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International Journal of (2004) 28, S70–S74 & 2004 Nature Publishing Group All rights reserved 0307-0565/04 $30.00 www.nature.com/ijo PAPER The prevalence of the metabolic syndrome and type 2 mellitus in children and adolescents

D Molna´r1*

1Department of Paediatrics, Medical Faculty, University of Pe´cs, Hungary

OBJECTIVE: To review the prevalence of the metabolic syndrome and in children and adolescents. METHOD: Literature review. RESULTS: It is well demonstrated that cardiovascular risk factors are frequent in and they tend to cluster. However, the frequency of the metabolic syndrome in childhood and adolescence has been investigated only by few studies. In spite of the diverse criteria used for defining the metabolic syndrome, it is evident that the syndrome is already highly prevalent among obese children and adolescents. Population-based data suggest that the epidemic of pediatric obesity is being followed by an increase of type 2 diabetes mellitus, especially in the United States and in minorities. For the European countries, there are no population-based incidence and prevalence data concerning type 2 diabetes mellitus in children and adolescents. From the available data, the magnitude of the problem in the European Caucasian population seems to be much less than in North America. CONCLUSION: There is an urgent need to establish internationally acceptable criteria for the metabolic syndrome in children and adolescents and to commence for this syndrome. Although type 2 diabetes mellitus is still rare among European children, screening is recommended for type 2 diabetes mellitus or impaired tolerance in children and especially in adolescents with substantial risk for the development of this disease. International Journal of Obesity (2004) 28, S70–S74. doi:10.1038/sj.ijo.0802811

Keywords: metabolic syndrome; type 2 diabetes mellitus; cardiovascular risk factors; children; adolescents

Introduction The metabolic syndrome People with the metabolic syndrome are at increased risk for Historical background and definition developing diabetes mellitus and cardiovascular diseases,1 It has long been realized that certain metabolic symptoms the number one killer in the adult population of Western often occur together, and that these symptoms predict the societies. Obesity plays a central role in the metabolic development of diseases. The combination of , syndrome, which includes / resis- and was reported as early as tance, hypertension and . Recent studies in- the 1920s. There is now substantial evidence that resistance dicate that the process of starts at an early age to insulin-stimulated glucose uptake is a common phenom- and is already linked to obesity and other components of the enon, associated with glucose intolerance, dyslipidemia, metabolic syndrome in childhood.2 Parallel with the obesity high blood pressure and coronary heart disease. Further- epidemic, the incidence of type 2 diabetes mellitus in more, these metabolic abnormalities tend to cluster together children has increased alarmingly and the presence of the in the same individual. Although several clinicians and metabolic syndrome in children and adolescents has also researchers had seen such a syndrome previously, it was been reported.3 probably Reaven4 who suggested in the late 1980s (last The aim of the present paper is to review the data century) the existence of a syndrome in which insulin concerning the prevalence of the metabolic syndrome and resistance was the primary defect, associated with hyper- type 2 diabetes mellitus during childhood and adolescence. insulinemia. He also proposed that the syndrome be titled Syndrome X. Later this syndrome was strongly associated with other metabolic aberrations, most notably with visceral obesity, and called ‘the deadly quartet’, *Correspondence: Dr D Molna´r, H-7623 Pe´cs, Jo´zsef A. u. 7., Hungary. the GHO syndrome (glucose intolerance, hypertension and E-mail address: [email protected] obesity) or the metabolic cardiovascular syndrome. At Metabolic syndrome and type 2 diabetes D Molna´r S71 present, the clustering of cardiovascular risk factors is called Ford et al8 and Meigs et al,9 the sex- and age-adjusted the metabolic syndrome. prevalence of the metabolic syndrome in the US population For adults, two definitions exist for the metabolic was 23.7 and 24%, respectively, which was influenced syndrome: significantly by age, sex and race. A large family study of (1) WHO criteria:5 and/or im- type 2 diabetes in Finland and Sweden found the prevalence paired glucose tolerance (IGT) and/or insulin resistance and of the metabolic syndrome to be 15% among men and 10% two or more of the following: among women with normal glucose tolerance, and 64% among men and 42% among women with glucose intoler-  WHR40.90 (men), 40.85 (women) or BMIZ30 kg/m2, ance.1 The gross prevalence of the metabolic syndrome in  TriglycerideZ1.7 mmol/l or HDL cholesterolo0.90 mmol/ Porto was 14.5% after age-adjustment.10 These data from the l (men), o1.0 mmol/l (women), US and Europe clearly demonstrate that the metabolic  Blood pressureZ140/90 mmHg (or treated hypertension), syndrome is highly prevalent in the adult population, which  . may have important health-care implications. (2) Third Report of the National Cholesterol Education The prevalence of cardiovascular risk factors in childhood Program’s Adult Treatment Panel (ATP III)6 criteria (any three obesity and the clustering of these risk factors have been of the following): studied extensively (for a review see Reilly et al11). All studies demonstrated that the cardiovascular risk factors are more  Fasting blood glucoseZ6.1 mmol/l, prevalent in obese than in nonobese children and that they  circumferenceZ102 cm (men), Z88 cm (women), 12 tend to cluster. For example, Freedman et al reported  TriglyceridesZ1.7 mmol/l, significant odds ratio in obese children for raised diastolic  HDL cholesterol 1.0 mmol/l (men), 1.16 mmol/l (wo- o o blood pressure (OR 2.4), raised systolic blood pressure (OR men), 4.5), raised LDL cholesterol (OR 3.0), low HDL cholesterol  Blood pressureZ130/85 mmHg (or treated hypertension). (OR 3.4), raised (OR 7.1) and high fasting For the metabolic syndrome in children and adolescents, insulin concentration (OR 12.1). In the same study, Freed- no such definition exists. The most frequently mentioned man and co-workers also found that 58% of obese 5–10 y olds components of childhood metabolic syndrome are obesity had at least one of these five cardiovascular risk factors, and (visceral obesity as suggested by Moreno et al7), hyperten- 25% had two or more. sion, hyperinsulinemia/insulin resistance, IGT/type 2 dia- There were only a few studies that gave a clear definition of betes mellitus and dyslipidemia (, low childhood metabolic syndrome and investigated the pre- 3,13,14 HDL cholesterol). However, the cutoff values generally differ valence of the syndrome as a primary goal (Table 1). from study to study and is not well Unfortunately, the results of these studies are not compar- defined (if included among the criteria) since no interna- able since the definitions they used for the childhood tional waist circumference and WHR standards exist for metabolic syndrome were different. children.

Conclusion Prevalence of the metabolic syndrome The common message of the reviewed studies is that the Several studies have investigated the prevalence of the metabolic syndrome is already detectable in children, metabolic syndrome in adults. According to the results of especially in obese children and its prevalence is consider-

Table 1 The prevalence of metabolic syndrome in childhood and adolescence

Study Country/population Criteria Results

Csa´bi et al3 Hungary; 8–18-y-old (Caucasian), obese (77 Presence of hyperinsulinemia, hypertension, Metabolic syndrome was detected in 8.9% of female, 103 male) and control (84 female, 155 impaired glucose tolerance and dyslipidemia obese children. In controls, no glucose male) children (high cholesterol and/or high and/ tolerance test was performed: three risk factors or low HDL cholesterol) occurred in 0.4% of controls

Cook et al13 United States; 12–19-y-old (white, black, Adult Treatment Panel III with modified cutoff Prevalence of metabolic syndrome was 4.2% Mexican American) representative sample values (6.1% in males, 2.1% in females). The (1280 female, 1150 male) syndrome was present in 28.7% of adolescents

Cruz et al14 United States; 8–13-y-old (Hispanic, n ¼ 126) Presence of at least three of the following: Metabolic syndrome was present in 30% of obese children abdominal obesity, low HDL cholesterol, obese children hypertriglyceridemia, hypertension and/or impaired glucose tolerance

International Journal of Obesity Metabolic syndrome and type 2 diabetes D Molna´r S72 able. In order to facilitate further studies providing compar- Prevalence of type 2 diabetes mellitus in children able results, and to establish recommendations for screening Although remains the main form of diabetes of the syndrome, uniform criteria for the metabolic syn- in the young, the much less common, inherited forms of drome in children and adolescents have to be defined diabetes, and type 2 diabetes mellitus (T2DM) can also urgently. Probably, the screening for the metabolic syndrome present in early life. T2DM in children and adolescents is should be linked to the screening for type 2 diabetes regarded as an emerging problem; however, there are only mellitus. few reliable reports of its true population prevalence or its prevalence in obese children. Population-based data suggest that the epidemic of pediatric obesity is being followed by an increase of the incidence and prevalence of type 2 diabetes mellitus. The Type 2 diabetes mellitus American Diabetes Association (ADA) has issued a consensus Historical background and definition statement on T2DM in youth, stating that 8–45% of newly The presence of hyperinsulinemia, IGT and chemical diagnosed DM children had nonimmune-mediated dia- diabetes (silent type 2 diabetes mellitus) has been well betes.18 known for a long time.15,16 Owing to the diverse criteria The phenomenon of a rapidly rising incidence of T2DM in applied, the results of these investigations were not compar- young patients is well known in North America.17 T2DM able and the exact prevalence of glucose intolerance and now accounts for as many as 8–46% of new cases of pediatric chemical diabetes was not known. This aspect of childhood diabetes and affects up to 5% of adolescents in some Native obesity was then forgotten until alarming data from the American tribes.17,20 However, the emergence of T2DM in United States were published17 in the late 1990s. With regard children is not limited to this country. Among Japanese to the definition of type 2 diabetes mellitus in children18,19 junior high school-aged youngsters,21 the incidence of (Table 2) and screening recommendation18 (Table 3), con- T2DM increased from 7.2/100.000 in 1976–1980 to 13.9/ sensus has been reached. 100.000 in 1991–1995. The annual incidence of T2DM was

Table 2 Criteria for the diagnosis of diabetes mellitus18

1. Symptoms of diabetes plus casual plasma glucose concentration Z200 mg/dl (11.1 mmol/l). Casual is defined as any time of day without regard to time since the last meal. The classic symptoms of diabetes include polyuria, polydipsia and unexplained .

Or

2. FPG (fasting plasma glucose) Z126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.

Or

3. The 2-h PG (plasma glucose) Z200 mg/dl (11.1 mmol/l) during OGTT. The test should be performed as described by WHO,19 using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water.

In the absence of unequivocal hyperglycemia with acute metabolic decomposition, these criteria should be confirmed by repeat testing on a different day. The third measure (OGTT) is not recommended for routine clinical use. FPG Z110 mg/dl (6.1 mmol/l) ¼ fasting glucose (IFG) 2-h PGZ7.8 mmol/l and o200 mg/dl (11.1 mmol/l) ¼ impaired glucose tolerance (IGT).

Table 3 Testing for type 2 diabetes in children18

Criteriaa

Overweight (BMI485th percentile for age and sex, weight for height485th percentile or weight4120% of ideal for height) Plus any two of the following risk factors: KFamily history of T2DM in first- or second-degree relative KRace/ethnicity (American Indian, African-American, Hispanic, Asian/Pacific Islander) KSigns of insulin resistance or conditions associated with insulin resistance (, hypertension, dyslipidemia, PCOS) Age of initiation of testing: age 10 y or at onset of puberty Frequency: every 2 y Test: fasting plasma glucose preferredb

aClinical judgement should be used to test for diabetes in high-risk patients who do not meet these criteria. bAccording to the experience of the author, the performance of oral is much more sensitive.

International Journal of Obesity Metabolic syndrome and type 2 diabetes D Molna´r S73 reported 2.5/100.000 in Australian children below the age of Acknowledgements 16 y.22 This work was supported by the Hungarian National Publications on the prevalence of T2DM in European Research Grant (OTKA T033066/2000 to D Molnar), Hungar- children and adolescents are anecdotal and there are no ian Ministry of Welfare (ETT 113/2003 to D Molnar) and population-based incidence and prevalence data. Agency for Research Fund Management and Research According to the data of the Pan-Birmingham Diabetes Exploitation (BIO-00023/2002 to D Molnar). Advisory Group,23 the first case of childhood T2DM in Europe was diagnosed in 1993, and until 2001, 17 other patients were reported, 15 of them being of South Asian References origin. 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Executive Summary of were in the pubertal age and male to female ratio was 1:3. the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of Analysis of the multicenter database from 148 pediatric 27 High Blood Cholesterol In Adults (Adult Treatment Panel III). diabetes centers from Germany and Austria revealed 130 JAMA 2001; 285: 2486–2497. (0.6%) children of Caucasian origin with T2DM compared to 7 Moreno LA, Pineda I, Rodrı´guez G, Fleta J, Sarria A, Bueno M. 19 796 patients with diabetes type 1. Patients with T2DM Waist circumference for the screening of the metabolic syndrome in children. Acta Paediatr 2002; 91: 1307–1312. were predominantly female, significantly older at the 8 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic diagnosis and more overweight as compared to those with syndrome among US adults. Findings from the Third National type 1 diabetes mellitus. Health and Examination Survey. 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J Clin Endocrinol Metab 2004; 89:108–113. 15 Chiumello G, Guercio MJ, Garnelutti M, Bidone G. Relationship Conclusion between obesity, chemical diabetes, and beta pancreatic function in children. Diabetes 1969; 18: 238–243. On the basis of the available data, it seems very likely that 16 Molna´r D. Insulin secretion and carbohydrate tolerance in the prevalence of T2DM in European children is not as high childhood obesity. Klin Pa¨diatr 1990; 202: 131–135. as it is in North America, although an increase in its 17 Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeiter P. Increased incidence of non-insulin-dependent diabetes prevalence and incidence can be expected. The crude mellitus among adolescents. J Pediatr 1996; 128: 608–615. prevalence of T2DM as compared to type 1 diabetes mellitus 18 American Diabetes Association. Type 2 diabetes in children and in children younger than 18 y is still negligible. adolescents. Pediatrics 2000; 105: 671–680.

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International Journal of Obesity