Insulin resistance is higher in prepubertal girls but switches to become higher in boys at age 16: A Cohort Study (EarlyBird 57).

BACKGROUND: The risk of type 2 diabetes is increasing in teenage girls, and is associated with their greater insulin resistance (IR). HYPOTHESIS: We hypothesized that the adverse metabolic profile of girls (compared with boys) would persist from childhood through adolescence. PATIENTS AND METHODS: Community-based longitudinal cohort of 292 children (147 boys) studied annually from 9 to 16 years. MEASURES: IR (homeostasis-model-assessment-2), high-density lipoprotein-cholesterol (HDL-C), triglycerides, % body-fat (dual-energy x-ray absorptiometry), pubertal stage (age at peak height velocity), physical activity (accelerometry). Multi-level modelling established the age-related trends in IR and lipids and the influence of covariates. RESULTS: Each year from 9 to 15 years, girls had 21% to 63% higher IR than boys (girls mean IR 0.73-1.33, boys 0.51-0.89, P < .005). At 16 years the gender difference was not significant (girls IR 0.60, boys 0.56, P = .45). Girls had lower HDL-C from 9 to 12 years, higher triglycerides from 9 to 14 years, greater adiposity throughout, and earlier puberty, but boys were more active than girls (all P < .05). After adjustment for %-fat, puberty and activity, the gender difference in IR between girls and boys aged 9 to 15 years became non-significant (IR girls 0.66-1.01, boys 0.65-1.04, P > .07). However, after adjustment at 16 years, girls' IR was 25% lower than boys' (girls 0.44, boys 0.63, P = .001), and they had 22% higher HDL-C (P < .001) and 20% lower triglycerides (P = .003). CONCLUSIONS: The higher IR of prepubertal and early pubertal girls diminishes during late puberty, and boys begin to exhibit greater metabolic risk. Despite being leaner and more active, boys at 16 years have higher IR than girls, suggesting future higher risk for diabetes, thus we reject our hypothesis.

Physical activity attenuates the mid-adolescent peak in insulin resistance but by late adolescence the effect is lost: a longitudinal study with annual measures from 9-16 years (EarlyBird 66).

AIMS/HYPOTHESIS: The aim of this work was to test whether the mid-adolescent peak in insulin resistance (IR) and trends in other metabolic markers are influenced by long-term exposure to physical activity. METHODS: Physical activity (7 day ActiGraph accelerometry), HOMA-IR and other metabolic markers (glucose, fasting insulin, HbA1c, lipids and BP) were measured annually from age 9 years to 16 years in 300 children (151 boys) from the EarlyBird study in Plymouth, UK. The activity level of each child was characterised, with 95% reliability, by averaging their eight annual physical activity measures. Age-related trends in IR and metabolic health were analysed by multi-level modelling, with physical activity as the exposure measure (categorical and continuous) and body fat percentage (assessed by dual-energy X-ray absorptiometry) and pubertal status (according to age at peak height velocity and Tanner stage) as covariates. RESULTS: The peak in IR at age 12-13 years was 17% lower (p < 0.001) in the more active adolescents independently of body fat percentage and pubertal status. However, this difference diminished progressively over the next 3 years and had disappeared completely by the age of 16 years (e.g. difference was -14% at 14 years, -8% at 15 years and +1% at 16 years; 'physical activity × age(2), interaction, p < 0.01). Triacylglycerol levels in girls (-9.7%, p = 0.05) and diastolic blood pressure in boys (-1.20 mmHg, p = 0.03) tended to be lower throughout adolescence in the more active group. CONCLUSIONS/INTERPRETATION: Our finding that physical activity attenuates IR during mid-adolescence may be clinically important. It remains to be established whether the temporary attenuation in IR during this period has implications for the development of diabetes in adolescence and for future metabolic health generally.

Metabolic risk in contemporary children is unrelated to socio-economic status: longitudinal study of a UK urban population (EarlyBird 42).

Lifestyle interventions to improve health in young children tend to target areas of relative deprivation, but the evidence for so doing is largely historical. Accordingly, we have re-examined the link between deprivation, obesity and metabolic risk in contemporary UK children. Using a postcode-based index of multiple deprivation (IMD), we assessed 269 children from the community-based EarlyBird Study, attending 53 schools representing a wide socio-economic range. Annual measures of fatness from 5 to 8 yr included body mass index (BMI), waist circumference (WC), and sum of five skinfolds (SSF). A metabolic risk score, based on blood pressure, lipids and insulin resistance, was derived from annual fasting blood samples. There were no significant associations between deprivation and any measure of adiposity in girls (all p > 0.37). In boys, there was a weak but consistently inverse relationship between deprivation and WC (r = -0.19, p = 0.03) and BMI (r = -0.14, p = 0.09) at 8 yr. Changes in adiposity over 3 yr were unrelated to deprivation in boys. In girls there was a slight but significant increase in SSF only (1 mm/yr per 20 IMD units, p = 0.001). Importantly, in both genders, metabolic risk score was unrelated to deprivation throughout (r values -0.05 to -0.13, all p > 0.12), as was change in metabolic risk (all p > 0.30). Our data do not support the assumption that obesity, metabolic disturbance and thus risk of type 2 diabetes are more prevalent among poorer children. In today's increasingly obesogenic environment, youngsters from all backgrounds appear to be vulnerable, with population-wide implications for public health spending, and the prevention of diabetes in contemporary youth.

Divergence between HbA1c and fasting glucose through childhood: implications for diagnosis of impaired fasting glucose (Early Bird 52).

OBJECTIVE: An HbA1c threshold of ≥ 6.5% has recently been adopted for the diagnosis of diabetes in adults, and of ≥ 5.7% to identify adults at risk. Little,however, is known of HbA1c's behaviour or diagnostic value in youth. Our aim was to describe the course of HbA1c during childhood, and its association with fasting glucose. RESEARCH DESIGN AND METHODS: HbA1c and glucose were measured every year in a cohort of 326 healthy children (162 boys) from 5 to 15 years. Mixed effects modelling was used to establish the determinants of HbA1c and its development over time. ROC analysis was used to determine the diagnostic value of HbA1c in the 55 individuals who showed impaired fasting glucose(IFG ­ glucose ≥ 5.6 mmol/L). RESULTS: Glucose rose progressively from 4.3 mmol/L at 5 years to 5.1 mmol/Lat 15 years, and although there were positive associations between HbA1c and glucose, from 10 to 13 years, HbA1c fell while glucose continued to rise. IFG developed in 55 children, but HbA1c exceeded 5.7% in only 16 of them. The maximum area under the ROC curve was 0.71 at the age of 14 (p<0.001), and the sensitivity and specificity were optimal at 50 and 80% respectively,corresponding to HbA1c of 5.4%. CONCLUSIONS: Although HbA1c retains a positive association with glucose throughout childhood, it is weak, and their trends diverge from 10 years,suggesting that factors other than glycaemia systematically influence the variance of HbA1c in youth. These findings therefore limit the interpretation of HbA1c for the diagnosis of IFG during childhood.

Evidence of early beta-cell deficiency among children who show impaired fasting glucose: 10-yr cohort study (EarlyBird 56).

OBJECTIVE: Impaired fasting glucose (IFG) is a predictor of future diabetes and is increasingly common in children, but the extent to which it results from excess insulin demand or failure of supply is unclear. Our aim was to compare the behaviour of insulin sensitivity and beta-cell function in children who developed IFG with those whose glucose levels remained within the normal range. METHODS: We examined trends in fasting glucose, insulin sensitivity (HOMA-S) and beta-cell function (HOMA-B) in 327 healthy children annually from 5 to 15 yr, and the parents at baseline. RESULTS: Fifty-five children showed IFG, mostly after age 11 yr. Fasting glucose rose progressively and was higher throughout in those who developed IFG compared with those who did not (p < 0.001). Beta-cell function was lower from the age of 5 yr in those who developed IFG (p = 0.006), but there was no difference in BMI (p = 0.71). A difference in insulin sensitivity was revealed on adjustment for covariates (p = 0.03). Glucose was higher (p < 0.001), beta-cell function lower (p = 0.01), and insulin sensitivity the same (p = 0.86) in the mothers of children who showed IFG, compared with those who did not. CONCLUSIONS: IFG is common in contemporary children, and appears to be related to a defect in beta-cell function already present at 5 yr. Similar findings in the mothers of IFG children suggest that the beta-cell defect may be transmissible.

Consistency of children's dietary choices: annual repeat measures from 5 to 13 years (EarlyBird 49).

The objective of the present study was to explore the consistency of dietary choices made by children as they grow up. The dietary habits of 342 healthy children were reported annually from 5 to 13 years on a forty-five-item FFQ and analysed by factor analysis. The same two principal dietary patterns--'Healthy' and 'Unhealthy'--emerged each year, and their consistency was assessed using Tucker's congruence coefficient (φ). Individual dietary z-scores for both of these patterns were then calculated every year for each child, and their consistency was measured by Pearson's correlation coefficient (r). Linear mixed-effects modelling was used to investigate individual trends and to quantify reliability of the individual dietary z-scores. Dietary patterns were moderately consistent and systematic over time (0·65 ≤ φHealthy ≤ 0·76; 0·62 ≤ φUnhealthy ≤ 0·78). Individual choices were also consistent year-on-year (0·64 ≤ rHealthy ≤ 0·71; 0·57 ≤ rUnhealthy ≤ 0·68). Reliability rose from 70 % with a single measure to over 90 % with four consecutive measures. The quality of diet diminished over time in 29 % of the children and improved in only 14 %. Dietary habits appear to be set early and seldom improve spontaneously.

Distribution of adiponectin, leptin, and metabolic correlates of insulin resistance: a longitudinal study in British children; 1: Prepuberty (EarlyBird 15).

BACKGROUND: The emergence of type 2 diabetes in young populations has mirrored a rising prevalence of obesity and insulin resistance during childhood and adolescence. At the same time, the role of adipokines as links between obesity and insulin resistance is becoming more appreciated. We sought to establish age- and sex-specific distributions of metabolic correlates of insulin resistance in healthy prepubertal children. METHODS: We collected fasting blood samples from a contemporary cohort of 307 British children at ages 5, 6, 7, and 8 years and measured insulin, glucose, triglycerides, total and HDL cholesterol, urate, glycohemoglobin, sex hormone-binding globulin (SHBG), leptin, and adiponectin. We used homeostasis model assessment (HOMA 2) to estimate insulin sensitivity (HOMA-%S) and beta-cell function (HOMA-%B). Anthropometric measures included body mass index. RESULTS: Body mass index increased from age 5 to 8 years (P < 0.001). HOMA-%B decreased (P < 0.001) and HOMA-%S increased (P < 0.05), but glucose also increased (P < 0.001) whereas glycohemoglobin decreased (P < 0.001). Consistent with the rise in insulin sensitivity, HDL cholesterol increased (P < 0.001) and triglycerides decreased (NS), whereas adiponectin decreased (P = 0.02). The patterns were similar in boys and girls, although girls were less insulin sensitive throughout. Accordingly, triglycerides tended to be higher in the girls, and HDL cholesterol and SHBG lower. CONCLUSIONS: The metabolic disturbances associated with insulin resistance appear to be more advanced in girls. Markers of metabolic health improve in both sexes from 5 to 8 years, despite rising adiposity.

Trends, associations and predictions of insulin resistance in prepubertal children (EarlyBird 29).

BACKGROUND: Rising obesity has been observed in all age groups. Anthropometric cut-points have been used to predict metabolic risk in children, although they are not based on known outcomes. AIM: We examined the trends, associations and predictions of metabolic health from anthropometry in prepubertal children. METHOD: Three hundred and seven healthy children were examined annually between 5 and 8 yr. MEASURES: height, weight, body mass index (BMI), sum of skinfold thickness at five sites (SSF) and waist circumference (WC). OUTCOME MEASURES: homeostasis model assessment of insulin resistance (HOMA-IR), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). RESULTS: Two hundred and thirty-one [131 boys (B) and 100 girls (G)] children had complete data sets at all four time points. (i) All measures of adiposity rose from 5 to 8 yr (BMI - B: +3.4%, G: +5.7%; WC - B: +10.4%, G: +11.8%; SSF - B: +23.3%, G: +30.7%, all p < 0.001). HOMA-IR unexpectedly fell (B: -16.6%, p = 0.01; G: -32.5%, p < 0.001). This fall was significant between 5 and 6 yr in both genders (5-6 yr - B: -17.8%, p < 0.001; G: -20.0%, p = 0.002) and between 6 and 7 yr in girls only (6-7 yr - B: -10.8%, p = 0.12; G: -19.2%, p = 0.001). HDL-C rose (B: +17.8%, G: +17.1%, both p < 0.001) and TG fell (B: -4.8%, p = 0.16; G: -11.6%, p = 0.006). (ii) Correlations between insulin resistance (IR) and anthropometry were poor at 5 yr but strengthened by 8 yr (BMI - B: r = 0.20/0.38, G: r = 0.28/0.49; WC - B: r = 0.25/0.40, G: r = 0.32/0.58; SSF - B: r = 0.11/0.36, G: r = 0.18/0.53). (iii) In girls, but not boys, adiposity at 5 yr predicted IR better at 8 yr (BMI - r(2 )= 0.17; WC - r(2 )= 0.28; SSF - r(2 )= 0.17, all p < 0.001) than it did at 5 yr (BMI - r(2 )= 0.08, p < 0.01; WC - r(2 )= 0.10, p < 0.01; SSF - r(2 )= 0.03, p = 0.07). CONCLUSIONS: Cross-sectional association cannot indicate direction of trend or predict the future. Predicting metabolic health from anthropometric measures in prepubertal children requires longitudinal data, tracking variables from childhood into adulthood. Until the data set reaches adulthood, it is probably not safe to make recommendations on which children to 'target' or whether early intervention would be of benefit.

The relative contributions of birth weight, weight change, and current weight to insulin resistance in contemporary 5-year-olds: the EarlyBird Study.

For more than a decade, the fetal programming hypothesis has taught that insulin resistance and its associated metabolic disturbances result from poor gestational environment, for which low birth weight is a surrogate. Low birth weight, however, is now uncommon in industrialized societies. We have investigated the relevance of birth weight, "catch-up" weight, and current weight to insulin resistance in 300 contemporary British children. Insulin resistance at 5 years was not related to birth weight but was correlated with current weight and weight catch-up in both sexes, more strongly so in girls (r = 0.33, P < 0.001 vs. r = 0.18, P = 0.03), who were intrinsically more insulin-resistant than boys. Weight change merely co-correlated with current weight (r = 0.67, P < 0.01 in both sexes) and did not improve on the prediction of insulin resistance. Most important, insulin resistance at 5 years was the same in children of heavier birth weight, whose weight SD score had not changed, as in those of lighter birth weight, matched for current weight, who had experienced so-called catch-up (boys 0.89 and 0.88 units, respectively, P = 0.96; girls 1.26 and 1.13 units, P = 0.41). Insulin resistance in contemporary children seems to be a function of excess current weight rather than of low birth weight or change in weight.

Lack of support for a role of the insulin gene variable number of tandem repeats minisatellite (INS-VNTR) locus in fetal growth or type 2 diabetes-related intermediate traits in United Kingdom populations.

The insulin gene variable number of tandem repeats minisatellite (INS-VNTR) class III allele is associated with altered fetal growth, type 2 diabetes risk (especially when paternally inherited), and insulin and IGF2 gene expression. Further studies are needed to establish the role of the INS-VNTR in fetal growth and assess whether its effects depend on the parent of origin. We analyzed the INS-VNTR-linked -23 Hph1 polymorphism in 2283 subjects, comprising 1184 children and 1099 parents. There were no differences (P < 0.05) in birth weight between offspring of the three genotypes: III/III (n = 108) vs. I/I (n = 558), effect size, -8 g (P = 0.87); and I/III (n = 464) vs. I/I, effect size, -19 g (P = 0.54). We observed no differences in head circumference [III/III (n = 95) vs. I/I (n = 470), effect size, -0.14 cm; P = 0.31] or birth length. No differences were observed when stratifying by postnatal growth realignments [nonchangers III/III (n = 37) vs. I/I (n = 170), effect size, -43 g; P = 1.00] or by parent of origin of the class III allele (presence of paternal III allele effect size, -15 g; P = 0.74). INS-VNTR was nominally associated (P < 0.05) with body mass index and insulin resistance, but not with beta-cell function, in young adults. In the largest study to date, we found a lack of support for a role for INS-VNTR in fetal growth and nominal association with type 2 diabetes-related intermediate traits.

Sex differences in resting energy expenditure and their relation to insulin resistance in children (EarlyBird 13).

BACKGROUND: Insulin resistance is believed to be the process underlying type 2 diabetes and premature cardiovascular disease. We have established that a relation between body mass and insulin resistance calculated by homeostasis model assessment (HOMA-IR) exists by 5 y of age in contemporary UK children. Resting energy expenditure (REE) is variable among individuals and is one of many factors controlling body mass. OBJECTIVE: The objective was to investigate the relations between REE, body mass, and HOMA-IR in young children. DESIGN: EarlyBird is a nonintervention prospective cohort study of 307 healthy 5-y-olds that asks the question: Which children develop insulin resistance and why? REE by indirect calorimetry and HOMA-IR were measured in addition to total body mass, fat-free mass (FFM) by bioimpedance, body mass index (BMI; in kg/m(2)), and skinfold thickness when the mean age of the cohort was 5.9 +/- 0.2 y. RESULTS: Whereas the BMI of the boys was lower than that of the girls (x +/- SD: boys, 15.9 +/- 1.9; girls, 16.5 +/- 1.9; P = 0.03), their REE was higher by 6% (x +/- SD: 4724 +/- 615 compared with 4469 +/- 531 kJ/d; P = 0.002). This difference persisted after adjustment for FFM and other anthropometric variables (P = 0.04). In boys, there was a weak, although significant, inverse correlation between REE and HOMA-IR, independent of fat mass and FFM (boys: r = -0.21, P = 0.03; girls: r = 0.12, P = 0.34). CONCLUSION: There is a sex difference in REE at 6 y of age that cannot be explained by body composition. The difference appears to be intrinsic, and its contribution to sex differences in adiposity and HOMA-IR in children merits further exploration.

The psychosocial consequences of short stature: a review of the evidence.

The advent of biosynthetic growth hormone (GH) has been accompanied by a transformation in the clinical management of youths with short stature. An important--if not always explicitly stated--goal of endocrine therapies is an improvement in the psychological adaptation of individuals with short stature. Negative stereotypes regarding short stature constitute a potential source of psychosocial stress for the affected child and, in turn, the entire family. Nevertheless, studies have demonstrated that the psychological adaptation of individuals who are shorter than average is largely indistinguishable from others, whether in childhood, adolescence or adulthood. "Short stature" as an isolated physical characteristic appears to hold little value as a predictor of the individual's psychological adaptation or quality of life. In order to avoid the unwarranted medicalizing of healthy short stature, clinicians would be well advised to incorporate factors beyond auxology in the decision-making algorithm when selecting and preparing patients for possible growth-promoting therapies.

The psychological burden of short stature: evidence against.

Short stature, per se, is clearly not a disease, but is commonly perceived to be associated with social and psychological disadvantage. The assumption, widely held by pediatricians that short children are likely to be significantly affected by their stature, has been founded largely on older, poorly designed clinic-based studies and laboratory investigations of beliefs about the association between stature and individual characteristics. In contrast, data from more recent and better designed clinic- and community-based studies show that, in terms of psychosocial functioning, individuals with short stature are largely indistinguishable from their peers, whether in childhood, adolescence or adulthood. Parents and children alike should be reassured by these findings. In the absence of clear pathology, physical or psychological, GH therapy for the short but otherwise normal child raises ethical concerns about so-called 'cosmetic endocrinology'.

Technical reliability of the CSA activity monitor: The EarlyBird Study.

PURPOSE: To evaluate the technical performance of the CSA accelerometer-based activity monitor. METHODS: Twenty-three CSA monitors were subjected to intra- and inter-instrument variability tests by controlled trials using a motorized turntable. The CSA monitor measures change in acceleration, and precision was tested by producing sinusoidal variations in speed around two fixed baseline speeds (fast and medium). The angle of the monitor to the line of force along the radius of the turntable was varied using tilted blocks. Three sets of tests were carried out. 1. Intra-instrument variability: seven monitors were tested three times in each of the four quadrants. 2. All 23 monitors were used for inter-instrument tests. 3. The effects of tilt at 15 degrees, 30 degrees, and 45 degrees were carried out on six monitors. RESULTS: Intra-instrument coefficients of variation (CV) never exceeded 2% for fast or medium speed and achieved "between run" intra-class correlation coefficients (ICC) of 0.92 and 0.84 respectively. There were no significant differences between the monitors in terms of repeatability (fast: = 0.97, medium: = 0.77). Although there were significant differences between monitors in terms of mean score, inter-instrument variability did not exceed 5% at either speed. Inter-batch ICCs ranged from 0.87 to 0.98 for fast and from 0.71 to 0.99 for medium. The angle test results corresponded closely to those predicted theoretically, with a loss in mean score of only 6% when the monitor was tilted from 0 degrees to 15 degrees. CONCLUSION: The CSA monitor provides a precise tool for measuring changes in acceleration in laboratory settings. Technically, the device performs well, and is likely to prove a useful tool in the assessment of physical activity in children and adults.

Preventable factors in childhood that lead to insulin resistance, diabetes mellitus and the metabolic syndrome: the EarlyBird diabetes study 1.

For a decade or more, poor nutrition during gestation, expressed as low weight at birth, was held to be the factor responsible for insulin resistance later in life. Birth weights, however, are rising and insulin resistant states, such as diabetes mellitus, faster still. Alternative explanations are needed to explain insulin resistance in contemporary industrialised populations. EarlyBird is a non-intervention prospective cohort study that asks the question 'Which children develop insulin resistance, and why?' It is unique in taking serial blood samples from a young age with which to monitor the behaviour of insulin resistance and its metabolic correlates. This, the baseline report of the EarlyBird Study, describes the rationale, design and methodology of the study, and the profile of the population at entry. It situates the anthropometric, physical activity and dietary status of the EarlyBird children and provides a detailed metabolic profile of the British 5 year-old in the year 2000.

The impact of pregnancy weight and glucose on the metabolic health of mother and child in the south west of the UK.

OBJECTIVE: to explore relationships between maternal pre-pregnancy weight, third trimester glucose, baby birth weight, weight and metabolic health of the mother and child 5 years after birth. DESIGN: an observational study set within a non-intervention, longitudinal cohort study looking at insulin resistance in children. SETTING: a teaching hospital in the south west of the United Kingdom. PARTICIPANTS: 300 mothers and their five-year-old children from randomly selected Plymouth schools, stratified according to socioeconomic status. MEASUREMENTS: were obtained from obstetric records maternal pre-pregnant weight, random and fasting third trimester blood glucose, baby birth weight. Five years later the following measurements were made of the mother and child: height, weight, glucose and insulin resistance. FINDINGS: five years after the pregnancy, 33% of the mothers were overweight, with an additional 19% obese. In the children 13% of boys were overweight (4% obese), and in the girls, 26% were overweight (5% obese). In the five-year-old children, weight (r=0.28, p<0.001) but not birth weight (r=0.03, p=0.573), correlated with insulin resistance. Maternal pre-pregnant weight was related to both random and fasting third trimester glucose, and to insulin resistance 5 years later. Third trimester fasting glucose, even within a normal range, was a better predictor than random glucose of the baby's birth weight (r=0.39, p=0.044) and the mother's future insulin resistance (r=0.67, p<0.001). No maternal measures predicted insulin resistance in the child at 5 years. CONCLUSIONS: maternal weight had an important influence on the gestational environment, and predicted insulin resistance 5 years later. Fasting glucose, even within the reference range, was a better predictor than random glucose of the baby's birth weight and the mother's future insulin resistance. IMPLICATIONS FOR PRACTICE: these concern the importance of pre-conception weight management, and support replacement of routine random glucose sampling during the third trimester with an earlier, fasting measurement.

PGC1α promoter methylation in blood at 5-7 years predicts adiposity from 9 to 14 years (EarlyBird 50).

The early environment, acting via epigenetic processes, is associated with differential risk of cardiometabolic disease (CMD), which can be predicted by epigenetic marks in proxy tissues. However, such measurements at time points disparate from the health outcome or the environmental exposure may be confounded by intervening stochastic and environmental variation. To address this, we analyzed DNA methylation in the peroxisome proliferator-activated receptor γ coactivator 1α promoter in blood from 40 children (20 boys) collected annually between 5 and 14 years of age by pyrosequencing. Body composition was measured annually by dual X-ray absorptiometry, physical activity by accelerometry, and pubertal timing by age at peak high velocity. The effect of methylation on transcription factor binding was investigated by electrophoretic mobility shift assays. Seven cytosine guanine dinucleotide (CpG) loci were identified that showed no significant temporal change or association with leukocyte populations. Modeling using generalized estimating equations showed that methylation of four loci predicted adiposity up to 14 years independent of sex, age, pubertal timing, and activity. Methylation of one predictive locus modified binding of the proadipogenic pre-B-cell leukemia homeobox-1/homeobox 9 complex. These findings suggest that temporally stable CpG loci measured in childhood may have utility in predicting CMD risk.

Age before stage: insulin resistance rises before the onset of puberty: a 9-year longitudinal study (EarlyBird 26).

OBJECTIVE: Insulin resistance (IR) is associated with diabetes. IR is higher during puberty in both sexes, with some studies showing the increase to be independent of changes in adiposity. Few longitudinal studies have reported on children, and it remains unclear when the rise in IR that is often attributed to puberty really begins. We sought to establish from longitudinal data its relationship to pubertal onset, and interactions with age, sex, adiposity, and IGF-1. RESEARCH DESIGN AND METHODS: The EarlyBird Diabetes study is a longitudinal prospective cohort study of healthy children aged 5-14 years. Homeostasis model assessment (HOMA-IR), skinfolds (SSF), adiposity (percent fat, measured by dual-energy X-ray absorptiometry), serum leptin, and IGF-1 were measured annually in 235 children (134 boys). Pubertal onset was adduced from Tanner stage (TS) and from the age at which luteinizing hormone (LH) first became serially detectable (≥0.2 international units/L). RESULTS: IR rose progressively from age 7 years, 3-4 years before TS2 was reached or LH became detectable. Rising adiposity and IGF-1 together explained 34% of the variance in IR in boys and 35% in girls (both P < 0.001) over the 3 years preceding pubertal onset. The contribution of IGF-1 to IR was greater in boys, despite their comparatively lower IGF-1 levels. CONCLUSIONS: IR starts to rise in mid-childhood, some years before puberty. Its emergence relates more to the age of the child than to pubertal onset. More than 60% of the variation in IR prior to puberty was unexplained. The demography of childhood diabetes is changing, and prepubertal IR may be important.

Direction of causality between body fat and insulin resistance in children--a longitudinal study (EarlyBird 51).

OBJECTIVE: To investigate the direction of causality in the association between adiposity and insulin resistance in children. METHODS: Body composition by DEXA, and insulin resistance by HOMA-2 IR were measured annually in 238 children aged from 7-13 years. Longitudinal modelling was used to establish whether baseline and/or trends in adiposity were associated with change in IR or whether, conversely, baseline and/or trends in IR were associated with change in adiposity. RESULTS: Baseline adiposity was associated with change in IR in the short-term (p < 0.001) but less so in the long-term (p < 0.09) in both genders. Baseline IR was not associated with short-term change in adiposity in either gender (p > 0.42). In the long-term, baseline IR appeared to be positively associated with change in adiposity in boys (p = 0.02) but inversely associated with change in adiposity (the higher the baseline IR, the lower the gain in %fat) in girls (p < 0.001). CONCLUSIONS: The dominant direction of causality appears to be from adiposity to insulin resistance. In boys, adiposity appears to be both a cause and an effect of IR in the long term. In girls, however, higher insulin resistance appeared to limit further gain in body fat in the long term, an observation consistent with insulin desensitization as an adaptive response to weight gain.