesterol (<1.1 mmol/L)
High triglycerides (>1.7 mmol/L)
Hypertension
Smoking
Family history (total)
Microalbuminuria
The metabolic syndrome
ALT >30 IU/L*
Z-BMI>Z-WC
Abdominal fat distribution
Z-BMI<Z-WC
Gluteal-femoral fat distribution
P value
38 (42.1%)
22 (57.9%)
13.8 3.5
24 (66.8%)
32 (84.2%)
12 (31.6%)
9 (23.7%)
7 (18.4%)
7 (18.4%)
0 (0%)
26 (68.4%)
2 (5.3%)
7 (18.4%)
4 (10%)
68 (35.3%)
24 (64.7%)
13.2 3.8
47 (68.7%)
52 (76.5%)
23 (33.8%)
16 (23.5%)
16 (23.5%)
19 (27.9%)
3 (4.4%)
46 (67.6%)
6 (8.8%)
10 (14.7%)
10 (9%)
<.001
.63
.77
.12
.87
.50
.52
.20
.56
.98
.55
.14
.90
*n = 153.
Hispanic white) from the SEARCH study, in which the prevalence was 45%.38 Interestingly, we found a high percentage
of children (21.2%) with low HDL-cholesterol, relative to
the two fore-mentioned studies (6.9% and 12%, respectively).9,38 High triglycerides occurred with similar frequency
in the SEARCH study.38 The differential prevalence of the
various cardiometabolic risk factors may in part be due to
the differences in populations studied, the differences in cutoff points and reference values used. Interestingly and unexpectedly, after stratification for weight status, we did not find
any statistically significant differences in the prevalence of
high triglycerides, low HDL-cholesterol, or high LDL-cholesterol, despite a higher proportion of pubertal children in the
overweight/obese group. A possible explanation for this finding is the higher mean ACR found in normal weight children
as compared with their overweight/obese peers because it has
been shown that microalbuminuria is related to both total
cholesterol and nonHDL-cholesterol levels in adolescents.39
We hypothesize that an increase in lipid abnormalities in the
overweight/obese group will develop over a longer period of
time with completion of puberty and increasing Z-BMI, with
the associated abnormalities including insulin resistance,
fatty liver, and MetS. The finding of a higher ACR in normal-weight children has been reported before; however,
a valid explanation for this observation has not been proposed.40 Apparently, other factors besides obesity play
a role in the development of microalbuminuria.
The role of glycemic control in the occurrence of cardiometabolic risk factors in children with T1DM in the present
study, both lean and overweight, cannot be readily established. Although in normal-weight children, we found a significantly higher frequency of LDL-cholesterol and high
triglycerides within the suboptimal HbA1c group, relative
to the optimal HbA1c group, we could not confirm this relation in overweight children. Still, we found an association between HbA1c and LDL-cholesterol, and triglycerides, which
was in accordance with the findings by a recent study showed
Overweight Is Highly Prevalent In Children with Type 1 Diabetes And Associates with Cardiometabolic Risk
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that glycemic control and HbA1c are independently associated with total cholesterol, LDL-cholesterol, triglycerides,
and nonHDL-cholesterol.41 Several studies have confirmed
hyperglycemia as risk factor for the development of CVD and
subsequently have shown that intensive glycemic control reduces cardiovascular risk, in spite of any undesired weight
gain, in both adults and adolescents.4,42,43
Limitations of this study include the lack of control group,
as well as detailed information regarding physical activity and
dietary habits, both of which are established risk factors
for CVD. Additionally, because Tanner stages were not systematically recorded, we used an age-cutoff to estimate
puberty.10 Conflicting data have been published with respect
to the onset of puberty in patients with T1DM; some studies
found a significant delay in puberty, and others did not.
However, most series report an onset of puberty within the
normal range and a delay in puberty may be associated
with extremely poor glycemic control.44-46 The final limitation of our study is that lipid levels were measured in the nonfasting state due to ethnical and practical reasons.9
Longitudinal studies are needed to assess the future risk for
CVD in patients with T1DM with established cardiometabolic risk factors in childhood. These studies should determine which combination of cardiometabolic risk factors
best predict adverse outcomes. n
Submitted for publication Jun 29, 2009; last revision received Oct 6, 2009;
accepted Dec 9, 2009.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Reprint requests: Dr Josine van der Heyden, Diabeter, Haringvliet 72, 3011 TG
Rotterdam, The Netherlands. E-mail: J.vanderHeyden@diabeter.nl.
19.
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