Type II diabetes mellitus and impaired glucose regulation in Caucasian children and adolescents with obesity living in Germany

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1 (2004) 28, & 2004 Nature Publishing Group All rights reserved /04 $ PAPER Type II diabetes mellitus and impaired glucose regulation in Caucasian children and adolescents with obesity living in Germany M Wabitsch 1 *, H Hauner 2, M Hertrampf 1, R Muche 3, B Hay 3, H Mayer 4, W Kratzer 5, K-M Debatin 1 and E Heinze 1 1 Department of Pediatrics, University of Ulm, Germany; 2 German Diabetes Research Institute, University of Duesseldorf, Germany; 3 Department of Biometry and Medical Documentation, University of Ulm, Germany; 4 Children s Hospital Hochried, Murnau, Germany; and 5 Department of Internal medicine, University of Ulm, Germany BACKGROUND: Recent studies reported an increased prevalence of type II diabetes mellitus in obese children and adolescents, especially in specific ethnic subgroups. The aim of this study was to determine the prevalence of type II diabetes mellitus and impaired glucose regulation in a large group of Caucasian children and adolescents with obesity living in Germany. PATIENTS AND METHODS: A total of 520 subjects (237 boys, 283 girls) (mean age: y (range y)) with a BMI497th percentile, BMI-SDS: (range ), who were consecutively admitted to an in-patient obesity unit participated in the study. A 2-h oral glucose tolerance test (1.75 mg of glucose per kilogram of body weight) was performed before entering a weight-loss program and capillary blood glucose concentrations were measured. Patients were categorized into normal glucose regulation, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and diabetes. In addition, fasting venous blood was taken to determine the circulating insulin, C-peptide and lipids. Insulin resistance was estimated by homeostatic model assessment. RESULTS: Type II diabetes was present in 1.5% (n ¼ 8) of the patients, two patients were admitted with already diagnosed type II diabetes and six patients were identified with yet unknown diabetes. IFG was detected in 3.7% (n ¼ 19) and IGT in 2.1% (n ¼ 11) of the patients. All together, in 6.7% (n ¼ 35) (95% confidence interval: %) of the patients, impaired glucose regulation (IFG, IGT) or diabetes was identified. These patients had a higher BMI-SDS, higher levels of fasting insulin and C- peptide and a higher insulin resistance index than the patients with normal glucose regulation. Risk factors for the occurrence of impaired glucose regulation were a BMI-SDS42.5 as well as a positive parents history for diabetes. CONCLUSIONS: This is the first report on the prevalence of type II diabetes in a large cohort of Caucasian children and adolescents with obesity living in Europe. regulation and type II diabetes were present in a substantial proportion of the patients studied. Screening for diabetes in severely obese children and adolescents (BMI-SDS42.5) is therefore recommended. Patients identified with impaired glucose regulation need specific treatment programs in order to prevent progression to diabetes. (2004) 28, doi: /sj.ijo Published online 13 January 2004 Keywords: obesity in children and adolescents; type II diabetes; impaired glucose regulation Introduction The prevalence of childhood obesity is increasing worldwide. 1 This development is accompanied by an increased prevalence of type II diabetes mellitus. 2 5 In the United States and *Correspondence: M Wabitsch, Department of Pediatrics, University of Ulm, Prittwitzstr. 43, Ulm, Germany. martin.wabitsch@medizin.uni-ulm.de Received 7 November 2003; revised 11 February 2003; accepted 16 April 2003 in Canada, type II diabetes in adolescents was found especially in specific ethnic subgroups, 6 9 being highest in Pima Indians (22.3/1000 in y-old children). 10 The estimated prevalence of diabetes (all types) in adolescents has been estimated to be in the 3rd NHANES, 0.41%, and that of impaired fasting glucose (IFG) 1.76%. 10 Recently, Sinha et al 11 investigated a multiethnic American cohort of 167 obese children and adolescents and found impaired glucose tolerance (IGT) in more than 20% of the subjects and silent type II diabetes in four subjects.

2 308 There is also evidence from European studies that the prevalence of childhood obesity has increased during the last few decades. 12 In a study of German schoolchildren, the prevalence of overweight increased from 10.0 to 16.3% in boys and from 11.7 to 20.7% in girls between 1975 and The prevalence of obesity increased from 5.3 to 8.2% in boys and from 4.7 to 9.9% in girls in the same period. 13 So far, no data are available on the prevalence of type II diabetes and IGT in European children and adolescents with obesity, except some recent case reports. 14 To prevent the development of type II diabetes and its lifeshortening sequelae, the early detection of impaired glucose regulation may represent an appropriate strategy, as subjects with IGT are at increased risk of developing this disease. 15 Recent intervention studies have convincingly demonstrated that adoption of a healthy lifestyle characterized by healthy eating, regular physical activity and subsequent modest weight loss can prevent the progression of IGT to clinical diabetes. 16,17 Since there are no data so far on the prevalence of type II diabetes and IGT in Caucasian children and adolescents with obesity living in Europe, we investigated glucose homeostasis in a large cohort of 520 German children and adolescents by performing an oral glucose tolerance test (OGTT). The aim of the study was to determine the prevalence of type II diabetes mellitus and impaired glucose regulation in this large group of Caucasian children and adolescents with obesity. In addition, established anthropometric and metabolic risk factors were assessed and related to the different categories of disturbed glucose metabolism. Patients and methods In all, 520 children and adolescents of Caucasian origin (237 boys and 283 girls) between 8.9 and 20.3 y old with a mean age of y were included in the study. All participants were obese with a BMI above the 97th percentile of recently determined, new German reference values. 18 The obese children and adolescents were consecutively referred to the Children s Hospital Hochried to participate in a multidisciplinary weight reduction program. Informed written consent was obtained from the parents of each participant or when appropriate from the patient. Family history A detailed family history was obtained using a standardized questionnaire filled out by one of the parents of the patients. Data were missing for 3.6% of the mothers, 14.2% of the fathers and for 28.7% of the grandparents. The main reasons for missing data were information unknown to the parent or biological parents not available. Clinical data Weight was measured to the nearest 0.1 kg on a calibrated balance beam scale and height to the nearest 0.5 cm. Systolic and diastolic (fifth phase) blood pressure was measured after a 10 min rest using a sphygmomanometer. The pubertal developmental stage was determined according to Marshall and Tanner 19,20 and categorized into three groups: prepubertal: boys with pubic hair and gonadal stage I, girls with pubic hair stage and breast stage I; intrapubertal: boys with pubic hair and gonadal stage II III, girls with pubic hair stage and breast stage II III; late pubertal/postpubertal: boys with pubic hair and gonadal stage IV V, girls with pubic hair and breast stage IV V. Clinical signs of acanthosis nigricans were carefully investigated in all subjects. Test procedure and laboratory measurements An OGTT was performed in all patients between 0700 and 0800 after an overnight fast of 12 h the morning after admission to the hospital but before entering the weight reduction program. The day prior to the glucose tolerance test, all subjects received a normo-caloric, mixed diet. The test was performed according to established recommendations. 21,22 Patients were given flavored glucose at a dose of 1.75 g/kg body weight (maximum 75 g) orally. At the time points 0 and 120 min, respectively, capillary blood samples (50 ml) were obtained to measure glucose concentration. The glucose concentration was determined in whole blood samples using the photometric GOD-PAP method (Dr Lange Test LCN 300/400, Berlin, Germany). Intra-assay and interassay variation was less than 3%. Normal and impaired glucose values were defined according to the American Diabetes Association guidelines 22 referring to the reference values for capillary whole blood glucose concentrations. Normal glucose values were defined as fasting glucoseo100 mg/dl and 2h-OGT glucoseo140 mg/dl. IFG was defined as fasting glucose of mg/dl and IGT was defined as 2 h glucose4140 and o200 mg/dl. Diabetes mellitus was defined as fasting glucose4110 mg/dl and/or 2 h glucose4200 mg/dl. The term impaired glucose regulation was used for the combined group of subjects with IFG and IGT. 21 In addition, a venous blood sample was taken in the fasting state in order to measure serum concentrations of the following variables: triglycerides, total cholesterol, HDL-, LDL-cholesterol, using commercially available test kits (CHOD-PAP-method, Dr Lange Test, Berlin, Germany), uric acid by the uricase method (Dr Lange Test, Berlin, Germany), insulin and C-peptide using specific radioimmunoassays (Pharmacia, Stockholm, DRG C-PEPTID EIA-1293, Berlin, Germany). Furthermore, serum leptin concentration was measured with a specific radioimmunoassay (mediagnost LEP-R42, Tübingen, Germany). Intra-assay and interassay variation for the serum concentrations of these variables was less than 10%. Autoantibodies related to autoimmune type I diabetes mellitus were determined in all subjects with diabetes and with impaired glucose regulation. Islet-cell-antibodies (ICA) were measured with fluorescein-conjugated affinipure goat

3 anti-human IgG (Dianova, Hamburg, Germany) using a fluorescence microscope (Zeiss, Jena, Germany). Antiinsulin antibodies were determined by a radioligand assay supplied by Medipan Diagnostica (Hamburg, Germany). The presence of anti-gad65 antibodies was analyzed with a specific radioligand assay from Medipan Diagnostica. Calculations Since BMI values were significantly age-dependent in the group under investigation, the standard deviation (s.d.) scores of BMI were calculated by LMS. 23 The insulin resistance index was determined by homeostatic model assessment (HOMA-R) and calculated as the product of the fasting plasma insulin level (in microunits per ml) and the fasting blood glucose (in milligrams per dl) divided by Lower insulin-resistance values indicate a higher insulin sensitivity, whereas higher insulin-resistance values indicate a lower insulin sensitivity. 24 The estimate obtained with HOMA-R correlated well with the measures of insulin resistance obtained from obese and nonobese children and adolescents 11, as well as with the results obtained by the euglycemic hyperinsulinemic clamp technique in adults. 24,25 Statistical methods The differences in continuous variables between the group of patients with normal glucose values and the three groups of patients with elevated glucose values were identified by the Wilcoxon test for unpaired observations. The description of the data was given as mean7s.d. for comparison reasons. The effects of dichotomous variables such as male gender, BMI-SDS42.5, positive family history for diabetes (parents), positive family history for diabetes (grandparents and parents) and acanthosis nigricans on the occurrence of impaired glucose regulation or diabetes were described by absolute and relative frequencies and tested by the w 2 test. To describe the association between insulin resistance and anthropometric and laboratory parameters, Spearman rank correlation coefficients were calculated. No adjustment for multiple comparisons or multivariate analysis was carried out due to the relatively small prevalence of impaired glucose regulation and the observational character of the study. All statistical calculations were carried out using SAS software (SAS, Version 8.0); the P-values of less than 0.05 were considered to be significant. Results Clinical data of the study group The patients had a mean height of cm (range: cm), a mean weight of kg (range: kg) and a mean BMI of kg/m 2 (range kg/m 2 ). The mean BMI-SDS of the study population was (range: ). Prevalence of IFG, IGT and silent type II diabetes A total of 35 of the patients, 14 boys and 21 girls, showed elevated blood glucose concentrations in the fasting state or at 2 h of the OGTT (Figure 1). The overall prevalence of elevated blood glucose levels was 6.7% (95% confidence interval: %). In total, 19 (3.7%) of these patients had elevated fasting blood glucose levels (4100 mg/dl) (mean mg/dl), 11 (2.1%) patients showed an IGT (2 h blood glucose4140 mg/dl) (mean value mg/dl), of which only three patients had both an increased fasting glucose level and an IGT. In eight patients (1.5%), two boys and six girls, overt type II diabetes was present: two of these patients have been previously admitted to a children s hospital with type II diabetes mellitus (as shown by two independent OGTTs with a 2h-glucose value 4200 mg/dl, respectively) and treated with glibenclamide and insulin, respectively. Six patients with as yet undiagnosed diabetes mellitus fulfilled the criteria for diabetes mellitus during the OGTT: six of the eight patients had an increased fasting glucose level (4110 mg/dl) (mean value: mg/dl), two of them also had an elevated 2 h glucose level (4200 mg/dl) in the OGTT. Determination of autoantibodies related to type I diabetes In each of the 35 patients with elevated blood glucose concentrations, we determined circulating autoantibodies characteristic for type I diabetes. Significant amounts of ICA, Anti-GAD65 antibodies and anti-insulin antibodies could not be detected in the serum from any of these patients. Family history for diabetes In the whole study group, 4.2% of the mothers and 4.7% of the fathers were reported to be treated for diabetes. In all, Normal glucose regulation n= % Impaired fasting glucose* n=19 3.7% Study group n= % tolerance* n=11 2.1% regulation n=35 6.7% Diabetes n=8 1.5% Figure 1 Numbers and prevalence of normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance and type II diabetes mellitus in the study group. *Three patients had both an impaired fasting glucose and an impaired glucose tolerance. 309

4 % of the grandparents were reported to have or to have had type II diabetes mellitus. Seven of the eight patients with overt type II diabetes mellitus had a positive history for type II diabetes mellitus in the grandparents, however, only one patient had a positive parental history for type II diabetes. Family history for obesity and cardiovascular disease In total, 62.7% of the mothers and 74.9% of the fathers were reported to have a BMI425 kg/m 2 and 81.7% of the patients had one or two parents with a BMI425.0 kg/m 2. In all, 0.8% of the mothers and 3.5% of the fathers were reported to have had a prior myocardial infarction and 0.6% of the mothers and 0.2% of the fathers reported a history of stroke. Clinical and metabolic phenotype Table 1 shows selected clinical and metabolic parameters of the patients with IFG, IGT and type II diabetes mellitus compared with the patient with normal glucose regulation. Differences in the clinical and metabolic variables were also calculated between the combined group of patients with impaired glucose regulation and diabetes and the patients with normal glucose regulation. As compared to patients with normal blood glucose regulation, patients with impaired glucose regulation or diabetes were older, had higher values for BMI and BMI-SDS, had higher serum concentrations of insulin, C-peptide, and showed a higher insulin resistance index (Table 2). In addition, the differences in the cardiovascular risk factor profile between the group of patients with impaired glucose regulation or diabetes and the patients with normal glucose regulation are shown in Table 2. Patients with impaired glucose regulation or diabetes had higher triglyceride and higher leptin levels. No differences were found for total cholesterol, LDL-cholesterol and uric acid. Table 3 shows the frequency distribution of patients with impaired glucose regulation or diabetes depending on the pubertal development stage. All girls and most of the boys were in the intra- or postpubertal stage. Risk factors for impaired glucose regulation In order to identify the risk factors for impaired glucose regulation or diabetes in the study group, we investigated the effect of selected variables on the occurrence of impaired glucose regulation by the w 2 test (Table 4). This analysis revealed that a BMI-SDS42.5 (w 2 P ¼ 0.005) as well as a positive parents history for type II diabetes mellitus (w 2, P ¼ 0.02) were significant risk factors for the occurrence of impaired glucose regulation or diabetes. No significant effect was seen for the presence of acanthosis nigricans, male gender or a positive family history including grandparents. Table 1 Clinical and metabolic phenotype of obese children and adolescents with normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance and type II diabetes mellitus a Variable Normal glucose tolerance (n ¼ 485) Impaired fasting glucose (n ¼ 19) P-value regulation or type II diabetes tolerance (n ¼ 1) P-value Type II diabetes P-value P-value c (n ¼ 8/n ¼ 6) b Sex (no.) Male Female Age (y) o NS NS o0.01 Range BMI (kg/m 2 ) o0.001 BMI-SDS o NS o0.001 Range Fasting insulin level (mu/ml) o o0.001 Range Fasting C-peptide (ng/ml) o o0.001 Range Insulin-resistance index d o o0.001 a 7 are means7s.d. P-values are for the comparison with the group with normal glucose tolerance by the Wilcoxon test. b Blood levels were measured only in the six patients with yet unknown diabetes. c P-values are for comparison of the combined group of patients with impaired glucose regulation with the group with normal glucose tolerance. d The insulin-resistance index was determined by homeostatic model assessment and calculated as the product of the fasting plasma insulin level (in microunits per milliliter) and the fasting blood glucose (in milligrams per deciliter) divided by Lower insulin-resistance values indicate a higher insulin sensitivity, whereas higher insulin-resistance values indicate a lower insulin sensitivity.

5 Table 2 diabetes Differences of selected cardiovascular risk factors between patient with normal glucose regulation and patients with impaired glucose regulation or type II Normal glucose regulation or type II diabetes (n ¼ 485) regulation (n ¼ 35) Significance (P-value) a 311 Age (y) Po0.01 BMI (kg/m 2 ) Po0.001 BMI-SDS Po0.001 Fasting insulin level (mu/ml) Po0.001 Fasting C-peptide (ng/ml) Po0.001 Insulin-resistance index b Po0.001 Systolic BP (mmhg) NS Diastolic BP (mmhg) NS Leptin (ng/ml) o0.001 Total cholesterol (mg/dl) NS LDL-cholesterol (mg/dl) NS Triglycerides (mg/dl) o0.001 Uric acid (mg/dl) NS a NS indicates Wilcoxon test P-values b See footnote d of Table 1. Table 3 Number of patients with impaired glucose regulation or type II diabetes in different pubertal developmental stages Girls Boys Prepubertal 0 (22) 4 (75) Intrapubertal a 6 (98) 3 (111) postpubertal 15 (142) 7 (37) The number of patients in the respective stages of the whole study group is given in parenthesis. a The intrapubertal stage includes all patients with a pubic hair stage II III. HOMA-R Table 4 Effects of male gender, BMI-SDS42.5, positive parental history, positive family history (grandparents and parents) and acanthosis nigricans on the occurrence of impaired glucose regulation or diabetes Variable Normal glucose regulation (%) regulation or type II diabetes (%) Significance (P-value) Male gender NS BMI-SDS o0.01 Positive FH o0.02 (parents) Positive FH NS Acanthosis NS Percentage of patients affected by the variable in the respective group and significance in w 2 -test is presented. Association of insulin resistance with anthropometric and laboratory parameters To characterize insulin resistance in the patients of the study group with respect to anthropometric and metabolic changes, a linear regression analysis was performed between the insulin resistance index (HOMA-R) and selected parameters. Figure 2 shows the relationship between HOMA-R and BMI-SDS (r ¼ 0.29, Po0.001). With higher BMI-SDS, the variation of HOMA-R increased considerably. However, HOMA-R was positively associated with age (r ¼ 0.12, BMI-SDS Figure 2 Relationship between BMI-SDS and the insulin resistance index (HOMA-R) in the study group. Po0.008), total cholesterol levels (r ¼ 0.09, P ¼ 0.04), triglycerides (0.52, Po0.001), uric acid (r ¼ 0.19, Po0.001) and systolic blood pressure (r ¼ 0.40, Po0.001), but was also inversely associated with HDL-cholesterol (r ¼ 0.23, Po0.001). Acanthosis nigricans As the clinical finding of acanthosis nigricans in our study group had no prognostic value for the occurrence of impaired glucose regulation or type II diabetes, we further looked for differences in metabolic variables between the group of patients with acanthosis nigricans and with the group of patients without acanthosis nigricans. Patients with

6 312 acanthosis nigricans had higher fasting insulin levels ( vs mu/ml, Po0.001), higher C-peptide ( vs ng/ml, Po0.001) and higher leptin levels ( vs ng/ml, Po0.001) compared with patients without acanthosis nigricans. Discussion In the present study, the prevalence of IFG, IGT and overt type II diabetes was assessed in a large cohort of Caucasian children and adolescents with obesity defined by a BMI497th percentile. The results show that all stages of disturbed glucose homeostasis could be found in significant numbers. Silent type II diabetes and IGT are, therefore, not only a feature of obese children and adolescents in the United States, where it occurs mainly in those of non- European ancestry (American of African, Hispanic, Asian and American Indian descent), but are also present in Caucasians in Europe. The prevalence rates observed in our study cohort were lower than those in particular ethnic groups in the US. 3 8 For example, in the study of Sinha et al 11 carried out in a multiethnic cohort of 167 obese children and adolescents, IGT was found in 25% of the children and in 21% of the adolescents and type II diabetes in 4% of the adolescents. Our study, however, has some limitations. The classification of disturbances in glucose homeostasis was based on one OGTT only (except for the two patients with already known diabetes type II). It should be stressed that this diagnostic procedure is not sufficient for a reliable diagnosis in asymptomatic patients. 21,22 Nevertheless, Sinha et al 11 demonstrated recently a high reliability of a single OGTT performed in obese children and adolescents by showing a good reproducibility of the results. As we performed the OGT testing in a very strictly standardized manner, the same reliability may hold true for our study. All patients with impaired glucose regulation or diabetes in our study were found to be negative for ICA, anti-gad65 antibodies and anti-insulin antibodies. No molecular genetic analysis for mutations related to maturity-onset diabetes of the young (MODY) was performed in our study. However, MODY is a rare form of diabetes in children and adolescents and is characterized by a strong parental history for diabetes. Such patients are usually nonobese and have low fasting insulin levels. 26 Although this possibility appears to be rather unlikely, we cannot definitively exclude that subjects with MODY were among the identified patients with impaired glucose regulation or diabetes. 27 It is well known from clinical studies in adults that excess fat mass is the most important modifiable risk factor for type II diabetes and impaired glucose regulation. 28,29 Our crosssectional study now provides evidence that this association also holds true in children and adolescents. The patients with impaired glucose regulation or diabetes in our study were also characterized by insulin resistance with fasting hyperinsulinemia and high values for the insulin resistance index confirming a recent report. 11 In the latter study, insulin resistance was the best predictor of IGT. In our sample, the patients with impaired glucose regulation or diabetes were also more obese, had higher insulin and C- peptide values and a higher insulin resistance index than the individuals with normal glucose regulation. Other risk factors for an impaired glucose regulation or a type II diabetes in our study group were a positive family history and severe obesity (BMI-SDS42.5). Acanthosis nigricans was a frequent clinical finding in the obese patients investigated in the present study, but in contrast to cohorts studied in the US, 5 acanthosis nigricans was not associated with impaired glucose regulation or type II diabetes. Patients with acanthosis nigricans, however, had significantly higher serum levels of insulin and leptin than subjects without indicating a state of insulin resistance. In contrast to type I diabetes, most children with type II diabetes are overweight or obese at diagnosis and present without ketonuria and polyuria, and have no history of weight loss. 5 Therefore, these patients are rarely detected by clinical signs at an early stage of the disease. In the present study, silent and yet unknown diabetes was diagnosed in six patients only by the screening test applied. These children had no clinical symptoms for diabetes. The classification of the patients with disturbed glucose homeostasis was performed according to the revised recommendations of the American Diabetes Association. 22 In adults, both elevated fasting glucose and elevated 2 h glucose in the OGTT were found to be associated with an increased risk for cardiovascular disease. IGT is an intermediate stage in the natural history of type II diabetes and is a strong predictor of the risk of developing diabetes 30 and cardiovascular disease. 31 When adults are defined as having diabetes or IFG or IGT on either fasting or 2-h values but not on both, the different patterns of cardiovascular and mortality risk have been defined. 32,33 At present, there is no information available about the risk factors and the prognostic value of IFG and IGT for the development of type II diabetes in children and adolescents. It should also be mentioned that the number of patients with IFG levels was rather low in the group of patients with IGT, similar to the finding of Sinha et al, 11 whereas the two patients with a 2-h blood glucose4200 mg/dl also had IFG levels. Recent studies suggest that progression from IGT to frank diabetes can be delayed or even prevented by appropriate lifestyle intervention 16,17 Although similar studies are missing for children and adolescents with IGT, a strategy appears to be justified where great emphasis is given to the early detection of impaired glucose regulation. On the basis of the results of the present study, screening for impaired glucose regulation and diabetes is recommended for obese children and adolescents with severe obesity and a positive parental history for diabetes, although it is still a matter of debate as to which screening would be most appropriate for this young risk group. It is also noteworthy in this context that a successful intervention could prevent not only the develop-

7 ment of diabetes but also the development of many other comorbidities of obesity. In conclusion, our study shows a significant number of patients with IFG, IGT or overt asymptomatic diabetes in a large group of obese children and adolescents of Caucasian origin living in Europe. Additional information and a thorough discussion are urgently needed to develop new strategies to screen for the disturbances of glucose homeostasis and to initiate early intervention. Acknowledgements We gratefully acknowledge the support of the doctors, nurses and assistants of the Children s Hospital Hochried. We thank Christian Denzer, Alexandra Kessler and Dorothee Ultsch for their kind assistance. This study was supported in part by a grant of the Foundation Das zuckerkranke Kind of the German Diabetes Association. References 1 Rocchini AP. Childhood obesity and a diabetes epidemic. N Engl J Med 2002; 346: WHO. Obesity. Preventing and managing the global epidemic. Report of a WHO consultation on obesity, WHO technical report Series 894, Rosenbloom AL, Joe JR, Young RS, Winter NE. Emerging epidemic of type 2 diabetes in youth. Diabetes Care 1999; 22: Fagot-Campagna A, Pettitt DJ, Engelgau MM, Burrows NR, Geiss LS, Valdez R, Beckles GL, Saadine J, Gregg EW, Williamson DF, Narayan KM. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr 2000; 136: American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000; 23: Dabelea D, Hanson RL, Bennett PH, Roumain J, Knowler WC, Pettitt DJ. Increasing prevalence of type II diabetes in American Indian children. Diabetologia 1998; 41: Dabelea D, Pettitt DJ, Jones KL, Arslanian SA. Type 2 diabetes mellitus in minority children and adolescents. An emerging problem. Endocrinol Metab Clin N Am 1999; 28: Glaser NS, Jones KL. Non-insulin dependent diabetes mellitus in Mexican-American children. WJMed1998; 168: Harris SB, Gittelson J, Hanley A, Barnie A, Wolever T, Gao J. The prevalence of NIDDM in native Canadians. Diabetes Care 1997; 20: Fagot-Campagna A, Saaddine JB, Flegal KM, Beckles GLA. Diabetes, impaired fasting glucose, and elevated HbA1c in US adolescents: the third National Health and Nutrition Examination Survey. Diabetes Care 2001; 24: Sinha R, Fisch G, Teague B, Tamborlane WV, Banyas B, Allen K, Savoye M, Rieger V, Taksali S, Barbetta G, Sherwin RS, Caprio S. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 2002; 346: Livingstone B. Epidemiology of childhood obesity in Europe. Eur J Pediatr 2001; 159 (Suppl 1): S14 S Kromeyer-Hauschild K, Zellner K, Jaeger U, Hoyer H. Prevalence of overweight and obesity among school children in Jena (Germany). Int J Obes Relat Metab Disord 1999; 23: Drake AJ, Smith A, Betts PR, Crowne EC, Shield JP. Type 2 diabetes in obese white children. Arch Dis Child 2002; 86: The DECODE Study Group. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet 1999; 354: Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hamalainen H, Hanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M, Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: Kromeyer-Hauschild K, Wabitsch M, Kunze D, Geller F, Ziegler A, Gei HC, Hesse V, Hippel V, Jäger U, Johnsen D, Kiess W, Korte W, Menner K, Müller M, Niemann-Pilatus A, Remer T, Schäfer F, Wittchen HU, Zabransky S, Zellenr K, Hebebrand J. Perzentile für den Body-mass-Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher Stichproben. Monatsschr Kinderheilkd 2001; 149: Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969; 44: Marshall WA, Tanner JM. Variations in pattern of pubertal changes in boys. Arch Dis Child 1970; 45: Alberti K. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation. Diabetes Med 1999; 15: S39 S The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2002; 25 (Suppl 1): S5 S Cole TJ. The LMS method for constructing normalized growth standards. Eur J Clin Nutr 1990; 44: Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadonna RC, Muggeo M. Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes 1998; 47: Velho G, Froguel P. Genetic metabolic and clinical characteristics of maturity onset diabetes of the young. Eur J Endocrinol 1998; 138: Stride A, Vaxillaire M, Tuomi T, Barbetti F, Niolstad PR, Hansen T, Costa A, Conget I, Pedersen O, Sovik O, Lorini R, Groop L, Froguel P, Hattersley AT. The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabteologia 2002; 45: Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994; 17: Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 1995; 22: Edelstein SL, Knowler WC, Bain RP, Anders R, Barrett-Connor EL, Dowse GK, Haffner SM, Pettitt DJ, Sorkin JD, Muller DC, Collins VR, Hamman RF. Predictors of progression from impaired glucose tolerance to NIDDM: an analysis of six prospective studies. Diabetes 1997; 46: Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals: does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA 1990; 263: Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, Wiedmever HM, Byrd-Holt DD. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults. The Third National Health and Nutrition Examination Survey, Diabetes Care 1998; 21: Lim S, Tai E, Tan B, Chew S, Tan C. Cardiovascular risk profile in individuals with borderline glycaemia: the effect of the 1997 American Diabetes Association diagnostic criteria and the 1998 World Health Organization Provisional Report. Diabetes Care 2000; 23: