J Pediatr Endocrinol Metab 2016; aop

Liene Bervoets and Guy Massa*

Classification and clinical characterization of metabolically “healthy” obese children and adolescents DOI 10.1515/jpem-2015-0395 Received October 4, 2015; accepted December 14, 2015

Introduction

Abstract

Although it is assumed that the prevalence of childhood obesity is stabilizing [1], the number of children being overweight and obese is still considerably high [2, 3]. Childhood obesity is often associated with metabolic complications such as prediabetes, insulin resistance, dyslipidemia and hypertension [4], which may eventually lead to the development of type 2 diabetes mellitus (T2DM) and premature cardiovascular disease (CVD) [5, 6]. Nevertheless, it appears that some obese children do not show any of these cardiometabolic complications, and they are so-called metabolically “healthy” or protected obese (MHO) [7, 8]. The classification of obese children according to their risk for cardiometabolic complications – i.e. the concept of MHO – could therefore shed new light on current prevention and treatment strategies [9, 10]. MHO is mostly defined as the absence of the metabolic syndrome (MetS), a clustering of cardiometabolic risk factors including atherogenic dyslipidemia, hypertension, and hyperglycemia in obese adults [11]. Although there is still no universally accepted definition for MetS in children and adolescents, it is suggested to use the consensusbased pediatric International Diabetes Federation (IDF) criteria in an attempt to achieve uniformity [12]. However, the subdivision of obese children and adolescents in MHO and metabolically unhealthy obese (MUO) according to the pediatric IDF definition may lead to an underestimation of the number of obese children and adolescents at increased risk for cardiometabolic complications because insulin resistance – a  central factor leading to the abnormalities observed in MetS – is not part of the definition [13, 14]. It is known that hyperinsulinemia (i.e. greater pancreatic β-cell insulin secretory response and/or reduced insulin clearance) occurs before glucose metabolism becomes dysregulated (i.e. impaired glucose tolerance (IGT) and T2DM) [15]. In addition, fasting glucose alone often fails to detect obese individuals with prediabetes or T2DM [16]. Therefore, it can be hypothesized that the addition of insulin resistance to the pediatric MetS definition could identify more obese children and adolescents at risk for cardiometabolic complications.

Background: Some obese children do not show cardiometabolic complications such as prediabetes, dyslipidemia or insulin resistance. The objective of the study was to classify obese children and adolescents as metabolically “healthy” obese (MHO) on the basis of three different definitions, and to compare cardiometabolic features with metabolically unhealthy obese (MUO) children and adolescents. Methods: The study included 156 obese children and adolescents aged between 10 and 18. Subjects were classified as MHO or MUO using three definitions based on the: (1) pediatric International Diabetes Federation (IDF) criteria; (2) homeostatic model assessment of insulin resistance (HOMA-IR); (3) combination of the previous two definitions. Cardiometabolic features were compared between MHO and MUO subjects. Results: Six to 19% obese children and adolescents were classified as MHO, and showed a better insulin sensitivity, lower prevalence of prediabetes, lower triglycerides and lower triglyceride-to-HDL-C ratio compared to MUO. Conclusions: Less than 20% obese children and adolescents are identified as MHO and show a healthier cardiometabolic profile as compared to MUO. Implementation of the proposed classifications in future clinical research could contribute towards the standardization of the MHO definition and offer new insights into the manifestation of the pediatric MHO phenotype. Keywords: adolescents; children; insulin resistance; meta­bolic syndrome; obesity.

*Corresponding author: Prof. Dr. Guy Massa, Department of Pediatrics, Jessa Hospital, Stadsomvaart 11, 3500 Hasselt, Belgium, Phone: +32 11 30 89 80, Fax: +32 11 30 98 98, E-mail: [email protected]; and Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium Liene Bervoets: Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium

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2      Bervoets and Massa: Metabolically “healthy” obese children and adolescents One recent study in overweight and obese children and adolescents already used a combination of the MetS with insulin resistance in the definition of the MHO phenotype [8]. It was found that dietary fat intake and moderate-­tovigorous physical activity are strong predictors of insulin sensitivity and MHO phenotypes, respectively. However, they did not use the pediatric consensus-based IDF criteria to define MHO but a self-assembled definition based on various pediatric references [8]. The aim of the current study was to classify obese children and adolescents as MHO using three different definitions based on: (1) the absence of MetS defined according to the pediatric IDF criteria; (2) the absence of insulin resistance as defined by homeostatic model assessment of insulin resistance (HOMA-IR); (3) the combination of the previous two definitions. Subsequently, cardiometabolic features were compared between MHO and MUO children and adolescents classified according to the three different definitions.

Materials and methods Study population Obese children and adolescents who attended the outpatient pediatric obesity clinic from the Jessa Hospital Hasselt (Belgium) between January 2006 and December 2013 were considered for inclusion in this retrospective cross-sectional study (Figure  1). Exclusion criteria were: (1) aged younger than 10 or older than 18 years; (2) not

classified as obese according to the International Obesity Task Force (IOTF) criteria [17]; (3) taking any medication or having any serious medical illness. The presence of parental obesity/T2DM and ethnic background were queried. Subjects of non-Flemish origin were classified as non-native. Data were collected during their first visit to the clinic and during an oral glucose tolerance test (OGTT), and were retrieved retrospectively from the medical records. The study was conducted in accordance with the ethical rules of the Helsinki Declaration. The study protocol was approved by the Ethics Committee of the Jessa Hospital. Informed and written consent was obtained from all patients and their parents or legal guardian.

Anthropometric measurements Subjects were measured wearing underwear only. The pubertal developmental stage was evaluated by a pediatric endocrinologist according to Tanner on the basis of breast development and genital size [18], and subjects were categorized into three groups: pre-pubertal (Tanner stage M1 or G1), pubertal (Tanner stage M2-M4 or G2-G4) and post-pubertal (Tanner stage M5 or G5). Body weight was measured with an electronic scale and rounded to the nearest 0.1 kg. Standing height was measured with a Harpenden stadiometer to the nearest 0.1 cm. Body mass index (BMI) was calculated by dividing weight in kilograms by height in meters squared (BMI = kg/m2). BMI standard deviation score (SDS) was calculated on the basis of the LMS values using the formula: BMI SDS = [(BMI/M)L-1]/[L × S] as presented by Cole and Lobstein [17]. BMI classes were defined according to ageand gender-specific IOTF centile curves passing through BMI 30 as ‘class I obesity’, through BMI 35 as ‘class II obesity’, and through BMI 40 as ‘class III obesity’ [17, 19]. Blood pressure was measured using an electronic sphygmomanometer (Omron®, Omron Healthcare, IL, USA) and a cuff appropriate for the participants’ arm diameter. The blood pressure measurement was obtained after the participants have been seated for 5 min.

Figure 1: Flowchart of study subjects. IOTF, International obesity task force.

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Bervoets and Massa: Metabolically “healthy” obese children and adolescents      3

Biochemical analyses After an overnight fast, venous blood samples were taken from the patients for the measurement of biochemical parameters (see below). Following the fasting blood sampling, a standard OGTT was performed using 1.75 g/kg (maximum 75 g) glucose and venous blood samples were obtained at 30, 60, 90 and 120  min for the determination of plasma glucose and serum insulin levels. Plasma glucose was measured by the glucose oxidase method using a Synchron LX20 analyzer (Beckman Coulter, Brea, CA, USA). Serum insulin was determined by IRI assay (ADVIA Centaur Insulin IRI; Siemens Medical Solutions Diagnostics, Tarrytown, NY, USA). Hemoglobin A1C (HbA1C) was measured using ion exchange chromatography (Menarini HA-8160 HbA1C auto-analyzer, Menarini Diagnostics, B ­ elgium). Serum total cholesterol, high-density lipoprotein cholesterol ­(HDL-C) and triglycerides (TG) were measured on a Beckman Coulter AU 2700 automatic analyzer (Brea, CA, USA). Two lipid ratios were calculated: total cholesterol divided by HDL-C, and TG divided by HDL-C. Low-density lipoprotein cholesterol (LDL-C) was calculated according to the Friedewald equation [20]. Aspartate transaminase (AST), alanine transaminase (ALT), γ glutamyl transpeptidase (g-GT) and uric acid (UA) were measured on a Beckman Coulter AU 2700 automatic analyzer (Brea, CA, USA). White blood cell (WBC) count was automatically assessed using Siemens Advia 2120 (Siemens Healthcare Diagnostics, Deerfield, IL, USA). Sex hormone-binding globulin (SHBG) concentrations were measured by immunoassay on an Architect i2000SR (Abbott Diagnostics, IL, USA). For all blood measurements, the coefficient of variation was  

Classification and clinical characterization of metabolically "healthy" obese children and adolescents.

Some obese children do not show cardiometabolic complications such as prediabetes, dyslipidemia or insulin resistance. The objective of the study was ...
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