Early Pubertal Children Research Articles

Cognitive and Motor Capacities Are Poorly Correlated with Agility in Early Pubertal Children: Gender-Stratified Analysis

This research aimed to identify relations of cognitive and power capacities with reactive agility in pubescent boys (n = 55) and girls (n = 46). Cognitive abilities were evaluated by the Stroop test, while the BlazePod system was used to evaluate agility performance conducting 20 yard shuttle and triangle tests of non-reactive (TCODS) and reactive agility (TRAG), respectively. Performance in jumping power was assessed through the squat jump (SJ), countermovement jump (CMJ), and drop jump (DHJ) utilising the Opto Jump system (Microgate, Bolzano, Italy), while sprinting ability over distances of 10 and 20 m was measured using a photocells system. A principal component was extracted from the four Stroop test variables using factor analysis. Forward stepwise multiple regression analysis was conducted separately for boys and girls to evaluate the multivariate relationships among the predictors and the criterion. Among boys, 80% of the TRAG variance was explained (MultipleR = 0.9), with TCODS and SJ as significant predictors (β = 0.53 and −1.01, respectively). For girls, the TCODS was the significant predictor (β = 0.65), explaining 43% of the variance (MultipleR = 0.65). These results show that (i) cognitive abilities measured with the Stroop test were not a reliable tool for predicting TRAG, (ii) jumping power was a significant predictor of TRAG in boys, and (iii) TCODS was a significant predictor of TRAG in girls. The findings indicated that cognitive abilities do not significantly influence reactive agility in pubescent children. It seems that power features have a greater influence on reactive agility, particularly in boys who have more developed motor skills at this age compared to girls.

Gut microbiota and child behavior in early puberty: does child sex play a role?

ABSTRACT A growing number of studies have indicated relations between the gut microbiota and mental health. However, to date, there is a scarcity of microbiota studies in community samples in early puberty. The current preregistered study (https://osf.io/wu2vt) investigated gut microbiota composition in relation to sex in low-risk children and explored behavioral associations with gut microbiota composition and metabolites in the same samples, together with the potential role of sex. Fecal microbiota composition was analyzed in 12-year-old children (N = 137) by 16S rRNA gene sequencing and quantitative PCR. Modest sex differences were observed in beta diversity. Generalized linear models showed consistent behavioral relations to both relative and absolute abundances of individual taxa, including positive associations between Parasutterella and mother-reported internalizing behavior, and negative associations between Odoribacter and mother-reported externalizing behavior. Additionally, Prevotella 9 was positively related to mother-reported externalizing behavior, confirming earlier findings on the same cohort at 5 years of age. Sex-related differences were found in behavioral relations to Ruminiclostridium 5, Alistipes, Streptococcus, Ruminiclostridium 9, Ruminococcaceae UCG-5, and Dialister, for relative abundances, as well as to Family XIII AD3011 group and an unidentified bacterium within the Tenericutes, for absolute abundances. Limited behavioral relations were observed regarding alpha diversity and fecal metabolites. Our findings describe links between the gut microbiota and child behavior, together with differences between child sexes in these relations, in low-risk early pubertal children. Importantly, this study confirmed earlier findings in this cohort of positive relations between Prevotella 9 and externalizing behavior at age 10 years. Results also show the merit of including absolute abundances in microbiota studies.

Catabolism of fats and branched-chain amino acids in children with Type 1 diabetes: Association with glycaemic control and total daily insulin dose.

Hyperglycaemia in Type 1 diabetes (T1D) results from an absolute insulin deficiency. However, insulin resistance (IR) may exacerbate glycaemic instability in T1D and contribute to long-term cardiovascular complications. We previously showed that IR in teenagers with obesity is associated with sex-dependent derangements in the catabolism of branched-chain amino acids (BCAA) and fatty acids. Here we hypothesized that byproducts of BCAA and fatty acid metabolism may serve as biomarkers or determinants of glycaemic control and IR in prepubertal or early pubertal children with T1D. Metabolites, hormones and cytokines from fasting blood samples were analysed in 28 children (15 females, 13 males; age 6-11 years) with T1D. Principal components analysis (PCA) and multiple linear regression models were used to correlate metabolites of interest with glycaemic control, total daily insulin dose (TDD, units/kg/d), adiponectin and the triglyceride (TG) to high-density lipoprotein (HDL) ratio. Males and females were comparable in age, BMI-z, insulin sensitivity, glycaemic control, inflammatory markers, BCAAs and C2/C3/C5-acylcarnitines. The majority of components retained in PCA were related to fatty acid oxidation (FAO) and BCAA catabolism. HbA1c correlated positively with Factor 2 (acylcarnitines, incomplete FAO) and Factor 9 (fasting glucose). TDD correlated negatively with C3 and C5 and Factor 10 (BCAA catabolism) and positively with the ratio of C2 to C3 + C5 and Factor 9 (fasting glucose). These findings suggest that glucose intolerance in prepubertal or early pubertal children with T1D is accompanied by incomplete FAO while TDD is associated with preferential catabolism of fats relative to amino acids.

Comparison of Commonly Used Methods to Predict the Final Height in Constitutional Tall Stature

To determine the accuracy of adult height prediction in children with constitutional tall stature. The medical records of 138 non-syndromatic prepubertal and early pubertal children (52 male, 86 female) with a height of ≥90th percentile born between the years 1975 and 1988 were included in this study. Using the Bayley-Pinneau (BP) and Tanner-Whitehouse I (TWI) prediction methods, their height standard deviation score (SDS) at referral was compared with their height SDS at age 17 years when measured at the IDF conscription center. While remaining tall, the height SDS at age 17 years was lower than that at referral decreasing from 2.13±1 to 1.65±1.21 in boys and from 2.48±1 to 2.15±1 in girls. The prediction by the BP and TWI methods can be useful for estimating adult height in constitutional tall stature even in the prepubertal and early pubertal period. However, the fallibility of these methods should be kept in mind during clinical practice. We think that this study will shed light on these issues.

Long-Term Outcomes With Adalimumab Therapy in Pediatric Crohn Disease: Associations With Adalimumab Exposure.

Pediatric Crohn disease (CD) treatment goals have evolved. Among children receiving adalimumab (ADA) we examined long-term durability of clinical remission, linear growth, and associations of trough concentration (TC) with biomarker, endoscopic and imaging outcomes. Single-center retrospective study. Pediatric CD activity index, C-reactive protein, fecal calprotectin, and height measured longitudinally. Discontinuation due to secondary loss of response (LOR) was assessed using Cox proportional hazards model. Associations between TC and clinical and biomarker remission, endoscopic and magnetic resonance imaging (MRI) improvements were assessed using Cox regression with time-dependent covariates. Between January 2007 and June 2018, 213 children (median age 14.1 years (interquartile range [IQR] 12.5-15.7) 65% males) initiated ADA. One hundred and seventy-four (82%) achieved clinical remission (PCDAI < 10). During 24.8 (IQR 15.6-38.4) months follow-up, 26 (15%) discontinued ADA due to LOR, and 10 (6%) due to adverse events. Being anti-tumor necrosis factor (TNF) naïve and inflammatory behavior associated with increased likelihood of clinical remission (odds ratio [OR] 2.39, P = 0.033, and 3.13, P = 0.013, respectively) and with decreased LOR (hazard ratio [HR] 0.3, P = 0.002, and HR 0.35, P = 0.01, respectively). Cumulative LOR among 135 anti-TNF naïve patients: 0%, 8%, 15% within 1, 2, 3 years, similarly durable with mono- and immunomodulator combination therapy. Among pre-/early pubertal children mean height (-0.82) normalized to -0.07. TC consistently >7.5 ug/mL was associated with durable clinical remission (HR = 17.24, P < 0.001); TC >10 ug/mL with durable biomarker remission (HR = 6.56, P < 0.001) and endoscopic (OR 10.4, P = 0.002) and MRI (OR 7.6, P = 0.001) improvements. ADA monotherapy maintains durable clinical remission. Biomarker remission, mucosal and transmural improvements were associated with greater ADA exposure.

Genetic risk score prediction of leg fat and insulin sensitivity differs by race/ethnicity in early pubertal children.

In the United States, the underlying reasons for racial/ethnic disparities in type 2 diabetes risk remain unclear. However, differences in genetic risk for insulin resistance and peripheral adipose tissue distribution may be contributing factors. To investigate racial/ethnic differences in associations of genetic risk for insulin resistance with leg fat and insulin sensitivity in a cohort of American children. Participants were healthy European-American (n=83), African-American (n=79) and Hispanic-American (n=74) children aged 7-12 years. Genetic risk scores were derived from published variants associated with insulin resistance phenotypes in European adults. Body composition was assessed using dual-energy X-ray absorptiometry. Insulin sensitivity was determined from the frequently sampled intravenous glucose tolerance test and minimal modelling. Statistical models were adjusted for age, sex, pubertal stage and body composition. In the combined cohort, risk score was inversely associated with insulin sensitivity (p=0.033) but not leg fat (p=0.170). Within Hispanic Americans, risk score was inversely associated with insulin sensitivity (p=0.027) and leg fat (p=0.005), while associations were non-significant in European and African Americans (p > 0.200). The higher type 2 diabetes risk observed among Hispanic Americans may have a genetic basis related to an inability to store lipid in peripheral adipose tissue.

The Effect of Growth Hormone Treatment on Physical Performance Indices in Children With Idiopathic Short Stature.

To examine the effect of growth hormone (GH) treatment on physical performance in children with idiopathic short stature and normal GH secretion. A total of 24 children participated in the study (13 GH-treated, 11 non-treated, aged 8-13y, 11 males and 13 females, Tanner stage 1-2). Participants performed a battery of motor skill performance tests (Eurofit), as well as the Wingate anaerobic test. No statistically significant differences in any of the Eurofit physical fitness test results (eg,20-m shuttle run 33.0 [15.1] vs 25.1 [21.0] laps in treated and nontreated participants, respectively, P = .25) or the Wingate anaerobic test were found between the groups (eg,peak power 5.0 [2.9] vs 3.9 [2.6]watts/kg in treated and nontreated participants, respectively, P = .2). Therapeutic usage of exogenous GH for pre and early pubertal children with idiopathic short stature and normal GH secretion was not associated with beneficial effects on physical performance indices. This suggests that the use of GH as a potential performance enhancing agent, in this age group, at least at commonly used doses, is not advantageous.

Substrate Oxidation Is Altered by Obesity During Submaximal Cycling in Prepubertal and Early Pubertal Children: A Quality Study.

To examine substrate oxidation in prepubertal and early pubertal children as a function of body weight, body composition, and sex during an exhaustive cycling test. This study included 320 children in prepubertal and early puberty (Tanner stage 1 or 2; n = 188 males) who completed a minimum of 4 stages (2-5min/stage) of an adapted version of the McMaster exhaustive exercise protocol on an upright cycle ergometer. Substrate utilization, relative to individual VO2peak, was determined using VO2 and VCO2 data, obtained with breath-by-breath gas analysis during exercise. Both peak (mg/kg lean body mass·min) and submaximal lipid oxidation (mg/kg lean body mass·min) were highest (P < .01) in children with healthy weight (HW), then overweight, and lowest in obese (OB). Both females with HW (compared with males with HW) and females with OB (compared with males with OB) had higher (P < .01) peak and submaximal lipid oxidation. In children with OB, fat-free mass correlated positively (P < .01) with submaximal lipid oxidation (r = .50). In contrast, in children with HW and overweight, fat-free mass correlated positively (P < .01) with carbohydrate oxidation (r = .52 and r = .47, respectively). Obesity during childhood may alter substrate oxidation during exercise. These results may have implications in the implementation of exercise programs in prepubertal or early puberty to control adiposity.

1651-P: Low Leg Fat and Ethnicity Are Predictors for Genetic Insulin Resistance in a Multiethnic Sample of Early Pubertal Children

In the United States, Hispanic- and African-Americans (HA and AA, respectively) have been shown to have a higher prevalence of type 2 diabetes than their European-American (EA) counterparts. A recent genome-wide association study revealed that genetic variants linked to insulin resistance (IR) phenotypes were associated with lower levels of leg fat mass. We investigated whether leg fat deposition and genetic risk for IR differed by ethnicity in a cross-sectional study of 82 AA, 75 HA, and 83 EA children aged 7-12 years. Participants were genotyped with the Metabochip array for 46 single nucleotide polymorphisms (SNPs) associated with IR, and a genetic risk score (GRS) was developed using the weighted sum of the risk alleles. An intravenous glucose tolerance test and minimal modeling were used to derive the insulin sensitivity index (SI), while body composition was measured by DXA. Multiple linear regression was used to compare differences among ethnicity after adjustment for sex, age, Tanner stage, and socioeconomic status. Leg fat models were also adjusted for total body fat and BMI percentile, while SI models were adjusted for adiposity. Mean leg fat deposition relative to total body fat was significantly lower in HA compared to EA and AA (P &amp;lt; 0.001 for both comparisons). Additionally, GRS independently predicted both leg fat (β = -0.34 (0.13), P = 0.012) and SI (β = -1.33 (0.59), P = 0.027) in HA. In contrast, GRS was not an independent predictor of either outcome in AA or EA. These results suggest that HA may have a genetically impaired ability to store lipid in peripheral adipose tissue depots, consequently leading to deposition in ectopic regions and IR. Our findings highlight a potential mechanism contributing to the higher rate of type 2 diabetes observed in Hispanic-American populations. Disclosure L.A. Fowler: None. J.R. Fernandez: None. B. Gower: None. Funding National Institutes of Health (R01DK067426); National Center for Research Resources (M01RR000032); University of Alabama at Birmingham Nutrition Obesity Research Center (P30DK056336, T32DK062710); University of Alabama at Birmingham Diabetes Research Center (P60DK079626)

Effects of metformin administration on endocrine-metabolic parameters, visceral adiposity and cardiovascular risk factors in children with obesity and risk markers for metabolic syndrome: A pilot study.

BackgroundMetformin treatment (1000–2000 mg/day) over 6 months in pubertal children and/or adolescents with obesity and hyperinsulinism is associated with a reduction in body mass index (BMI) and the insulin resistance index (HOMA-IR). We aimed to ascertain if long-term treatment (24 months) with lower doses of metformin (850 mg/day) normalizes the endocrine-metabolic abnormalities, improves body composition, and reduces the carotid intima-media thickness (cIMT) in pre-puberal and early pubertal children with obesity.MethodsA pilot double-blind, placebo-controlled trial was conducted on 18 pre-puberal and early pubertal (Tanner stage I-II) children with obesity and risk markers for metabolic syndrome. Patients were randomly assigned (1:1) to receive metformin (850 mg/day) or placebo for 24 months. Clinical, biochemical (insulin, lipids, leptin, and high-sensitivity C-reactive protein [hsCRP]), and imaging (body composition [dual-energy X-ray absorptiometry and magnetic resonance imaging]) parameters as well as cIMT (ultrasonography) were assessed at baseline and at 6, 12, and 24 months.ResultsThe 12-month treatment tend to cause a reduction in weight standard deviation scores (SDS), BMI-SDS, leptin, leptin–to–high-molecular-weight (HMW) adiponectin ratio, hsCRP, cIMT, fat mass, and liver fat in metformin-treated children compared with placebo. The effect of metformin on the reduction of BMI-SDS, leptin, leptin-to-HMW adiponectin ratio, hsCRP, and liver fat seemed to be maintained after completing the 24 months of treatment. No changes in insulin sensitivity (HOMA-IR) or adverse effects were detected.ConclusionIn this pilot study, metformin treatment in pre-puberal and early pubertal children with obesity seemed to improve body composition and inflammation markers. Our data encourage the development of future fully powered trials using 850 mg/day metformin in young children, highlighting its excellent tolerance and potential long-term benefits.

Relationship between bone mineral content and bone turnover markers, sex hormones and calciotropic hormones in pre- and early pubertal children.

It is still debated whether BM including bone turnover markers (BTM), sex hormones and calciotropic (including cortisol) hormones provide information on BMC changes during growth. Three hundred fifty-seven girls and boys aged 6 to 13 years were included in this study. BM was measured at baseline and BMC twice at 9 months and 4 years using DXA. Relationship between BMs was assessed using principal component analysis (PCA). BM was tested in its ability to explain BMC variation by using structural equation modelling (SEM) on cross-sectional data. Longitudinal data were used to further assess the association between BM and BMC variables. BMC and all BMs, except calciotropic hormones, increased with age. PCA in BM revealed a three-factor solution (BTM, sex hormones and calciotropic hormones). In the SEM, age accounted for 61% and BTM for 1.2% of variance in BMC (cross-sectional). Neither sex nor calciotropic hormones were BMC explanatory variables. In the longitudinal models (with single BM as explanatory variables), BMC, age and sex at baseline accounted for 79-81% and 70-75% in BMC variance at 9 months and 4 years later, respectively. P1NP was consistently associated with BMC. BMC strongly tracks in pre- and early pubertal children. In this study, only a small part of BMC variance was explained by single BTM at the beginning of pubertal growth.

Children Born Small for Gestational Age: Differential Diagnosis, Molecular Genetic Evaluation, and Implications.

Children born small for gestational age (SGA), defined as a birth weight and/or length below -2 SD score (SDS), comprise a heterogeneous group. The causes of SGA are multifactorial and include maternal lifestyle and obstetric factors, placental dysfunction, and numerous fetal (epi)genetic abnormalities. Short-term consequences of SGA include increased risks of hypothermia, polycythemia, and hypoglycemia. Although most SGA infants show catch-up growth by 2 years of age, ∼10% remain short. Short children born SGA are amenable to GH treatment, which increases their adult height by on average 1.25 SD. Add-on treatment with a gonadotropin-releasing hormone agonist may be considered in early pubertal children with an expected adult height below -2.5 SDS. A small birth size increases the risk of later neurodevelopmental problems and cardiometabolic diseases. GH treatment does not pose an additional risk.

Muscle Deoxygenation during Incremental Exercise is Delayed in Children Compared to Young Adults

The mechanisms regulating O2 delivery and utilization during endurance exercise differ with maturation and are incompletely understood. This is important to understand the development of cardiovascular and neuromuscular diseases that originate early in life. Time-resolved near-infrared spectroscopy (TRS-NIRS) provides a quantitative non-invasive measurement of deoxy- hemoglobin + myoglobin concentration ([HHb]) at the muscle, an indicator of muscle deoxygenation during exercise. PURPOSE: To compare [HHb] dynamics during incremental ramp exercise in healthy early pubertal children and young adults. METHODS: 23 early pubertal children (16 F; 7-11 years) and 15 young adults (7 F; 21-35 years) underwent an incremental ramp exercise test on a cycle ergometer. Pulmonary gas exchange was measured breath-by-breath (Vmax, Carefusion). Vastus lateralis [HHb] was quantified by TRS-NIRS (TRS-21, Hamamatsu Photonics). RESULTS: Peak VO2 was not different between children and adults normalized to body mass (46.7±8.1 vs. 48.9±7.7 mL/min/kg). Absolute [HHb] was not different between children and adults during unloaded pedaling (23.5±5.5 vs 26.8±10.0 uM, p=0.20) but adults had a higher peak exercise [HHb] (32.0±8.2 vs 44.4±22.6 uM, p=0.01). Two way RM-ANOVA of relative HHb dynamics revealed an effect of age (F(1,36) = 6.895, p=0.013) and interaction with % peak power (p=0.001, Figure). Post-hoc, relative HHb was lower at 60% peak power in children vs adults (57±10% vs 68±13%, p=0.0006), while VO2 did not differ (33.5±4.9% vs 30.6±6.2%, p=0.12). CONCLUSION: Muscle deoxygenation is both attenuated and delayed during incremental exercise in children compared to adults, despite similar relative VO2. This is consistent with a closer matching of muscle microvascular O2 delivery to utilization over a greater range of aerobic power in children. The mechanisms contributing to this improved regulation of muscle blood flow during exercise in children warrant further study.Figure

Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility.

In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility. We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2years (range 0.9-21.1years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes. Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51years in rapid progressors (n=42, 17%) and 5.4years in slower progressors. Rapid progression was observed both among young (<5years) and early pubertal children (>7years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (≥2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all four autoantibodies at seroconversion. At seroconversion, individuals with rapid progression to type 1 diabetes were characterised by a younger age, higher autoantibody titres, positivity for multiple autoantibodies and higher prevalence of a FUT2 SNP. The double-peak profile for seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.

Increased Sensitivity of the Circadian System to Light in Early/Mid-Puberty.

Late adolescence is marked by a delay in sleep timing, which is partly driven by a delay shift of the circadian timing system. This study examined whether the sensitivity of the circadian system to light-the primary entraining stimulus to the circadian system-differs between pre- to mid-pubertal and late to postpubertal adolescents. The study was designed to determine the influence of puberty on the sensitivity of the circadian system to light in humans. Melatonin suppression to low and moderate light levels was assessed in 38 pre- to mid-pubertal (9.1-14.7 years) and 29 late to postpubertal (11.5-15.9 years) adolescents. They received 1 hour of four light levels on consecutive nights: approximately 0.1 (near-dark baseline condition), 15, 150, and 500 lux. One group received evening light beginning at 11:00 pm (n = 39); a second group received morning light beginning at 3:00 am (n = 28). Salivary melatonin was sampled every 30 minutes. Melatonin suppression for 15, 150, and 500 lux was calculated relative to unsuppressed baseline levels in the 0.1 lux setting, within individuals. The pre- to mid-pubertal group showed significantly greater melatonin suppression to 15 lux (9.2 ± 20.5%), 150 lux (26.0 ± 17.7%), and 500 lux (36.9 ± 11.4%) during evening light exposure compared to the late to postpubertal group (-5.3 ± 17.7%, 12.5 ± 17.3%, and 23.9 ± 21.7%, respectively; P < .05). No significant differences were seen between developmental groups in morning melatonin suppression. These results indicate support for a greater sensitivity to evening light in early pubertal children. The increased sensitivity to light in younger adolescents suggests that exposure to evening light could be particularly disruptive to sleep regulation for this group.

Common variants in the LAMA5 gene associate with fasting plasma glucose and serum triglyceride levels in a cohort of pre- and early pubertal children

Laminins are large glycoproteins found in basement membranes where they play a vital role in tissue architecture and cell behavior. Previously, we reported the association of two LAMA5 polymorphisms (rs659822 and rs944895) with anthropometric traits, fasting lipid profile, and plasma glucose levels in pre-menopausal women and elderly subjects. Furthermore, earlier work in mice showed that Lama5 is involved in organogenesis and placental function during pregnancy. The objective of this study was to investigate whether LAMA5 rs659822 or rs944895 are associated with inter-individual variability in birth weight as well as anthropometric, fasting lipid profile, and fasting glucose levels in children. Two hundred and eighty nine healthy children aged 7-12 years of European, Hispanic, and African-American ancestry were studied. Co-dominant models adjusted for genetic admixture, age, gender, and stages of puberty were used to test for the association of the polymorphisms with each trait. Our analysis showed significant associations of rs659822 with fasting plasma glucose levels (p = 0.0004) and of rs944895 with fasting serum triglycerides (p = 0.004) after Bonferroni correction for multiple testing. Our results corroborate our previous findings that genetic variants in LAMA5 contribute to variation in metabolic phenotypes and provide evidence that this may occur early in life.

Differences in Cardiometabolic Risk between Insulin-Sensitive and Insulin-Resistant Overweight and Obese Children.

It is known that 15-30% overweight/obese adults do not suffer cardiometabolic consequences. There is limited literature examining factors that can be used to assess cardiometabolic health in overweight/obese children. If such factors can be identified, they would aid in differentiating those most in need for aggressive management. Baseline data from 7- to 12-year-old, overweight, and obese children enrolled in a weight management program at an urban hospital were analyzed. Homeostatic model assessment for insulin resistance (HOMA-IR) <2.6 was used to define insulin-sensitive and HOMA-IR ≥2.6 was used to defined insulin-resistant participants. Demographics, physical activity measures, and cardiometabolic risk factors were compared between the two phenotypes. Odds ratios (ORs) examining the association between intermediate endpoints (metabolic syndrome [MetS], nonalcoholic fatty liver disease [NAFLD], systemic inflammation, and microalbuminuria) and the two metabolic phenotypes were evaluated. Of the 362 overweight/obese participants, 157 (43.5%) were insulin sensitive and 204 (56.5%) were insulin resistant. Compared to the insulin-sensitive group, the insulin-resistant group was older (8.6±1.6 vs. 9.9±1.7; p<0.001) and had a higher BMI z-score (1.89±0.42 vs. 2.04±0.42; p=0.001). After multivariable adjustment, compared to the insulin-sensitive group, the insulin-resistant group had higher odds of having MetS (OR, 5.47; 95% confidence interval [CI]: 1.72, 17.35; p=0.004) and NAFLD (OR, 8.66; 95% CI, 2.48, 30.31; p=0.001), but not systemic inflammation (OR, 1.06; 95% CI: 0.56, 2.03; p=0.86) or microalbuminuria (OR, 1.71; 95% CI, 0.49, 6.04; p=0.403). Using a HOMA-IR value of ≥2.6, clinical providers can identify prepubertal and early pubertal children most at risk. Focusing limited resources on aggressive weight interventions may lead to improvement in cardiometabolic health.

Neutrophil-to-lymphocyte ratio: an inflammation marker related to cardiovascular risk in children.

Low-grade chronic inflammation plays a pathogenic role in cardiovascular disease. An increase in the ratio of circulating neutrophils to lymphocytes (N/L ratio) may serve as a marker of cardiovascular risk in adults. It was the study objective to study whether N/L ratio associates with vascular parameters in children. Subjects were 501 prepubertal and early pubertal Caucasian children (mean age 8.0 years; mean body mass index (BMI) Z-score 0.2 ± 0.9; 266 boys and 235 girls) recruited within an ongoing population-based study. The subjects were stratified into three groups according to age. Neutrophil, lymphocyte, BMI, waist circumference, systolic blood pressure (SBP) and carotid intima-media thickness (cIMT), assessed in all children. The N/L ratio, derived from the absolute neutrophil and lymphocyte counts. In children aged < 7 years (n=190, all prepubertal), no associations were observed between N/L ratio and either anthropometric or cardiovascular parameters. In children aged 7-9 years (n=171, 1.7% early pubertal), higher N/L ratio associated with higher BMI Z-score and waist circumference (p=0.008 to p < 0.0001). In children aged >9 years (n=140, 29.2% early pubertal), N/L ratio associated again with BMI Z-score and waist circumference and also positively with SBP and cIMT (all p=0.008 to p<0.0001). These associations remained significant in linear regression models following adjustment for possible confounding variables such as age, gender, fasting triglycerides, C-reactive protein and puberty (and for SBP and cIMT, adjustment also for BMI). In conclusion, our results provide the first evidence that a higher N/L ratio is associated with a less favourable cardiovascular profile in children and delineate the development of these associations from late childhood onwards.

Relation of adrenal-derived steroids with bone maturation, mineral density and geometry in healthy prepubertal and early pubertal boys

BackgroundLittle is known about the effects of adrenal steroids on skeletal maturation and bone mass acquisition in healthy prepubertal boys. ObjectiveTo study whether adrenal-derived steroids within the physiological range are associated with skeletal maturation, areal and volumetric bone mineral density (aBMD and vBMD) and bone geometry in healthy prepubertal and early pubertal boys. Methods98 healthy prepubertal and early pubertal boys (aged 6–14y) were studied cross-sectionally. Androstenedione (A) and estrone (E1) were determined by liquid chromatography tandem mass spectrometry and DHEAS was determined by immunoassay. Whole body and lumbar spine aBMD and bone area were determined by dual-energy X-ray absorptiometry. Trabecular (distal site) and cortical (proximal site) vBMD and bone geometry were assessed at the non-dominant forearm and leg using peripheral QCT. Skeletal age was determined by X-ray of the left hand. ResultsAdrenal-derived steroids (DHEAS, A and E1) are positively associated with bone age in prepubertal and early pubertal children, independently of age. There are no associations between the adrenal-derived steroids and the studied parameters of bone size (lumbar spine and whole body bone area, trabecular or cortical area at the radius or tibia, periosteal circumference and cortical thickness at the radius or tibia) or BMD (aBMD or vBMD). ConclusionIn healthy prepubertal and early pubertal boys, serum adrenal-derived steroid levels, are associated with skeletal maturation, independently of age, but not with bone size or (v)BMD. Our data suggest that adrenal derived steroids are not implicated in the accretion of bone mass before puberty in boys.

Fibroblast growth factor-21, body composition, and insulin resistance in pre-pubertal and early pubertal males and females.

Accumulating evidence derived primarily from animal models suggests that fibroblast growth factor-21 (FGF-21) may affect the musculoskeletal system via effects on the capacity of tissues to respond to insulin. A proportion of musculoskeletal properties and underpinnings of promoting/preventing insulin resistance are established early in the pubertal transition. Thus, the objective of this study was to test the hypothesis that insulin resistance and/or obesity will promote greater FGF-21 concentration which will be inversely associated with musculoskeletal parameters [lean mass and bone mineral content (BMC)] in pre-/early pubertal children. Given the sexual dimorphic nature of musculoskeletal development of fat mass accrual, differences by obesity status and sex were also investigated. Cross-sectional. Children ages 7-12years (n=69, 38% male, 48% non-Hispanic black, 45% obese). Fasting FGF-21, glucose and insulin measures were obtained. An estimate of insulin resistance was derived using the homoeostatic model assessment of insulin resistance (HOMA-IR). Body composition (BMC, lean mass and fat mass) was assessed by DXA. Multivariate regression analysis was used to evaluate the influence of FGF-21 on BMC, lean mass and HOMA-IR as dependent variables. Obesity status was established based on BMI z-score. FGF-21 concentrations did not differ by obesity status or by sex. There was an inverse association between FGF-21 and BMC among nonobese individuals (P=0·01) and an inverse association between FGF-21 and lean mass among females (P=0·02), which were both independent of fat mass. FGF-21 was inversely associated with HOMA-IR in males, but not females (P=0·04). The existence of relationships of FGF-21 with musculoskeletal parameters and insulin resistance raises the possibility of crosstalk between these systems. These findings suggest that circulating FGF-21 may differ in its association with bone, lean mass and insulin resistance depending on sex and weight status.