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World J Diabetes. Sep 15, 2010; 1(4): 129-134
Published online Sep 15, 2010. doi: 10.4239/wjd.v1.i4.129
Risk factors for impaired glucose tolerance in obese children and adolescents
Michaela Kleber, Sophie Papcke, Thomas Reinehr, Vestische Hospital for Children and Adolescents, University of Witten/Herdecke, Datteln 45711, Germany
Gideon de Sousa, Hospital for Children and Adolescents, Dortmund 45801, Germany
Author contributions: Reinehr T and Kleber M designed the research; Reinehr T, de Sousa G, Kleber M and Papcke S performed the research; Papcke S and Reinehr T analyzed the data; and all authors wrote the paper.
Supported by the Grants from the German ‘Competence Net Obesity’, which is supported by the German Federal Ministry of Education and Research, No. 01 GI0839, the University of Witten/Herdecke and the German Ministry of Education and Research (Bundesministerium für Bildung und Forschung; National Genome Research Network, NGFNplus, No. 01GS0820)
Correspondence to: Thomas Reinehr, Professor, Head, Department of Pediatric Endocrinology, Diabetes, and Nutrition Medicine, Vestische Hospital for Children and Adolescents, University of Witten/Herdecke, Dr. F. Steiner Str. 5, Datteln 45711, Germany. t.reinehr@kinderklinik-datteln.de
Telephone: +49-2363-975229 Fax: +49-2363-975218
Received: April 26, 2010
Revised: August 23, 2010
Accepted: August 30, 2010
Published online: September 15, 2010

Abstract

AIM: To investigate which obese children have an increased risk for impaired glucose tolerance (IGT), a risk factor for later diabetes.

METHODS: We studied 169 European untreated obese children and adolescents with normal glucose tolerance at baseline. Waist circumference, fasting glucose, lipids, blood pressure, pubertal stage, 2 h glucose in oral glucose tolerance test (oGTT), and HbA1c were determined at baseline and 1 year later.

RESULTS: One year after baseline, 19 (11.2%) children demonstrated IGT, 4 (2.4%) children had impaired fasting glucose, no (0%) child suffered from diabetes, and 146 (86%) children still showed normal glucose tolerance. At baseline, the children with IGT and with normal glucose tolerance in a one-year follow-up did not differ significantly in respect of any analyzed parameter, apart from pubertal stage. The children developing IGT entered puberty significantly more frequently (37% vs 3%, P < 0.001). One year after baseline, the children with IGT demonstrated significantly increased waist circumference, blood pressure values, insulin and triglyceride concentrations, and insulin resistance index HOMA. The children remaining in the normal glucose tolerance status 1 year after baseline did not demonstrate any significant changes.

CONCLUSION: During the study period of 1 year, more than 10% of the obese children with normal glucose tolerance converted to IGT. Repeated screening with oGTT seems meaningful in obese children entering puberty or demonstrating increased insulin resistance, waist circumference, blood pressure, or triglyceride concentrations.

Key Words: Impaired glucose tolerance; Risk factors; Lipids; Blood pressure; Pubertal stage; Waist circumference



INTRODUCTION

Obesity and associated insulin resistance are considered the main risk factors for developing type 2 diabetes mellitus (T2DM), regardless of genetic predisposition[1-3]. The current worldwide increase in obesity already in childhood is associated with an increase of T2DM and prediabetes defined as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)[2-8]. While IFG and T2DM are still relatively rare in European children and adolescents[1,3,9], IGT occurred in 10% up to 30% of obese Caucasian children and adolescents[1,3,9].

Early identification of children and adolescents with IGT is beneficial for several reasons: We know that IGT in childhood predicts T2DM later in life[10,11]. In adults, approximately 30% of patients with IGT will convert to T2DM within 5 years[12,13]. Furthermore, children and adults with IGT have an increased risk of developing cardiovascular diseases prior to progressing to diabetes[14-17]. Additionally, clustering of cardiovascular risk factors summarized in the definition of the metabolic syndrome such as abdominal adiposity, elevated triglycerides, low HDL-cholesterol and elevated blood pressure is also common among children with IGT[18].

The oral glucose tolerance test (oGTT) is necessary for the diagnosis of IGT but is time-consuming and not easy to use on every obese child and adolescent. It would therefore be very helpful to be able to identify the major risk factors for IGT among obese children and adolescents. Furthermore, models to predict which children are at greater risk of developing IGT could provide diagnostic and therapeutic insights into the etiologic relations of insulin resistance and IGT, and could assist in the provision of therapeutic approaches which could slow down or even reverse the current trends of pandemic obesity and T2DM in young adulthood[10,19].

In a recent cross-sectional study, we identified extreme obesity, pubertal stage, and positive family history for T2DM as the main risk factors for IGT in two independent collectives of European obese children[20]. However, these findings have to be proven in longitudinal studies. Consequently, we examined a large number of obese children and adolescents with normal glucose tolerance at baseline and then 1 year later to identify the risk factors for developing IGT.

MATERIAL AND METHODS

The local ethics committee of the University of Witten/Herdecke approved this study. Written informed consent was obtained from all subjects and their parents.

We prospectively examined 169 obese children and adolescents aged 10 to 17 years with normal glucose tolerance at baseline who were attending our outpatient center specialized in pediatric obesity and endocrinology, following a standardized diagnostic procedure based on the guidelines of the German Pediatric Obesity Association[21,22]: All the children were screened for degree of overweight, hypertension, dyslipidemia, and disturbed glucose metabolism at baseline and 1 year later, as described below. None of the children suffered from endocrine or syndromal disorders, or were on any medication. All 169 obese children chose not to participate in our lifestyle intervention “Obeldicks”[23] or other lifestyle interventions due to lack of time, lack of means of transport, or lack of motivation.

Degree of overweight was derived from body mass index (BMI). Height was measured to the nearest centimeter using a rigid stadiometer. Weight was measured in underwear to the nearest 0.1 kg using a calibrated balance scale. Obesity was defined by a BMI above the 97th percentile for German children[24]. All children were also obese according to the International Task Force for childhood obesity[25]. We used box-cox transformation to calculate SDS-BMI as a measure for degree of overweight due to the skewness of the BMI distribution[26].

Pubertal stage was determined by trained physicians according to Marshall and Tanner[27,28]. Pubertal developmental stage was categorized into two groups, based on breast and genital stages (prepubertal: boys with genital stage I, girls with breast stage I, pubertal: boys with genital stage ≥ II; girls with breast stage ≥ II).

As measurement of abdominal obesity, waist circumference was determined. Blood pressure was measured using a validated protocol[29]. Systolic (SBP) and diastolic (DBP) blood pressure were measured at the right arm twice after a 10 min rest in the supine position by using a calibrated sphygmomanometer and averaged. The cuff-size was based on the length and circumference of the upper arm and was as large as possible without having the elbow skin-crease obstructing the stethoscope[29]. The intra- and inter- operator variability was < 5% for SBP and DBP.

Blood sampling was performed in the fasting status. Serum triglyceride, LDL-, HDL-cholesterol, HbA1c, insulin, and glucose concentrations were measured using commercially available test kits (HDL-C- and LDL-C PlusTM Roche Diagnostics, Mannheim, Germany; VitrosTM analyzer Ortho Clinical Diagnostics, Neckargemuend, Germany; MEIATM, Abbott, Wiesbaden, Germany, Tina-quant Hemoglobin A1c Gen. Cobas Integra 400/800 Roche, Mannheim, Germany). Intra- and interassay variations for the concentrations (CV) of these variables were less than 5%. Homeostasis model assessment (HOMA) was calculated as follows[28]: resistance (HOMA) = [insulin (mU/L) × glucose (mmol/L)]/22.5.

An oral glucose tolerance test (oGTT) was performed on all children according to guidelines[2]. IGT was defined by 2 h serum glucose > 140 mg/dL in an oGTT. Impaired fasting glucose (IFG) was defined as fasting serum glucose ≥ 100 mg/dL[30]. Diabetes was defined according to the guidelines of the American Diabetes Association[2].

Statistical methods

Statistical analyses were carried out with Winstat for ExelTM. All variables were normally distributed as tested by the Kolmogorov-Smirnov test. Significance was tested by student t-test for unpaired observations, χ2 test, and Fisher’s exact test as appropriate. Since the frequency of IFG was very low at one-year follow-up (n = 4), no statistical comparison of these children with other children was performed. A P value < 0.05 was considered significant. Data are presented as mean and standard deviation or percentages.

RESULTS

The characteristics of the 169 analyzed obese children with normal glucose metabolism at baseline are demonstrated in Table 1.

Table 1 Study characteristic of 169 obese children and adolescents with normal glucose tolerance at baseline (data as mean ± SD or percentage).
Age (years)13.6 ± 2.1
Gender66% female
Pubertal stage84% pubertal
Weight (kg)83.5 ± 17.4
Height (cm)163.7 ± 10.1
BMI (kg/m²)31.0 ± 5.2
SDS-BMI2.45 ± 0.60
Waist circumference (cm)97 ±14
Systolic blood pressure (mmHg)119 ± 12
Diastolic blood pressure (mmHg)70 ± 12
Triglycerides (mg/dL)115 ± 65
HDL-cholesterol (mg/dL)53 ± 18
LDL-cholesterol (mg/dL)96 ± 31
Glucose (mg/dL)85 ± 8
2 h glucose in oGTT (mg/dL)114 ± 16
Insulin (mU/L)22 ± 15
HOMA4.6 ± 3.2
HbA1c (%)5.5 ± 0.8

At follow-up 1 year later, 19 (11.2%) children demonstrated IGT, 4 (2.4%) children had IFG, no child had IGT and IFG, no (0%) child suffered from T2DM, and 146 (86%) children still showed normal glucose tolerance.

At baseline, the children with IGT and with normal glucose tolerance at one-year follow-up did not differ significantly in respect of age, gender, degree of overweight, fasting glucose levels, 2 h glucose in oGTT, or HbA1c levels, while children developing IGT at one-year follow-up were significantly more frequently prepubertal (Table 2).

Table 2 Anthropometrics, lipids, and glucose parameters of 165 overweight children with normal glucose tolerance at baseline separated to glucose metabolism 1 year later (data as mean ± SD or percentage).
Remaining in normal glucoseStatus of metabolismP value comparison baseline and 1 year laterConverting to glucoseImpaired tolerance
n146-19
Gender64% female-79% female
baseline1 year laterbaseline1 year later
Age (years)13.6 ± 2.014.6 ± 2.0< 0.00113.7 ± 2.614.7 ± 2.6
Pubertal stage86% pubertal90% pubertal0.36853% pubertal89% pubertal
Weight (kg)83.4 ± 16.788.6 ± 17.8< 0.00184.3 ± 22.390.1 ± 20.5
Height (cm)164.0 ± 9.9166.6 ± 12.1< 0.001161.6 ± 11.8165.9 ± 9.5
BMI (kg/m²)30.9 ± 5.031.5 ± 5.00.20132.0 ± 6.632.6 ± 6.5
SDS-BMI2.43 ± 0.592.42 ± 0.670.5592.57 ± 0.722.61 ± 0.65
Waist circumference (cm)97 ± 1397 ± 120.18100 ± 20104 ± 14
Systolic blood pressure (mmHg)119 ± 12117 ± 110.219117 ± 11128 ± 17
Diastolic blood pressure (mmHg)70 ± 1171 ± 100.88768 ± 1074 ± 10
Triglycerides (mg/dL)115 ± 65124 ± 690.069117 ± 65154 ± 82
HDL-cholesterol (mg/dL)52 ± 1451 ± 130.48553 ± 1357 ± 17
LDL-cholesterol (mg/dL)96 ± 3195 ± 280.983104 ± 32103 ± 29
Glucose (mg/dL)86 ± 887 ± 100.58683 ± 787 ± 9
2 h glucose in oGTT (mg/dL)113 ± 16110 ± 150.116116 ± 16146 ± 7
Insulin (mU/L)23 ± 1522 ± 140.83520 ± 1025 ± 12
HOMA4.6 ± 3.34.7 ± 3.20.9824.1 ± 2.05.4 ± 2.5
HbA1c (%)5.5 ± 0.75.4 ± 0.50.4145.6 ± 0.95.5 ± 0.3

The children developing IGT entered puberty significantly more frequently (37% vs 3%, P < 0.001) as compared to children remaining in the status of normal glucose tolerance.

One year after baseline, the children with IGT demonstrated significantly increased waist circumference, blood pressure values, insulin and triglyceride concentrations, increased insulin resistance index HOMA and showed a tendance to increased fasting glucose levels as compared to their baseline levels (Table 2), while there was no significant change in LDL- and HDL- cholesterol, degree of overweight (SDS-BMI), and HbA1c levels.

The children remaining in the normal glucose tolerance status one year after baseline did not demonstrate any significant changes in respect of waist circumference, lipids, parameters of glucose metabolism, blood pressure, or SDS-BMI (Table 2).

The four children (mean age 13.5 ± 1.4 years, 25% female, 25% prepubertal at baseline) developing IFG increased their SDS-BMI, insulin levels and insulin resistance index HOMA, triglycerides, LDL-cholesterol concentrations, blood pressure, and waist circumference (Table 3).

Table 3 Anthropometrics, lipids, and glucose parameters of 4 obese children with normal glucose tolerance at baseline and impaired fasting glucose one year later (mean ± SD).
BaselineOne year later
Weight (kg)96.1 ± 6.4102.9 ± 5.4
Height (cm)166.4 ± 4.7170.0 ± 8.1
BMI (kg/m²)34.8 ± 11.935.9 ± 2.6
SDS-BMI2.73 ± 0.2722.90 ± 0.19
Waist circumference (cm)112 ± 4113 ± 8
Systolic blood pressure (mmHg)131 ± 16138 ± 18
Diastolic blood pressure (mmHg)71 ± 1173 ± 9
Triglycerides (mg/dL)155 ± 67164 ± 86
HDL-cholesterol (mg/dL)46 ± 6.243 ± 1
LDL-cholesterol (mg/dL)117 ± 16113 ± 26
Glucose (mg/dL)84 ± 7107 ± 5
2 h glucose in oGTT (mg/dL)108 ± 8116 ± 17
Insulin (mU/L)31 ± 2647 ± 17
HOMA3.8 ± 1.212.1 ± 7
HbA1c (%)5.6 ± 0.26.0 ± 0.1
DISCUSSION

This is the first longitudinal study analyzing which obese children develop IGT in the natural course of obesity without intervention. In a one-year follow-up period, more than 10% of obese children developed IGT, demonstrating the need to repetitively screen for IGT. In contrast to a previous study reporting a higher prevalence of IGT in males, we did not find any gender difference[11].

Our study demonstrated that entry into puberty is one main risk factor for IGT in obese children and adolescents. This finding concurs with our previous cross-sectional analysis[20]. Entry into puberty is associated with an increase in insulin resistance[31,32] suggesting that this change could be the cause for shifting from normal glucose tolerance to IGT in our study. Accordingly, we found a significant increase of insulin resistance index HOMA in the children converting to IGT in our study. However, further operating factors may be involved. Concentrations of sex hormones and adipocytokines change dramatically during pubertal development. For example, adiponectin decreases with the onset of puberty and is negatively correlated to insulin resistance and many cardiovascular risk factors[33].

Furthermore, we were able to demonstrate in our longitudinal study that factors of the metabolic syndrome which are associated with IGT, such as hypertriglceridemia, abdominal obesity, and elevated blood pressure[34], deteriorated in the children converting to IGT. These findings concur with previous cross-sectional studies reporting a clustering of these cardiovascular risk factors among children with IGT[15,17], suggesting a link between these cardiovascular risk factors and IGT.

Our study did not find a relationship between change of weight status and deterioration of glucose metabolism, while our previous cross-sectional study demonstrated that extreme obesity in particular is a strong risk factor for IGT, and a longitudinal study reported that weight loss is associated with an improvement in IGT[35]. One possible explanation for these apparently different findings may be the fact that the children in our study changed their weight status only marginally. Interestingly, waist circumference increased significantly only in the children converting to impaired glucose tolerance supporting the role of abdominal obesity on deterioration of glucose metabolism.

Changes of HbA1c did not predict IGT significantly. Therefore, the oGTT cannot be replaced by other measurements such as HbA1c. However, fasting glucose demonstrated an increase in the number of children converting to IGT.

Repeating oGTT in obese children at onset of puberty or in children with deterioration of factors of the metabolic syndrome maybe also helpful to detect T2DM in children and adolescents. In the literature, children and adolescents with T2DM in Europe were predominately pubertal and suffered from hypertension and dyslipidemia[3,8]. However, to validate this conclusion, our criteria have to be examined in cohorts with children suffering from T2DM. Such studies are very difficult to perform in Europe due to the low prevalence of T2DM in childhood and adolescence.

Strengths and limitations of the study

The strengths of this study are its longitudinal and prospective design and its large study sample. However, some potential limitations have to be considered. First, the HOMA model is only an assessment of insulin resistance, and clamp studies are the gold standard for the analysis of insulin resistance. However, since the HOMA- model correlated with clamp studies, it seems to be a suitable method to study insulin resistance in field studies[36]. Second, this is a clinic-based observation study and not a population-based study, thereby possibly leading to an overestimation of the frequency of IGT in obese children.Also, the obese children presented primarily to our obesity clinic for their obesity, and not for their comorbidity or cardiovascular risk factors. The overall frequency of hypertension and dyslipidemia at baseline was similar to previous reports[20,37-40] Third, the number of children with IFG was too low for statistical analysis. However, all four children with IFG increased their BMI, thus pointing towards change of weight status as a risk factor. Furthermore, all cardiovascular risk factors, such as increased blood pressure, dyslipidemia, and increased waist circumference, deteriorated in a similar manner to changes of IGT. Fourth, we studied only European children. Therefore The findings must therefore be confirmed in other ethnic groups. It is well known that black and Hispanic children have a higher risk for disturbed glucose metabolism[10,13]. Finally, a recent study reported a low reproducibility of IGT in the oGTT in overweight children[41] probably also influencing our findings.

In summary, more than 10% of obese children and adolescents had converted to IGT in the one-year follow-up, suggesting the necessity of repeated screening with oGTT in risk populations. Risk factors for developing IGT in our study were entry into puberty and deterioration of parameters of the metabolic syndrome (increase of waist circumference, blood pressure, and triglyceride levels). Converting to IGT was associated with an increase of the insulin resistance index HOMA, suggesting an interaction. Screening for IGT is also helpful for the identification of children with increased cardiovascular risk, since development of IGT was associated with deterioration of cardiovascular risk factors.

COMMENTS
Background

Early identification of children and adolescents with impaired glucose tolerance (IGT), a precursor of type 2 diabetes, is beneficial for several reasons: IGT in childhood predicts type 2 diabetes mellitus (T2DM) later in life. In adults, approximately 30% of patients with IGT will convert to T2DM within 5 years. Furthermore, children and adults with IGT have an increased risk for developing cardiovascular diseases prior to progressing to diabetes. Furthermore, models to predict which children are at greater risk of developing IGT could provide diagnostic and therapeutic insights into the etiologic relations of IGT and could allow providing therapeutic approaches to slow or even reverse the current trends of pandemic T2DM in young adulthood.

Research frontiers

Obesity and the associated insulin resistance are considered as the main risk factors for developing (T2DM). The current worldwide increase of obesity already in childhood is associated with an increase of T2DM and prediabetes defined as impaired glucose tolerance (IGT).

Innovations and breakthroughs

More than 10% of obese children and adolescents convert to IGT in one-year follow-up suggesting the necessity of repeated screening of IGT in risk populations. Risk factors for developing IGT in our study were entry into puberty and deterioration of parameters of the metabolic syndrome (increase of waist circumference, blood pressure, and triglyceride levels). Screening for IGT is also helpful to identify children with increased cardiovascular risk since development of IGT was associated with deterioration of cardiovascular risk factors such as hypertension and dyslipidemia.

Applications

Obesity children with risk factors (entry into puberty, hypertension, dyslipidemia) should be screened for (pre-) diabetes once per year.

Peer review

This manuscript examines risk factors for IGT in obese children. The main finding of this paper is that increase of insulin resistance, waist circumference, blood pressure, and triglyceride concentrations are all linked with IGT in children. Entry into puberty is another major risk factor for IGT in obese children. This is a potentially interesting area of clinical research and the findings are relevant to biomarkers of diabetes risk in obese children.

Footnotes

Peer reviewer: Sebastien G Bouret, PhD, Department of Pediatrics, University of Southern California, the Saban Research Institute, Neuroscience, LA 90027, United States

S- Editor Zhang HN L- Editor Herholdt A E- Editor Liu N

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