Objective: To evaluate the dependence of body mass index (BMI) values on pubertal stage in subjects similar in age. Design, subjects and measurements: Height and weight were recorded cross-sectionally in school subjects from three provinces in central Italy. The subjects were subdivided into three groups: (1) 4271 school subjects (2125 males and 2146 females; 8.5 ± 15.5 y old), in whom the pubertal development was also recorded, were selected to subdivide BMI values according to pubertal stage and age; (2) 6345 females (10.5 ± 14.5 y old), who were asked whether or not they had had their ®rst menstrual period, were selected to subdivide BMI values according to age in pre-menarche and post-menarche girls, separately; and (3) 1919 females (10.5 ± 14.5 y old), who had presented their menarche within the previous 6 months, were selected to subdivide short-term postmenarche BMI values according to age. Results: The medians and interquartile ranges of BMI varied according to age and pubertal stage. Kruskall ± Wallis test performed in subjects similar in age demonstrated that signi®cant differences existed among the medians of BMI values of subjects at different pubertal stages in 12 ± 14-y-old males (P`0.05), and in 11 ± 14-yold females (P`0.001). The difference also proved to be signi®cant between stage I and stage II (P`0.05) in 10-y-old females, but not in 10 ± 11-y-old males. The Kruskal ± Wallis test performed in subjects similar in pubertal stage demonstrated that signi®cant differences among the medians of BMI at different ages existed only in females at stages II and III. A signi®cant positive trend was observed in both genders according to pubertal stage for BMI values of subjects similar in age (z-test for trend, P`0.01). On the contrary, a negative age trend proved to be signi®cant in females at stages I (P`0.01), II (P`0.01) and III (P`0.001), but not in males when the subdivision of BMI was made according to age in subjects similar in pubertal stage. BMI values were signi®cantly higher in post-menarche girls as compared to pre-menarche girls similar in age (P`0.001). However, at partial regression analysis BMI values were in¯uenced by pubertal stage and, to a lesser extent, by age, but not by menarcheal status. An inverse association between short-term post-menarche BMI and age was observed, with the highest values in girls presenting menarche at 11 y of age (P`0.05). The negative trend was demonstrated at the z-test for trend (P`0.001). Conclusions: BMI values depend on pubertal degree of maturation, especially in girls. This in¯uence should be taken into account when BMI is evaluated in adolescents.

The polymorphism of the major histocompatibility complex class I chain-related A gene is associated with type 1 diabetes mellitus. The major histocompatibility complex class I chain-related A gene 5 allele is significantly more frequent in Caucasian type 1 diabetes mellitus children than in healthy subjects, but no information is available on the association with adult-onset type 1 diabetes mellitus or with the so-called slowly progressive latent autoimmune diabetes of the adult in the same ethnic group. In this study we estimated the frequency of major histocompatibility complex class I chain- related A gene alleles and human leukocyte antigen-DRB1*03-DQA1*0501-DQB1*0201 and human leukocyte antigen-DRB1*04- DQA1*0301-DQB1*0302 in 195 type 1 diabetes mellitus subjects, in 80 latent autoimmune diabetes of the adult subjects, and in 158 healthy subjects from central Italy. Major histocompatibility complex class I chain-related A gene 5 was significantly associated with type 1 diabetes mellitus only in the 1-25 yr age group at diagnosis, and the odds ratio of the simultaneous presence of both major histocompatibility complex class I chain-related A gene 5 and human leukocyte antigen-DRB1*03- DQA1*0501-DQB1*0201 and/or human leukocyte antigen-DRB1*04-DQA1*0301-DQB1*0302 was as high as 54 and higher than 388 when compared with double negative individuals. Adult-onset type 1 diabetes mellitus (age at diagnosis, >25 yr) and latent autoimmune diabetes of the adult were significantly associated with major histocompatibility complex class I chain-related A gene 5.1, which was not significantly increased among diabetic children. Only the combination of major histocompatibility complex class I chain-related A gene 5.1 and human leukocyte antigen-DRB1*03-DQA1*0501-DQB1*0201 and/or human leukocyte antigen-DRB1*04-DQA1*0301-DQB1*0302 conferred increased risk for adult-onset type 1 diabetes mellitus or for latent autoimmune diabetes of the adult. Our study provides demonstration of the existence of distinct genetic markers for childhood/young-onset type 1 diabetes mellitus and for adult-onset type 1 diabetes mellitus/latent autoimmune diabetes of the adult, namely major histocompatibility complex class I chain-related A gene 5 and major histocompatibility complex class I chain-related A gene 5.1, respectively.

Whether genetic susceptibility for insulin-dependent diabetes mellitus (IDDM) at the 5' insulin gene polymorphic region (5' INS) interacts with human leukocyte antigen (HLA)-DQ-linked disease risk and whether it is associated with autoantibody formation is presently controversial. Diabetes registries allow more systematic reassessment of these questions. Two hundred and ninety-six Caucasian IDDM patients were recruited by the Belgian Diabetes Registry and sampled at disease onset, together with 195 ethnically matched control subjects. 5'INS genotypes were determined by Southern blotting, HLA-DQ by allele-specific oligotyping, and autoantibodies by validated immunoassays. The 5' INS 1/1 genotype was more prevalent in patients than in controls [relative risk (RR) = 2.3; P < 10(-4)]. Regardless of age at onset, the 5' INS 1/1 genotype occurred less frequently in patients with the high-risk genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 than in patients without it (P < 0.04). The RR associated with this high-risk HLA-DQ genotype (24.9; P < 10(-6)) was not affected by the presence or absence of the 5' INS 1/1 genotype. Combined positivity for the 5' INS 1/1 genotype and for one of three other HLA-DQ genotypes associated with an intermediate risk for IDDM conferred an age-independent RR of 12.1 (P < 10(-4)). In the absence of the 5' INS 1/1 genotype, intermediate-risk HLA-DQ genotypes no longer conferred a significant risk (2.9; not significantly different from 1). In subjects carrying neutral, protective, or infrequent HLA-DQ genotypes, the overall RR for IDDM was significantly lower than 1 (0.2; P < 10(-6)) in the absence of the 5' INS 1/1 genotype but not in its presence (0.8; not significantly different from 1). The 5' INS 1/1 genotype was not preferentially associated with immune markers for IDDM. In conclusion, regardless of age at onset and the presence of autoantibodies, 5' INS polymorphisms contribute preferentially to IDDM susceptibility in subjects without the highest HLA-DQ-associated risk.

OBJECTIVE: Leptin, the product of the ob gene, is present in higher concentrations in blood of obese subjects than of lean subjects. There is scarce information on the role of leptin in the pathogenesis of human obesity and little is known about leptin serum levels in obese children. DESIGN, SUBJECTS AND MEASUREMENTS: To evaluate the in¯uences of age, sex, pubertal development and weight excess on serum leptin levels, we have studied 390 obese subjects (OS) and 320 normal weight subjects (NWS) aged 5±16 y. Fasting insulin concentrations were assayed in NWS, and an oral glucose tolerance test was carried out in OS and total insulin area under the curve (TIA) was calculated. RESULTS: Log-transformed values of leptin serum concentrations appeared to be distributed according to an acceptable Gaussian pattern. As observed in adults, serum leptin concentrations in children and adolescents were also increased (4±5 times) in OS as compared to NWS. In both males and females, subdivided according to pubertal stages, serum leptin varied signi®cantly in stage IV±V as compared to the lower stages, with a reduction in males and an increase in females. On comparing the two sexes, greater serum leptin concentrations were observed in females of both NWS and OS. A signi®cant linear correlation was found in both groups, subdivided according to sex and pubertal stage, between log values of serum leptin and standard deviation scores (SDS) of body mass index (BMI), and logtransformed relative body weight (RBW). Using partial correlation analysis in subjects subdivided according to sex and pubertal stages, log values of serum leptin and fasting insulin values, adjusted by age and SDS of BMI, correlated signi®cantly with a weaker correlation in males than in females. In OS, the leptin concentrations correlated better with TIA than with fasting insulin. A weight reduction program (WRP) was carried out in 141 OS and signi®cant reductions of serum leptin and fasting insulin were observed, showing a reduction of RBW. There was a correlation between the reduction of RBW and of serum leptin, but not of fasting insulin. No variation was found in non-responsive OS. RBW reduction correlated with leptin, but not with insulin (fasting and TIA), evaluated before the therapeutic program started. CONCLUSION: As observed in adults, obese children and adolescents have higher serum leptin concentrations. However, several conditions should be taken into account when evaluating leptin concentrations in children. There are differences, independent of BMI, relative to pubertal stage and sex, females having greater leptin concentrations than males. There is evidence of a possible role for leptin in the effectiveness of a weight reduction program in OS.

Objectives: (a) to explore the relationship between waist circumference and certain cardiovascular risk factors in a group of girls; and (b) to assess the clinical relevance of waist circumference in identifying girls with higher cardiovascular risk across puberty. Subjects and methods: One-hundred and fifty-five overweight or obese girls aged 5 -16 y were recruited. Overweight and obesity were defined on the basis of BMI, according to Cole. Results: Waist circumference was significantly correlated with plasma insulin (r ¼ 0.43; P < 0.001), systolic blood pressure (r ¼ 0.22; P ¼ 0.007) and IR HOMA (r ¼ 0.40; P < 0.001). A multivariate linear correlation analysis showed that, when adjusted for age and Tanner stage, waist circumference was significantly associated with plasma insulin (r 2 ¼ 0.23; P < 0.01), IR HOMA (r 2 ¼ 0.17; P < 0.02), systolic and diastolic blood pressure (r 2 ¼ 0.20; P ¼ 0.006 and r 2 ¼ 0.32; P < 0.001, respectively). A logistic regression analysis, using IR HOMA as the dependent variable, showed that waist circumference was a significant independent risk factor of insulin resistance (IR HOMA 5 2.6) in this group of girls (OR 1.10; 95% CI 1.03 -1.18; P ¼ 0.003), independently of their age and Tanner stage. Conclusions: Waist circumference of these girls was independently associated with certain cardiovascular risk factors, in particular insulin resistance and diastolic blood pressure, independently of age and Tanner stage. Thus suggesting that waist circumference may be reasonably included in clinical practice as a simple tool that may help to identify sub-groups of obese girls at higher metabolic risk across puberty.