history for type 2 diabetes have at least one feature of the which impaired glucose tolerance, diabetes, and insulin resis …
The Metabolic Syndrome in Children and Adolescents
Martha L Cruz, PhD, and Michael I Goran, PhD
Address Department of Preventive Medicine, Physiology and Biophysics, Keck School of Medicine, University of Southern California, 1540 Alcazar Street, CHP Room 208-D, Los Angeles, CA 90089, USA E-mail: goran@uscedu Current Diabetes Reports 2004, 4:5362 Current Science Inc ISSN 15344827 Copyright 2004 by Current Science Inc
The metabolic syndrome was recently defined by the Adult Treatment Panel III Despite a lack of uniform definition of the syndrome in pediatrics, recent studies have shown that the syndrome develops during childhood and is highly prevalent among overweight children and adolescents The hypothesized central role of insulin resistance and obesity as a common underlying feature of the metabolic syndrome also appears to be already manifested in childhood In view of the current obesity epidemic in children and adolescents, there is a vital need to provide adequate guidelines for the definition of the metabolic syndrome in pediatrics and for the development of screening and treatment strategies This article focuses on the above issues, as well as on the impact of the
syndrome on two major disease outcomes, type 2 diabetes and cardiovascular disease
on its potential impact on the health and well-being of children and adolescents This article presents the following information: 1 Provides evidence to show that the metabolic syndrome develops during childhood, has a higher prevalence in overweight children, and is more pronounced in certain ethnic minorities 2 Examines the underlying pathophysiology of the syndrome during childhood and argues that the underlying defect suggested in adults obesity coupled with insulin resistance is evident early in life 3 Looks at available evidence linking the metabolic syndrome and its individual components with disease outcomes during childhood, namely type 2 diabetes and cardiovascular disease 4 Proposes the creation of a working definition of the metabolic syndrome in children 5 Suggests strategies for screening and treatment of the syndrome in youth
Prevalence of the Metabolic Syndrome in Children and Adolescents
Several large population studies have established the prevalence of the metabolic syndrome during childhood [8,9 11] Although direct comparison across studies is hampered due to differences in the
definition of the syndrome, the overall prevalence in children and adolescents is relatively low 3 to 4 when compared to the adult population For instance, the age-adjusted prevalence of the metabolic syndrome based on the ATP III definition in US adults was 237, whereas in adults aged 20 to 29 years it was 67 [2] In the Bogalusa Heart study a population-based longitudinal study of cardiovascular disease risk factors in black and white children, the metabolic syndrome was defined as having four components 75th percentile for age and gender derived from their own population data Table 1 [10] Based on this definition, the prevalence of the metabolic syndrome was 4 and 3 in white and black children, respectively [10] Similarly, in the Cardiovascular Risk in Young Finns Study a large multicenter study of risk factors for heart disease in children and young adults, the prevalence of the metabolic syndrome was 4 Table 1 More recently, the prevalence of the metabolic syndrome was established in US adolescents n 2400 aged 12 to 19 years who participated in NHANES III third National Health and Nutrition Examination Survey [8] In this study the authors chose to use a definition similar to
that proposed in ATP III Table 1 with threshold values based on pediatric
Introduction
Although the components of the metabolic syndrome were first described over 40 years ago, it was only recently that both the World Health Organization WHO and the United States US National Cholesterol Education Program NCEP Adult Treatment Panel ATP III provided a clinical definition of the syndrome These criteria, although similar in that they focus on obesity, dyslipidemia, hyperglycemia, and hypertension, differ in the individual constituents and threshold levels The uniform case definition of the syndrome has promoted epidemiologic investigations to establish the prevalence and characteristics of the syndrome across different adult populations [17] Most importantly, these studies have provided new evidence to support the role of the syndrome as an entity that places individuals at risk for type 2 diabetes [6,7] and cardiovascular disease [4,5] that is associated with increased cardiovascular disease mortality [4,5] The findings from studies in adults, coupled with the obesity epidemic in childhood, have resulted in a renewed interest in the study of the metabolic syndrome in youth
and
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Insulin Resistance Syndrome, Including Polycystic Ovary Syndrome
Table 1 Summary of the prevalence of the MS in children and adolescents
Characteristics Population Chen et al [9] White n 3631 and black children n 2127 517 4 components 75th percentile for age and gender BMI Raitakari et al [11] Finnish children n 1865 618 3 components 75th percentile for age and gender NA Cruz et al [12] Overweight Hispanic children mean BMI 97th percentile; n 126 813 3 components Cook et al [8] White n 646, black n 824, Mexican-American n 846 children 1219 3 components
Age, y Definition of MS Components of the MS Obesity
Hyperglycemia Hypertension
Dyslipidemia
Insulin resistance Prevalence of MS
Waist circumference 90th percentile for age/gender/ethnicity NHANES III NA NA Impaired glucose tolerance 2-hour glucose 140 mg/dL Mean arterial pressure Blood pressure High blood pressure 90th percentile for height, age, and gender TG/HDL ratio TGs 75th percentile; TGs 90th percentile for age/gender; HDL cholesterol 25th percentile HDL 10th percentile for age and gender NHANES III Fasting insulin NA NA 4 30 62 27 67 26 22
Waist circumference 90th percentile for age/gender
Impaired fasting glucose glucose 110 mg/dL High blood pressure 90th percentile for height, age, and gender TGs 110 mg/dL; HDL 40 mg/dL
NA Overall 42 Overall 98 15 233 234 49 Overweight 287 Overweight 745 26 50 518 112
4 in white and 3 in black children Prevalence of components, High waist circumference Hyperglycemia Low HDL cholesterol High triglycerides High blood pressure
BMI–body mass index; HDL–high-density lipoprotein; MS–metabolic syndrome; NA–not available; NHANES–third National Health and Nutrition Examination Survey; TGs–triglycerides
guidelines The overall prevalence of the metabolic syndrome in US adolescents was 42 Prevalence rates were higher in men 61 than in women 21 The prevalence of one and two components of the metabolic syndrome was 41 and 142, respectively The most commonly found abnormality was high triglycerides and low high-density lipoprotein HDL cholesterol In contrast, the prevalence rates of high fasting glucose were very low 15
Impact of obesity on the metabolic syndrome Although the previous studies suggest that overall the prevalence rates of the metabolic syndrome in childhood are low, the perspective is very different in overweight
adolescents [8,12] In NHANES III, the prevalence of the metabolic syndrome was 287 in overweight adolescents body mass index [BMI] 95th percentile, compared to 61 in adolescents at risk for overweight BMI 85th but lower than the 95th percentile and 01 in those with a BMI below the
85th percentile [8] Eighty-nine percent of overweight adolescents had at least one abnormality of the metabolic syndrome and more than half 56 had two abnormalities In this NHANES III adolescent population, the vast majority 80 of youth who were classified as having the metabolic syndrome were also classified as being overweight based on a BMI greater than the 95th percentile In view of the increasing rise in childhood overweight, the overall prevalence of the metabolic syndrome in US adolescents is likely to be higher than that estimated from NHANES III data Results from the 1999 to 2000 NHANES indicate that an estimated 15 of children and adolescents ages 6 to 19 years are overweight BMI 95th percentile, a value 4 higher than that reported in NHANES III 1988 to 1994 [13]
Impact of ethnicity on the metabolic syndrome In US adults, the prevalence of the metabolic syndrome has been shown to be higher
among Hispanic 319 and
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lower among black 216 compared to white adults 238 [2] Likewise, the prevalence of the metabolic syndrome in US adolescents was highest among Hispanics 56 and lowest among black 20 compared to white adolescents 48 The higher prevalence of the metabolic syndrome among Hispanic adolescents is likely to be associated with the high prevalence of overweight in this ethnic group The prevalence of overweight in Hispanic youth has approximately doubled in the past 10 years, such that 234 of Hispanic adolescents are now overweight compared to 127 of white adolescents [14] We recently explored the prevalence of the metabolic syndrome among a group of overweight Hispanic children aged 8 to 13 years with a family history for type 2 diabetes [12], who are part of an ongoing longitudinal study on the natural history of type 2 diabetes in childhood known as the Solar Diabetes Project We developed a pediatric definition of the metabolic syndrome based on the ATP III guidelines as a model Our cut points were based on a combination of clinical [12] and pediatric guidelines [15], as well as on child and
adolescent NHANES III data [16] as outlined in Table 1 Using this definition, we found that 30 of overweight Hispanic children with a family history for type 2 diabetes have the metabolic syndrome [12] Furthermore, nine out of 10 Hispanic overweight children with a family history for type 2 diabetes have at least one feature of the metabolic syndrome Table 1 [12], which is similar to that reported in overweight US adolescents [8] Although the prevalence of obesity among AfricanAmerican adolescents in the United States is also high 236, paradoxically African-American children and adolescents have a lower prevalence of the metabolic syndrome [8,9,10], at least when a similar definition of ATP III is used This is not entirely surprising because African-American youth like adults have lower triglycerides and higher HDL cholesterol levels compared to their white counterparts, although blacks have higher blood pressure [9] These findings suggest that the impact of obesity on the components of the metabolic syndrome may vary by ethnic group, as has been shown to be the case in South Asians, in whom the prevalence of the syndrome is higher than in white persons [17]
Pathophysiology of the
Metabolic Syndrome in Childhood
Although a consensus was reached in terms of defining the metabolic syndrome in adults [5,18], controversy regarding the underlying etiologic factors still remains Nevertheless, the most accepted hypothesis, and one that is supported by prospective studies, is that obesity and insulin resistance [1922] may be the key underlying abnormalities of the metabolic syndrome The role of obesity and insulin resistance in the etiology of the metabolic syndrome has recently been explored in children through cross-sectional and prospective studies [12,23]
The Cardiovascular Risk in Young Finns Study was one of the first groups to explore the childhood predictors of the metabolic syndrome [11] In this study, fasting insulin at baseline was related to the development of the metabolic syndrome defined as having the three following factors: high triglyceride and high blood pressure [ 75th percentile] and low HDL cholesterol [ 25th percentile] after 6 years of follow-up in 1865 children and adolescents 6 to 18 years The results from this study showed that baseline insulin concentration was higher in children who subsequently developed the metabolic syndrome, lending
support to the view that insulin resistance precedes the development of the metabolic syndrome in childhood Because obesity in childhood is closely associated with insulin resistance, it would have been important to establish if children and adolescents who developed the metabolic syndrome after a 6-year follow-up period were also more overweight More recently, researchers from the Bogalusa Heart Study a bi-racial longitudinal cohort attempted to disentangle the relative contribution of childhood obesity measured via BMI versus insulin resistance measured via fasting insulin to the adulthood risk of developing the metabolic syndrome [24] A total of 718 children, aged 8 to 17 years at baseline, were followed for an average of 116 years The metabolic syndrome was defined as having the following four factors: BMI, fasting insulin, systolic or mean arterial blood pressure, and triglyceride/HDL ratio in the highest quartile for age, gender, ethnicity, and study year Significant positive trends were seen between childhood BMI as well as insulin quartiles and the incidence of clustering in adulthood Children in the top quartile of BMI and insulin versus those in the bottom quartile were
117 and 36 times more likely to develop clustering, respectively, as adults A high childhood BMI was significantly associated with the incidence of clustering in adulthood, even after adjustment for childhood insulin levels However, in this study, adjustment for childhood BMI eliminated the influence of insulin on the incidence of clustering in adulthood Thus, in this bi-ethnic, community-based study, childhood obesity measured via BMI was more closely associated with the presence of the metabolic syndrome in adulthood than was fasting insulin These findings suggest that obesity in childhood precedes the development of the metabolic syndrome in adulthood Although obesity in childhood may be more closely associated with the development of the metabolic syndrome than insulin resistance, the question remains as to why some obese children develop the metabolic syndrome and others do not The recent NHANES III data on the prevalence of the metabolic syndrome among US adolescents found that approximately 30 of overweight children BMI 95th percentile had the metabolic syndrome whereas the remaining 70 did not We recently addressed this issue in a cohort n 126 of overweight Hispanic
adolescents mean BMI percentile 97 29; age 8 to 13 years with a family history for type 2 diabetes [12] We hypothesized that in overweight
56
Insulin Resistance Syndrome, Including Polycystic Ovary Syndrome
Figure 1 Estimated marginal means for insulin sensitivity in overweight Hispanic youth according to a number of features of the metabolic syndrome For clarity of interpretation, data are presented using the non-log transformed insulin sensitivity However, statistical analysis was performed on log-transformed insulin sensitivity Data were adjusted for gender, age, Tanner stage, total body fat, and total lean mass One asterisk indicates log-insulin sensitivity was different between subjects with zero features of the metabolic syndrome versus those with two or three features P 0001 Two asterisks indicate log-insulin sensitivity was different between subjects with one feature of the metabolic syndrome versus those with two or three features P 001 Log-insulin sensitivity was not different between children with one versus two features or between those with two versus three features From Cruz et al [12]
Hispanic children, insulin resistance would be more closely associated
with the metabolic syndrome than overall adiposity In this study, insulin sensitivity was measured via the frequently sampled intravenous glucose tolerance test and minimal modeling, and overall adiposity was measured via dual-energy x-ray absorptiometry We found that insulin sensitivity after adjustment for differences in adiposity was 62 lower in overweight youth with the metabolic syndrome defined as having three of the following: hypertriglyceridemia, low HDL cholesterol, high blood pressure, high waist circumference, or impaired glucose tolerance compared to overweight youth without the metabolic syndrome Fig 1 Furthermore, in multivariate regression analysis, insulin sensitivity, but not fat mass, was independently and negatively related to triglycerides and blood pressure and positively related to HDL cholesterol These results suggest that the effect of adiposity on lipids and blood pressure control is mediated via insulin resistance Our findings in overweight Hispanic youth are in agreement with previous results in children, in which directly measured insulin sensitivity has been shown to be independently associated with the separate components of the metabolic syndrome
[23,25] For instance, we previously reported that after adjustment for differences in body composition fat and lean tissue mass, insulin sensitivity measured via the frequently sampled intravenous tolerance test was negatively associated with systolic blood
pressure in a mixed cohort of African-American and white pre-pubertal children with wide varying degrees of adiposity [25] Insulin sensitivity measured via the euglycemic insulin clamp has also been shown to be correlated with fasting triglycerides and HDL cholesterol in white children and adolescents n 357, mean age 13 years, and this relationship remained after adjustment for BMI [23] Despite significant differences in the definition of the metabolic syndrome and in the pediatric populations studied, collectively, the above findings suggest that both obesity and insulin resistance contribute to the development of the metabolic syndrome during childhood It is likely that among overweight children, insulin resistance may be more important than overall adiposity in the development of the metabolic syndrome In this respect, the preferential accumulation of visceral fat, as opposed to subcutaneous abdominal fat, or alternatively
increased ectopic fat storage, may play a significant role in the pathophysiology of the metabolic syndrome in childhood We have recently shown that visceral fat in addition to total fat are important contributors to differences in insulin sensitivity among overweight Hispanic youth with a family history for type 2 diabetes [26] Similarly, a recent study showed that both visceral fat measured via magnetic resonance imaging and intramyocellular lipid accumulation measured via nuclear magnetic resonance spectroscopy were inversely related to the glucose disposal and nonoxidative glucose metabolism in overweight children and adolescents [27] In summary, results in children and adolescents suggest that obesity and perhaps more importantly, central obesity, or ectopic fat storage, coupled with increased susceptibility to insulin resistance, may contribute to the development of the metabolic syndrome in childhood
Impact of the Metabolic Syndrome on Premature Cardiovascular Disease and Type 2 Diabetes
In adults, the metabolic syndrome is a risk factor for type 2 diabetes and cardiovascular disease [18] that is associated with increased cardiovascular disease mortality [4] Although no
studies to date have directly explored the impact of the metabolic syndrome on disease outcomes in childhood, autopsy studies in youth have shown that cardiovascular risk factors including obesity, high blood pressure, high triglycerides, and low HDL cholesterol are related to the early stages of coronary atherosclerosis [28,29] Furthermore, the extent of lesions increases markedly with the presence of multiple risk factors [28] Therefore, the high prevalence of the metabolic syndrome among overweight youth coupled with the epidemic increase in childhood obesity could lead to a disproportionate increase in cardiovascular disease in adulthood Type 2 diabetes and impaired glucose tolerance have recently emerged as a critical health problem in overweight adolescents [30,31,32] Although little is known regarding
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the pathophysiology of type 2 diabetes in childhood, the disease process is likely to be similar to that of adults In this respect, a state of impaired fasting glucose or impaired glucose tolerance in adults is considered an intermediate stage in the natural history of type 2 diabetes and predicts the risk
of development of diabetes [3335] Furthermore, insulin resistance and insulin secretory dysfunction, commonly found in subjects with impaired glucose homeostasis, predict the development of type 2 diabetes [3638] The prevalence of impaired fasting glucose in childhood is relatively low 18, even among overweight children 25 [8,39] In contrast, the prevalence of impaired glucose tolerance after a glucose challenge is strikingly high among overweight children and adolescents [30,32] Several reports have found that the prevalence of impaired glucose tolerance in overweight children and adolescents ranged from 21 to 28 [30,32] A state of impaired glucose tolerance in overweight children and adolescents was associated with decreased insulin sensitivity [27], in some but not all studies [32], and a deterioration in -cell function [27,32] and may, as in adults, signal the premature development of disease In summary, overweight in children and adolescents may serve to accelerate the onset of type 2 diabetes in childhood, through early and chronic exposure of the cell to chronic insulin resistance, which may in turn result in insulin secretory dysfunction
increases the risk for type 2
diabetes More importantly, these studies have shown that specific clustering of traits better predicts the risk burden of coronary heart disease or type 2 diabetes in diverse populations Because several of these traits, particularly lipid risk factors and blood pressure [40], not to mention obesity [41], tend to track into adulthood, early identification of the clustering of risk factors in childhood should prove very valuable in targeting efforts for chronic disease prevention In summary, evidence from both adult and pediatric studies supports the need to create a definition of the metabolic syndrome in childhood
Definition of the Metabolic Syndrome in Children and Adolescents
In considering a definition of the metabolic syndrome in children at least three major issues need to be confronted: 1 Should a definition be created at all? 2 What components should define the syndrome? 3 What thresholds should be used? As one can imagine, these three issues alone could generate considerable debate
Should the metabolic syndrome be defined in children and adolescents? To address this initial question, it may be important to first consider findings in adults In recent years, both the US
NCEP ATP III and the WHO provided a clinical definition of the metabolic syndrome in adults In general, the ATP III definition is more of a risk factorbased definition Table 1, whereas the WHO definition is a disease-based definition in which impaired glucose tolerance, diabetes, and insulin resistance are thought to be central components Regardless of the differences in the individual features and threshold values applied, surprisingly, the prevalence of the metabolic syndrome has been shown to be consistent and very common in adult populations [15] Those with the syndrome are more insulin resistant [3] and are at greater predicted risk for coronary heart disease [35] and diabetes [6,7] Furthermore, the presence of the metabolic syndrome doubles the risk for coronary heart disease events and dramatically
What components should be included in a definition of the metabolic syndrome in children and adolescents? Based on evidence that several traits of the metabolic syndrome track into adulthood, it seems appropriate for the most part to include the same set of risk factors that in adults have the most predictive power on disease outcomes Perhaps with this in mind it may be
appropriate to develop a definition in childhood that is comparable to that of adults, as has been implemented in two recent studies [8,12] Two specific components need further evaluation in pediatrics For instance, we and others have shown that the prevalence of impaired fasting glucose in childhood is very low, even among children at high risk for type 2 diabetes [8,12, 30,32] In contrast, impaired glucose tolerance defined as 2hour glucose 140 mg/dL is fairly common, at least in overweight children [30,32] This raises the issue of whether impaired glucose tolerance as opposed to fasting glucose should be one of the components of the syndrome Alternatively, perhaps the fasting glucose threshold should be lowered as was suggested recently by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus in their follow-up report on the diagnosis of diabetes [42] In this report, the committee decided to lower the threshold for the diagnosis of impaired fasting glucose from 110 to 100 mg/dL [42], a value that is somewhat arbitrary Ideally, the threshold value of fasting plasma blood glucose should be one at which the risk of a clinical or metabolic outcome rises
sharply; however, this remains to be established Finally, the question remains as to whether BMI percentile or waist circumference should be included as a component of the syndrome; we favor the latter but recommend only screening overweight children BMI 95th percentile, as outlined in Table 2 What threshold values should be used? Earlier studies in childhood focused on the clustering of risk factors for cardiovascular disease [9,11], used their own study cut-off values, and were less concerned with the risk for type 2 diabetes or the presence of hyperglycemia In contrast, and probably in response to the need to be able to compare prevalence rates in childhood to those of adults, recent studies in children adopted a definition based on ATP III Table 1 [8,12]; however, there were significant differences in the
58
Table 2 Summary of pediatric guidelines for the prevention and treatment of disease states associated with the MS
Type 2 diabetes [31] Type 2 diabetes Fasting glucose or oral glucose tolerance test Hypertension/high BP BP measurement Hypertension [15] CVD health [43,45,46] Proposed guidelines for MS
Guidelines
Obesity [44]
Screening Type of screening
Obesity
Calculation of BMI percentile
Who should be screened
All children
CVD risk factors MS Family Hx, BMI, BP, diet and physical BMI, oral glucose tolerance activity, smoking, fasting lipids test, waist circumference, fasting lipids, BP All children with BMI 95th All children 2 y of age; lipids: percentile only in those with positive premature family Hx of CVD or when other risk factors are present eg, BMI 95th percentile, diabetes, smoking, hypertension LDLC 160 mg/dL; TGs 150 mg/ dL; HDLC 35 mg/dL; BP 95th percentile; BMI 95th percentile; smokers; people with T2D Children with 3 features of the syndrome
Who should be treated
Children 10 y of age All children 3 y of age or at onset of puberty with a BMI percentile 85th 2 more risk factors family Hx for T2D, ethnic minority, signs of insulin resistance Children with T2D Children with BP 95th percentile for height/age/gender
Aim of therapy Lower BP to value 95th percentile; weight loss Lifestyle modification dietary and physical activity based and pharmacologic
Children with BMI 85th percentile with complications and children with BMI 95th percentile with or without complications Weight loss or weight maintenance
Normalization of glucose and hemoglobin A1c; weight loss Lifestyle modification dietary and physical activity based and pharmacologic
Improve insulin resistance Lifestyle modification dietary and physical activity based; need research on pharmacologic approaches
Insulin Resistance Syndrome, Including Polycystic Ovary Syndrome
Type of therapy
Lifestyle modification dietary and physical activity based
Improve lipids and BP; weight loss; management of T2D; cessation of smoking Lifestyle modification dietary and physical activity based; pharmacologic when LDLC 190 mg/dL or TGs 400 mg/dL
BMI–body mass index; BP–blood pressure; CVD–cardiovascular disease; HDLC–high-density lipoprotein cholesterol; Hx–history; MS–metabolic syndrome; LDLC–low-density lipoprotein cholesterol; T2D–type 2 diabetes; TGs–triglycerides
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Table 3 Proposed cut-off values for the various features of the MS in children and adults
Features of MS High glucose Fasting 2-hour after a standard oral glucose tolerance test Systolic blood pressure, mm Hg Age, y — – 8 12 15 17 Adult 8 12 15 17 Adult 1219 1619 NCEP Adult 68 911 1215 1619
NCEP Adult 8 12 15 17 Adult Males 100 mg/dL 140 mg/dL 112 119 125 133 130 73 77 79 83 85 135 165 150 150 37 39 35 33 35 40 709 845 944 101 102 Females 100 mg/dL 140 mg/dL 111 119 124 125 130 71 76 80 81 85 170 168 150 150 37 38 36 37 35 50 704 819 898 97 88
Diastolic blood pressure, mm Hg
Triglycerides, mg/dL
HDL cholesterol, mg/dL
Waist circumference, cm
Data are based on the American Diabetes Association recommendations and are the same for children and adults [26,31,47] Data are from the Update on the Task Force for High Blood Pressure in Children and Adolescents [15] Data are values for the 90th percentile assuming a height percentile of 50 Data are available for ages 1 to 17 years Data are from the NHANES III [16] Values are 90th percentile for age and gender Values for children from 8 to 11 years are not published Data are from NHANES III [16] Values are 10th percentile for age and gender Data are from NHANES III Unpublished data Values are 90th percentile for age, gender, and white or African-American ethnicity The 90th percentile for Hispanics is slightly higher Adult Treatment Panel definition of the MS in adults [18] National Cholesterol
Education Program NCEP [47] HDL–high-density lipoprotein; MS–metabolic syndrome; NHANES III–third National Health and Nutrition Examination Survey
threshold values applied Table 3 This is particularly true for lipid risk factors and waist circumference because pediatric recommendations either may require revision, as in the case of lipids current guidelines are based on NCEP recommendations set over a decade ago [43], or may not exist as in the case of waist circumference As discussed earlier, another issue that needs to be addressed is whether impaired fasting glucose recently defined as fasting glucose 100 mg/dL as opposed to impaired glucose tolerance should be used as the threshold for hyperglycemia in childhood Also, the question of whether cut-off values should be ethnic and gender specific needs to be addressed We would like to propose that in developing a pediatric definition of the metabolic syndrome three issues be considered: 1 Individual components should be similar to those of adults for the sake of comparison and to evaluate tracking 2 Current recommendations and cutoff values need to be developed or re-evaluated, particularly
for waist circumference,
dyslipidemia, and perhaps hyperglycemia 3 The use of single cut-off values as opposed to multiple cut-off values depending on gender, age, and ethnicity may be easier to apply but less sensitive in identifying children at risk A working definition of the metabolic syndrome in childhood should certainly be put forth, but will require consensus among both clinicians and scientists and hopefully will be developed in the near future
Strategies for Screening and Treatment of the Metabolic Syndrome in Children and Adolescents
Who should be screened? Despite the lack of a uniform definition of the metabolic syndrome in childhood, and the use of different cut-off values, the data summarized in Table 1 demonstrate that the prevalence of the metabolic syndrome in childhood and
60
Insulin Resistance Syndrome, Including Polycystic Ovary Syndrome
adolescence is relatively low, irrespective of the definition used The exception is overweight youth Two recent studies have shown that the metabolic syndrome is strikingly high among overweight children and adolescents [8,12], and suggest that Hispanic youth predominantly of MexicanAmerican ancestry may be at increased risk compared to white
youths [8] These findings suggest that although screening for the metabolic syndrome is probably not warranted in the pediatric population as a whole, screening of overweight children and adolescents, and particularly those belonging to specific minority groups, may be necessary Although current pediatric guidelines recommend screening for obesity [44], type 2 diabetes [31], hypertension [15], and dyslipidemias [43,45,46,48] in at-risk children and adolescents, they do so under the domain of individual pediatric specialties Table 2 Therefore, screening for the metabolic syndrome in overweight children and adolescents as opposed to screening for individual disease outcomes related to the syndrome may help simplify screening strategies and raise awareness, both at the physician level and in the individual member or family level of the combined risk for both type 2 diabetes and cardiovascular disease among overweight youth In addition, it may simplify the need for multiple recommendations and guidelines for the identification and treatment of overweight youth for separate diseases processes eg, obesity, hypertension, type 2 diabetes, which in reality overlap due to a shared
pathophysiology Table 2 Although this may be viewed by some as cumbersome and difficult to implement, the fact is that the current recommendations for screening put forth by the different established guidelines already include screening for several features of the syndrome and all agree that overweight youth are at particular risk The exception is waist circumference for which there are no recommendations, and to a certain extent fasting lipids Based on our current understanding of obesity, insulin resistance, and the metabolic syndrome, screening for adverse lipids should be instituted in all overweight children and adolescents Support for this view is provided by the finding that adverse lipids eg, high triglycerides and low HDL cholesterol are by far the most common risk factor associated with the metabolic syndrome in childhood [8,12] and appear to be due to underlying insulin resistance [12] In summary, pediatric recommendations may need to be updated so that the multiple guidelines that exist are more consistent and address the purpose of screening, identifying, and treating children at risk The development of comprehensive guidelines to screen and identify children with the
metabolic syndrome may prove more useful in the prevention of the major disease outcomes related to the metabolic syndrome, type 2 diabetes, and cardiovascular disease in childhood
resistance rather than on individual risk factors We propose that targeting insulin resistance as opposed to weight loss may be more effective in preventing or delaying the onset of cardiovascular disease and type 2 diabetes in highrisk youth, because strategies aimed at reducing body weight have been, for the most part, unsuccessful For instance, insulin resistance and its associated risk factors may be improved directly or indirectly through specific exercise modalities, dietary interventions, or through pharmacologic agents without the need to make large changes in body fatness For example, a recent study showed that high-intensity physical training for 8 months in overweight adolescents resulted in improvements in fasting plasma triglycerides, low-density lipoprotein particle size, and diastolic blood pressure despite little changes in body fatness [49] Alternatively, nonweight-bearing activities such as strength training may be more acceptable in overweight children and may serve to enhance
long-term health [50] Specific nutrients such as dietary fiber, for example, may improve insulin sensitivity and glucose homeostasis through various mechanisms related to decreased gastric emptying, increased fat oxidation, decreased hepatic output of glucose, and stimulation of glucagon-like peptide-1 secretion [51] Support for this view comes from a recent report in which whole grain consumption was found to be associated with greater insulin sensitivity and lower BMI in adolescents and that this association was stronger among the heaviest adolescents [23] Other nutrients that may have beneficial effects on insulin sensitivity are the phytoestrogens Nutritional intervention studies performed in animals and humans suggest that the ingestion of soy protein associated with isoflavones and flaxseed rich in lignans improves glucose control and insulin resistance [52] Also, in very high-risk insulin-resistant children, pharmacotherapy may be indicated A recent double-blind randomized trial in obese, insulin-resistant youth aged 12 to 19 years treated with metformin for 6 months resulted in significant improvements in glucose tolerance and fasting insulin [53] Other agents that may
prove beneficial in the treatment of insulin resistance in high-risk youth are the thiazolidinediones, which are much more potent insulin sensitizers than metformin Thiazolidinediones have been shown to improve insulin sensitivity, glucose tolerance, and cardiovascular risk factors in type 2 diabetes, impaired glucose tolerance, and in nondiabetic insulin-resistant obese subjects [5457] In summary, more research needs to be conducted to establish the effectiveness of different types of interventions on insulin sensitivity in children It is likely that beneficial and long-lasting health effects will only be achieved through the combined approaches that are gender, age, and culture sensitive
Strategies for treatment of the metabolic syndrome The identification of children with the metabolic syndrome may help to direct treatment strategies by focusing on the underlying pathophysiology eg, insulin
Conclusions
The prevalence of the metabolic syndrome, although very low in normal weight children BMI 85th percentile, is
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high in those who are overweight BMI 95th percentile Approximately 30 of overweight children
have the metabolic syndrome and nine out of 10 have at least one feature of the syndrome The underlying insulin resistance of obesity seems to be an important pathophysiologic event contributing to the syndrome, and this is already evident in childhood Because the number of overweight children is increasing, and because it is evident that the pathology begins early in life, we advocate the creation of a definition of the metabolic syndrome in childhood with comprehensive screening of overweight children based partly on current pediatric guidelines Future research is needed to investigate the effects of lifestyle and pharmacologic interventions aimed at improving insulin resistance in overweight children
Acknowledgments
This work was supported by a National Institutes of Health grant R01 DK 59211; HD 33064
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance
Alexander CM, Landsman PB, Teutsch SM, Haffner SM: NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older Diabetes 2003, 52:12101214 2 Ford ES, Giles
WH, Dietz WH: Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey JAMA 2002, 287:356359 3 Meigs JB, Wilson PW, Nathan DM, et al: Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring Studies Diabetes 2003, 52:21602167 4 Isomaa B, Almgren P, Tuomi T, et al: Cardiovascular morbidity and mortality associated with the metabolic syndrome Diabetes Care 2001, 24:683689 5 Lakka HM, Laaksonen DE, Lakka TA, et al: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men JAMA 2002, 288:27092716 6 Laaksonen DE, Lakka HM, Niskanen LK, et al: Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study Am J Epidemiol 2002, 156:10701077 7 Hanson RL, Imperatore G, Bennett PH, Knowler WC: Components of the metabolic syndrome and incidence of type 2 diabetes Diabetes 2002, 51:31203127 8 Cook S, Weitzman M, Auinger P, et al: Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and
Nutrition Examination Survey, 1988-1994 Arch Pediatr Adolesc Med 2003, 157:821827 Provides prevalence rates of the metabolic syndrome in US adolescents who participated in the NHANES III 9 Chen W, Srinivasan SR, Elkasabany A, Berenson GS: Cardiovascular risk factors clustering features of insulin resistance syndrome Syndrome X in a biracial Black-White population of children, adolescents, and young adults: the Bogalusa Heart Study Am J Epidemiol 1999, 150:667674 1
Chen W, Bao W, Begum S, et al: Age-related patterns of the clustering of cardiovascular risk variables of syndrome X from childhood to young adulthood in a population made up of black and white subjects: the Bogalusa Heart Study Diabetes 2000, 49:10421048 11 Raitakari OT, Porkka KV, Ronnemaa T, et al: The role of insulin in clustering of serum lipids and blood pressure in children and adolescents The Cardiovascular Risk in Young Finns Study Diabetologia 1995, 38:10421050 12 Cruz ML, Weigensberg MJ, Huang TTK, et al: The metabolic syndrome in overweight hispanic youth and the role of insulin sensitivity J Clin Endocrinol Metab 2004, in press Results of this study show that decreased insulin sensitivity is related to the
metabolic syndrome and this relationship is independent of body fatness 13 Ogden CL, Flegal KM, Carroll MD, Johnson CL: Prevalence and trends in overweight among US children and adolescents, 1999-2000 JAMA 2002, 288:17281732 14 Strauss RS, Pollack HA: Epidemic increase in childhood overweight, 1986-1998 JAMA 2001, 286:28452848 15 Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: a working group report from the National High Blood Pressure Education Program National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents [no authors listed] Pediatrics 1996, 98:649658 16 Hickman TB, Briefel RR, Carroll MD, et al: Distributions and trends of serum lipid levels among United States children and adolescents ages 4-19 years: data from the Third National Health and Nutrition Examination Survey Prev Med 1998, 27:879890 17 McKeigue PM, Ferrie JE, Pierpoint T, Marmot MG: Association of early-onset coronary heart disease in South Asian men with glucose intolerance and hyperinsulinemia Circulation 1993, 87:152161 18 National Institutes of Health: The Third Report of the National Cholesterol Education Program
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Adult Treatment Panel III 01-3670 Bethesda, MD: National Institutes of Health; NIH Publication 01-3670; 2001 19 Reaven GM: Insulin resistance and compensatory hyperinsulinemia: role in hypertension, dyslipidemia, and coronary heart disease Am Heart J 1991, 121:12831288 20 Reaven GM: Banting lecture 1988 Role of insulin resistance in human disease Diabetes 1988, 37:15951607 21 Liese AD, Mayer-Davis EJ, Tyroler HA, et al: Development of the multiple metabolic syndrome in the ARIC cohort: joint contribution of insulin, BMI, and WHR Atherosclerosis risk in communities Ann Epidemiol 1997, 7:407416 22 Ferrannini E, Muscelli E, Stern MP, Haffner SM: Differential impact of insulin and obesity on cardiovascular risk factors in non-diabetic subjects Int J Obes Relat Metab Disord 1996, 20:714 23 Sinaiko AR, Jacobs DR Jr, Steinberger J, et al: Insulin resistance syndrome in childhood: associations of the euglycemic insulin clamp and fasting insulin with fatness and other risk factors J Pediatr 2001, 139:700707 24 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, 51:204209 25 Cruz ML, Huang TTK, Johnson MS, et al: Insulin sensitivity and blood pressure in black and white children Hypertension 2002, 40:1822 26 Cruz ML, Bergman RN, Goran MI: Unique effect of visceral fat on insulin sensitivity in obese Hispanic children with a family history of type 2 diabetes Diabetes Care 2002, 25:16311636 27 Weiss R, Dufour S, Taksali SE, et al: Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning Lancet 2003, 362:951957
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Insulin Resistance Syndrome, Including Polycystic Ovary Syndrome
Berenson GS, Srinivasan SR, Bao W, et al: Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults The Bogalusa Heart Study N Engl J Med 1998, 338:16501656 29 McGill HC Jr, McMahan CA, Herderick EE, et al: Obesity accelerates the progression of coronary atherosclerosis in young men Circulation 2002, 105:27122718 30 Sinha R, Fisch G, Teague B, et al: Prevalence of impaired glucose tolerance among children and
adolescents with marked obesity N Engl J Med 2002, 346:802810 31 Type 2 diabetes in children and adolescents American Diabetes Association [no authors listed] Pediatrics 2000, 105:671680 32 Goran MI, Bergman RN, Avila Q, et al: Impaired glucose tolerance and reduced beta-cell function in overweight Hispanic children J Clin Endocrinol Metab 2004, in press Study shows early evidence of impaired -cell function in overweight Hispanic adolescents with impaired glucose tolerance 33 Saydah SH, Miret M, Sung J, et al: Postchallenge hyperglycemia and mortality in a national sample of US adults Diabetes Care 2001, 24:13971402 34 Saydah SH, Loria CM, Eberhardt MS, Brancati FL: Subclinical states of glucose intolerance and risk of death in the US Diabetes Care 2001, 24:447453 35 Dinneen SF, Maldonado D III, Leibson CL, et al: Effects of changing diagnostic criteria on the risk of developing diabetes Diabetes Care 1998, 21:14081413 36 Lillioja S, Mott DM, Spraul M, et al: Insulin resistance and insulin secretory dysfunction as precursors of noninsulin-dependent diabetes mellitus Prospective studies of Pima Indians N Engl J Med 1993, 329:19881992 37 Buchanan TA, Xiang AH, Peters RK, et al:
Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women Diabetes 2002, 51:27962803 38 Weyer C, Bogardus C, Mott DM, Pratley RE: The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus J Clin Invest 1999, 104:787794 39 Fagot-Campagna A, Saaddine JB, Flegal KM, Beckles GL: Diabetes, impaired fasting glucose, and elevated HbA1c in US adolescents: the Third National Health and Nutrition Examination Survey Diabetes Care 2001, 24:834837 40 Bao W, Srinivasan SR, Valdez R, et al: Longitudinal changes in cardiovascular risk from childhood to young adulthood in offspring of parents with coronary artery disease: the Bogalusa Heart Study JAMA 1997, 278:17491754 41 Steinberger J, Moran A, Hong CP, et al: Adiposity in childhood predicts obesity and insulin resistance in young adulthood J Pediatr 2001, 138:469473 42 The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Follow-up Report on the Diagnosis of Diabetes Mellitus Diabetes Care 2003, 26:31603167 43 National Cholesterol Education Panel: Report of
the expert panel on blood cholesterol levels in children and adolescents NIH Publication No 91-2732 Bethesda, MD: National Heart, Lung and Blood Institute and National Institutes of Health; 1991:119
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Barlow SE, Dietz WH: Obesity evaluation and treatment: Expert Committee recommendations The Maternal and Child Health Bureau, Health Resources and Services Administration and the Department of Health and Human Services Pediatrics 1998, 102:E29 Williams CL, Hayman LL, Daniels SR, et al: Cardiovascular health in childhood: a statement for health professionals from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young AHOY of the Council on Cardiovascular Disease in the Young, American Heart Association Circulation 2002, 106:143160 Kavey RE, Daniels SR, Lauer RM, et al: American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood Circulation 2003, 107:15621566 American Diabetes Association: clinical practice recommendations 2002 [no authors listed] Diabetes Care 2002, 25suppl 1:S1S147 Steinberger J, Daniels SR: Obesity, insulin resistance,
diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Atherosclerosis, Hypertension, and Obesity in the Young Committee Council on Cardiovascular Disease in the Young and the Diabetes Committee Council on Nutrition, Physical Activity, and Metabolism Circulation 2003, 107:14481453 Kang HS, Gutin B, Barbeau P, et al: Physical training improves insulin resistance syndrome markers in obese adolescents Med Sci Sports Exerc 2002, 34:19201927 Bernhardt DT, Gomez J, Johnson MD, et al: Strength training by children and adolescents Pediatrics 2001, 107:14701472 Pereira MA, Ludwig DS: Dietary fiber and body-weight regulation Observations and mechanisms Pediatr Clin North Am 2001, 48:969980 Bhathena SJ, Velasquez MT: Beneficial role of dietary phytoestrogens in obesity and diabetes Am J Clin Nutr 2002, 76:11911201 Freemark M, Bursey D: The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes Pediatrics 2001, 107:E55 Antonucci T, Whitcomb R, McLain R, et al: Impaired glucose tolerance is normalized by treatment with the thiazolidinedione
troglitazone Diabetes Care 1987, 20:188193 Ghazzi MN, Perez JE, Antonucci TK, et al: Cardiac and glycemic benefits of troglitazone treatment in NIDDM The Troglitazone Study Group Diabetes 1997, 46:433439 Miyazaki Y, Mahankali A, Matsuda M, et al: Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients J Clin Endocrinol Metab 2002, 87:27842791 Yamasaki Y, Kawamori R, Wasada T, et al: Pioglitazone AD-4833 ameliorates insulin resistance in patients with NIDDM AD-4833 Glucose Clamp Study Group, Japan Tohoku J Exp Med 1997, 183:173183
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