Recent Advances in Obesity in Children

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1 Recent Advances in Obesity in Children Avid Science

2 Chapter 1 Prevalence of Metabolic Comorbidities in Obese Pediatric Population: A Cross- Sectional Study Teodoro Durá-Travé 1,2,3, Fidel Gallinas-Victoriano 2, María Jesús Chueca Guindulain 2,3 and Sara Berrade- Zubiri 2,3 1 Department of Pediatrics, School of Medicine, University of Navarra, Spain 2 Department of Pediatrics, Navarra Hospital Complex, Spain 3 Instituto de Investigación Sanitaria de Navarra (IdisNA), Spain * Corresponding Author: T Durá-Travé, Department of Pediatrics Navarra Hospital Complex Avenue Irunlarrea, Pamplona, Spain; Tel: ; Fax: ; tduratra@cfnavarra.es First Published November 16, 2015 Copyright: 2015 T Durá-Travé et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source. Abstract Background: Childhood obesity represents the most relevant nutritional disorder in our environment. Objectives: To determine the prevalence of metabolic comorbidities and its relation to serum leptin concentrations in a group of children and adolescents with obesity. Methods: A cross-sectional clinical and metabolic study were accomplished in a group of 106 obese children (47 males and 59 females). Patients were classified in prepubertal/school group and pubertal/adolescent group. Results: Prevalence of insulin resistance (IR), hypertriglyceridemia, low high-density lipoprotein (HDL) and arterial hypertension (HTA) were 51, 38, 32 and 21% respectively. In the adolescent group the percentage of patients with IR and hypertriglyceridemia were significantly higher (p<0.05) than in the school group. There were no statistically significant differences among both age groups regarding the percentage of patients with low HDL and HTA. There was a positive correlation (p<0.05) between leptin plasma levels and BMI in the school group (r=0.721) and adolescent group (r=0.642). In addition, there was a positive correlation (p<0.,05) between leptin plasma concentrations and IR in the adolescent group (r=0.672) Conclusions: Clinical and metabolic disorders associated to obesity and related to the so-called metabolic syndrome are already present in school age and, especially, in adolescence. Leptin could play an important role in the ethiopathogenesis of the metabolic syndrome. 2 3

3 Keywords Adolescence; Leptin; Metabolic Syndrome; Puberty; School Children Background Excess body weight (overweight and obesity) represents the most relevant nutritional disorder in our environment [1,2]. It usually initiates at early stages in life, when child feeding depends almost exclusively- on habits and feeding preferences in a family setting, and is later exacerbated, by the time of school attendance and/or adolescence, probably in relation to the adoption of unhealthy feeding habits and lifestyle [3,4]. Additional Studies except for uncommon situations such as endocrine, genetic or metabolic pathologies, which justify excess body weight- are used for the diagnosis and/or early detection of metabolic complications and, particularly, the metabolic syndrome. This syndrome is characterized by a cluster of symptoms associated to obesity, such as insulin resistance, arterial hypertension and dyslipidemia, and its interest lies in the high predictive value for cardiovascular disease and type 2 diabetes in adulthood, especially when it is already present in school children and/or adolescents [5-9]. Even when the International Diabetes Federation (IDF) [10] refers to the inability for diagnosis in school age, epidemiological data allow suspecting that metabolic syndrome or its components are already present at early stages [11-14]. Leptin is an adipocytokine that, in addition to multiple neuroendocrine functions, has a role in the regulation of energy balance, as well as in carbohydrate and lipid metabolism and arterial pressure regulation. In this way, many authors have suggested that leptin might be involved in the etiopathogenesis of metabolic syndrome [15-17]. The aim of this work is to determine the prevalence of metabolic comorbidities and its relation to serum leptin concentrations in a group of patients diagnosed with obesity in school age and adolescence. Methods A clinical assessment and metabolic study was accomplished to all patients diagnosed with obesity who were attended follow-up consultation within the year 2014 in one of the three offices of the Pediatric Endocrinology Unit of the Navarra Hospital Complex. Pubertal stage was determined in each patient according to Tanner s criteria, and patients were classified in two different groups: prepubertal group (Tanner stage I) and pubertal group (Tanner stages II V). All those patients with personal history of endocrine disease, malformation syndromes or obesity yatrogenic (drug treatments) were excluded. 4 5

4 Clinical Assessment The assessment of weight and height was accomplished in underwear and barefoot. Weight was measured using an Año-Sayol scale, with a reading interval kg and precision 100 g, and height was measured using a Holtain wall stadiometer ranging cm, and precision 0.1 cm. Body mass index (BMI) was calculated according to the corresponding formula: weight (kg)/height2 (m). Values of Z-score for BMI were calculated using a Nutrition application (Aplicación Nutricional) program from the Spanish Society of pediatric Gastroenterology, Hepatology and Nutrition (available at nutritional/). The inclusion criterion was BMI (Z-score) values exceeding +2,0 (97 percentile) by age and sex according to growing charts from Ferrández et al (Centro Andrea Prader, Zaragoza 2002)[18]. Blood pressure (BP) was measured in the right arm with the patient in the supine position using Visomat comfort 20/40 (Roche Diagnostics Inc.) digital blood pressure monitor, recording the lowest of three measurements. Arterial hypertension (HTA) was considered when systolic and/or diastolic pressure was equal to or higher than 95th percentile by age, sex and height from the American reference charts (National high blood pressure Program in Children and Adolescents) [19]. The institutionalized program for Child Care in the Community of Navarre (Comunidad Foral de Navarra, Spain) includes periodic health examinations at ages 1, 2, 3, 4, 6, 8, 10 and 12 years. The anthropometric measurements (weight and height) are recorded in the corresponding clinical history. This record has allowed the registration of the age of onset for obesity and the time of evolution at the moment of the examination. Biochemical Measurements Plasma concentrations for glucose, insulin, triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL) and leptin were measured under basal fasting conditions using standardized methodologies. In order to determine insulin resistance, the HOMA (homeostasis model assessment) indexes were calculated from the fasting glucose and insulin concentrations (glucose levels in mmol x insulin in μuml/l/22.5). Insulin resistance was considered when HOMA value was equal to or higher than 3.8 [20]. The established upper cut point for leptin plasma concentrations was 9.6 ng/ml, a value that corresponds to +2 standard deviations from the average value in a control group with 56 healthy individuals (among 6.0 and 15.0 years of age) whose BMI ranges from +1 to -1 standard deviations from the mean according to the reference charts from Ferrández et al [18]. 6 7

5 Statistical Analysis Results are displayed as percentages (%) and means (M) with corresponding standard deviations (SD). Statistical analysis (descriptive statistics, student s T and Chi square test, Pearson s correlation) was done using the Statistical Packages for the Social Sciences version 20.0 (Chicago, Illinois, USA). Statistical significance was assumed when p value was lower than Results The sample of patients was made up of 106 patients (47 males and 59 females). The prepubertal or school group consisted of 56 patients (28 males and 28 females) and the prepubertal or adolescent group consisted of 50 patients (19 males and 31 females). Table 1 lists and compares the clinical features among both groups according to age and sex. Within the adolescent group, the average values for age of onset, age at examination and years of evolution were significantly higher (p<0.05); within the school group, BMI values (Z-score) at examination were higher (p<0.05). There were no statistically significant differences among the average values of systolic and/or diastolic blood pressure between the different groups. The average BMI values (Z-score) in both groups were significantly higher (p<0.05) in males. Finally, within adolescents, the average value for age of onset (obesity) was significantly lower (p<0.05) in males. Table 1: Average values (M±SD) for the clinical features in both age groups according to sex. Clinical data School group Adolescent group Sex (n) Age of onset (years) 3.50± ± ±1.70* 5.28±3.14** 7.24±3.54** 6.26±3.45* 4.61± ± ±3.09 Age at examination (years) 8.51± ± ±1.02* 12.29± ± ±1.36* 10.86± ± ±2.50 Evolution (years) 5.39± ± ±1.65* 7.33± ± ±2.92 * 6.61± ± ±2.56 BMI (Z-score) 4.48±1.37** 3.62±1.22** 3.92±1.32* 3.71±1.22** 2.64±0.45** 3.17±1.06* 4.00±1.32** 3.16±1.06** 3.52±1.24 Systolic BP (mmhg) ± ± ± ± ± ± ± ± ±15.99 Diastolic BP (mmhg) 64.85± ± ± ± ± ± ± ± ±13.39 (*) p<0.05 among age groups (**) p<0.05 between sexes 8 9

6 Table 2 displays and compares the average values for the results of the blood tests among the different groups according to age and sex. Within the adolescent group, average values for insulin, HOMA index, triglycerides and leptin were significantly higher (p<0.05) with respect to the school group. The average values for triglycerides within both groups were significantly higher (p<0.05) in males, and the average values for leptin within the adolescent group were significantly higher (p<0.05) in females. The plasma concentrations of leptin within the whole sample were above the cut point considered as normal in our laboratory (9.6 ng/ml), ranging from 15.8 to 76.1 ng/ ml. There was a significant positive correlation (p<0.05) between leptin plasma levels and BMI in the school group (r=0.721) as well as in the adolescent group (r=0.642). In addition, there was a positive and statistically significant correlation between leptin plasma concentrations and HOMA indexes in the adolescent group (r=0.672). There was also a significant positive correlation (p<0.05) between HOMA indexes and plasma concentrations of triglycerides in the school group (r=0.650) as in the adolescent group (r=0.56), as well as with age at examination (r=0.462). Table 2: Average values (M±SD) for metabolic study in both age groups according to sex. Biochemical data School group Adolescent group Glucemia (mg/dl) 90.21± ± ± ± ± ± ± ± ±8.18 Insulin (uu/ml) 17.27± ± ±7.17* 19.38± ± ±10.23* 18.53± ± ±9.63 HOMA 3.89± ± ±2.61* 4.76± ± ±3.29* 4.41± ± ±2.68 Cholesterol (mg/dl) ± ± ± ± ± ± ± ± ±19.48 LDL-C (mg/dl) 91.35± ± ± ± ± ± ± ± ±19.15 HDL-C (mg/dl) 47.85± ± ± ± ± ± ± ± ±9.06 Triglycerides(mg/dl) ±62.47** 87.45±42.32** 97.01±48.76* ±65.95** ±54.41** ±58.81* ±54.86** 94.74±45.90** ±50.67 Leptin (ng/ml) 28.16± ± ±10.38* 30.51±12.26** 50.98±24.68** 38.27±17.88* 29.67± ± ±10.53 (*) p<0.05 among age groups (**) p<0.05 between sexes 10 11

7 Table 3 presents and compares the percentage values for the different clinical and metabolic parameters used by different authors as constituents of the metabolic syndrome. Within the adolescent group, the percentage of patients who showed HOMA index values higher than 3.8 and plasma triglycerides higher than 110 mg/dl were significantly higher in the adolescent group (p<0.05) than in the school group; there were no statistically significant differences among both age groups regarding the percentage of patients who present HDL-C values lower than 40 mg/dl and systolic and/or diastolic blood pressure values higher than 95th percentile for the applied reference charts. Nevertheless, the percentage of patients with HDL- C values lower than 40 mg/dl in the adolescent group was significantly higher (p<0.05) in males. Table 4 sets forth and compares the average values for the clinical features and analytical findings in the patients according to the presence/absence of insulin resistance. The group of patients with insulin resistance (n=54) showed average values for age of onset and age at consultation, as well as glucose, insulin, triglycerides and leptin plasma levels and systolic blood pressure significantly higher (p<0.05) than the patients who did not present insulin resistance. Table 3: Prevalence of the different diagnostic criteria of metabolic syndrome in both groups. Diagnostic criteria HOMA >3,8 [23,24,26] HDL-C<40mg/dl [20,24-26,34] TG>110mg/dl[20,24-26,34] SBP >p95[23,24,34] DBP >p95[23,24,34] (*) p<0.05 among age groups (**) p<0.05 between sexes School group n (%) 7 (36.8%) 10 (32.3%) 17 (34.0%)* 5 (26.3%) 10 (32.3%) 15 (31.6%) 7 (36.8%) 8 (25.8%) 15 (30.0%)* 4 (21.1%) 6 (19.4%) 10 (20.0%) 1 (5.3%) 2 (6.5%) 3 (6.0%) Adolescent Group n (%) 18 (64.3%) 18 (64.3%) 36 (66.1%)* 12 (42.9%)** 7 (25.0%)** 19 (33.9%) 13 (46.4%) 12 (42.9%) 25 (44.6%)* 5 (17.9%) 7 (25.0%) 12 (21.4%) 2 (7.1%) 2 (7.1%) 4 (7.1%) n (%) 24 (50.6%) 28 (47.8%) 54 (50.9%) 17 (36.2%) 17 (28.8%) 34 (32.07%) 20 (42.6%) 20 (33.9%) 40 (37.7%) 9 (19.1%) 13 (22.0%) 22 (20.8%) 3 (6.4%) 4 (6.8%) 7 (6.6%) 12 13

8 Table 4: Clinical and biochemical data (M±DE) according to insulin resistance. Clinical-biochemical data (*) p<0.05 among groups Discussion Group of patients without insulin resistance Group of patients with insulin resistance (n=52) (n=54) Age of onset (years) 4.06±2.36* 5.85±3.37* Evolution (years) 5.89± ±2.01 Age at examination (years) 9.67±1.98* 11.15±2.36* Glucose (mg/dl) 87.00±8.14* 94.75±8.92* Insulin (uu/ml) 9.33±4.94* 26.65±13.85* Cholesterol (mg/dl) ± ±20.61 HDL-C (mg/dl) 48.36± ±10.93 LDL-D (mg/dl) 94.36± ±21.43 Triglycerides (mg/dl) 82.61±40.65* ±60.27* Leptin (ng/ml) 28.26±11.91* 38.14±14.62* SBP (mmhg) ±13.47* ±14.10* DBP (mmhg) ±15.89 The concept of metabolic syndrome is a very controversial issue, since the historic evolution in the selection of diagnosis criteria conveys a certain degree of arbitrariness owing to the absence of casual links among them; in fact, this association meets rather practical criteria. In addition, its predictive value for cardiovascular risk is not higher than every component by itself. In the pediatric age, there are no clearly defined parameters for its diagnosis, being several different criteria proposed on the basis of an extrapolation from clinical guides of adult populations; this would explain the disparity in published data with respect to the applied criteria [21-28]. Therefore, an appropriate approach to this issue in pediatric age would be the referral to clinical-metabolic comorbidities as risk factors in adult life rather than metabolic syndrome. The IDF considers fat distribution and, concretely, central or visceral obesity which is defined by abdominal perimeter- as a sine qua non criterion for the diagnosis of metabolic syndrome due to its high predictive value for cardiovascular disease in adult life [29,30]. However, there is some controversy regarding the adequacy of its use as a main and/or necessary diagnostic criterion [31,32]; in fact, recent studies conducted in pediatric population have used both abdominal perimeter [22-24,33] and BMI [25, 26, 34, 35] interchangeably. In this case, the inclusion criterion was BMI value (Z-score) higher than +2.0 (97th percentile) by age and sex according to the growing charts from Ferrández et al (Centro Andrea Prader, Zaragoza 2002) [18]. Insulin resistance, as several authors have highlighted [25, 35], has been the most frequently noted metabolic disorder in the population studied. It is worth indicating that, when Reaven [36] described the syndrome X, he considered insulin resistance as the determining pathophysiological factor and, in fact, the WHO included it as main and necessary criterion in order to diagnose the metabolic syndrome [37]. However, the diagnosed criteria subsequently proposed by the National Cholesterol Education Programs Adult Treatment Program III [38] as well as by the IDF [9] opted for a lipid centric theory, with special focus on dyslipidemia and/or fat distribution

9 Even though several criteria have been used to evaluate peripheral insulin sensitivity and/or alterations in glucose metabolism (fasting glucose, glycemia after an oral glucose tolerance test, fasting insulin levels, etc.), the use of a mathematical model called homeostasis model assessment (HOMA) as a criterion for insulin resistance has been widely contrasted as an early disorder in glucose homeostasis (hyperinsulinemia with euglycemia). In this case, despite the application of a quite restrictive cut point [20], insulin resistance was already detected in more than a half of the patients included in the study, especially in the adolescents. In addition, the existing correlation between the HOMA indexes and the age of the patients at the moment of examination suggests that the onset of this metabolic comorbidity associated to obesity is related to hormonal changes concomitant with puberty rather than to the evolution time of obesity. The situation of insulin resistance usually involves a disturbance in lipid profile by stimulating lipolysis and, therefore, an increase in plasma exchange of fatty acids that, at the same time, stimulates the hepatic triglyceride synthesis. This explains its correlation with the HOMA index of the patients. In addition, the concentration of low density lipoproteins is usually in normal range while the concentration of high density lipoproteins is usually low, being this considered as a side effect of hypertriglyceridemia [39-41]. Dyslipidemia observed in patients with insulin resistance corresponded with the situation expected in this metabolic condition. Furthermore, hyperinsulinemia causes water and sodium retention and activates the sympathetic nervous system, contributing to the development of hypertension. This work has revealed how the blood pressure values in patients with insulin resistance were significantly higher than those with normal glucose metabolism, which helps confirm the association between both conditions. Leptin is a hormone that is mainly released by adipocytes even though not exclusively by them- which interacts with hypothalamic receptors and performs multiple neuroendocrine functions; furthermore, it participates directly in the regulation of energy homeostasis through an anorectic effect and the increase of thermogenesis. The results obtained show elevated leptin plasma concentrations within the whole sample analyzed and confirm the existence of sexual dimorphism during adolescence [16]. The plasma concentrations reflect the reserve of organic fat and are considered as a predictive factor for insulin resistance [42]. This would explain, on one hand, the existing correlation between plasma concentrations and BMI, and, on the other hand, the correlation with the HOMA index in the patients included in this work. In addition, high plasma concentrations (as it occurred both in school children and adolescents) stimulate lipolysis in adipocytes and, consequently, contribute to dyslipidemia; they also stimulate angiogenesis and/or endothelial dysfunction and would explain, to a great extent, the development of 16 17

10 hypertension, which is frequently associated to obesity [15]. Conclusion As a conclusion, we remark the finding of clinical and metabolic disorders associated to obesity and related to the so-called metabolic syndrome, which, to a great extent, are already present in school age and, especially, in adolescence. In the same way, leptin serum levels usually high in obese patients could play an important role in the ethiopathogenesis of the metabolic syndrome and/or comorbidities that are associated to obesity. References 1. Odgen CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents, JAMA. 2002; 288: Tzotzas T, Krassas GE. Prevalence and trends of obesity in children and adults of South Europe. Pediatr Endocrinol Rev. 2004; 1: Durá-Travé T, Hualde-Olascoaga J, Garralda-Torres I, Grupo Colaborador de Navarra. Overweight among children in Navarra (Spain) and its impact on adolescence. Med Clin (Barc). 2012; 138: Durá-Travé T, Gallinas-Victoriano, Grupo Colavborador de Navarra. Natural evolution of excess body weight (overweight and obesity) in children. An Pediatr (Barc). 2013; 79: Srinivasan SR, Myers L, Berenson GS. Predictability of childhood adiposity and insulin for developing insulin resistance syndrome (syndrome X) in young adulthood: the Bogalusa Heart Study. Diabetes. 2002; 51: Bao W, Srinivasan SR, Wattigney WA, Berenson GS. Persistence of multiple cardiovascular risk clustering related to syndrome X from childhood to young adulthood. The Bogalusa Heart Study. Arch Intern Med. 1994; 154: Freedman DS, Khan LK, Dietz WH, Srinivasan SR, Berenson GS. Relationship of childhood obesity to coronary heart disease risk factors in adulthood: the Bogalusa Heart Study. Pediatrics. 2001; 108: Brambilla P, Lissau I, Flodmark CE, Moreno LA, Widhalm K, et al. Metabolic risk-factor clustering estimation in children: to draw a line across pediatric metabolic syndrome. Int J Obes (Lond). 2007; 31: Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al. Effect of potentially modifiable 18 19

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