Insulin resistance, C-reactive protein, diastolic to systolic blood pressure ratio and epicardial fat are related to sedentary time, and inversely related to physical activity in school-aged children.

Background: Physical activity (PA) is beneficial for the overall health. Objectives are: (1) To compare metabolic (MRM) and cardiovascular-risk-markers (CRM) in children according to their PA-level; (2) to explore the associations of MRM and CRM with PA and sedentary time (ST); and (3) to identify the associations between MRM and CRM in less (LA) and more active (MA) children. Methods: A total of 238 apparently healthy school-aged children were enrolled (132 boys/106 girls; 9.1 ± 1.8 years) and body mass index standard deviation score (BMI SDS) and blood pressure were assessed. Fasting venous blood sampling was performed to assess insulin resistance (HOMA-IR) and high-sensitivity-C-reactive protein (hsCRP). Epicardial fat, interventricular septal and left ventricular posterior wall thicknesses were assessed by high-resolution ultrasonography. PA and ST were assessed by enKid-questionnaire. Children were classified based on enKid-score as being LA and MA (below and above 50th percentile for PA). Results: MA-children had lower values for: BMI SDS, diastolic-to-systolic blood pressure ratio, HOMA-IR and hsCRP (7.02 to 61.5% lower, p = 0.040 to p < 0.0001) compared to LA-children. MRM and CRM were positively associated with ST (p = 0.003 to p < 0.001), and negatively associated with PA (p = 0.044 to p < 0.001). Finally, MRM were positively associated with CRM (p = 0.008 to p < 0.0001). Interestingly, the latter associations were observed in LA-children but were not present in MA-children. Conclusion: More PA is associated with better cardio-metabolic profile in school-aged children. PA seems to modulate the associations between MRM and CRM, thus reinforcing the idea that fostering PA in children may lower the risk for development of a cardio-metabolic disease.

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.

BACKGROUND: Metformin 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. METHODS: A 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. RESULTS: The 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. CONCLUSION: In 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.

Perirenal and epicardial fat and their association with carotid intima-media thickness in children.

Recent data suggest that subclinical atherosclerosis is more related to visceral adipose tissue distribution than to overall fat mass. Both perirenal fat and epicardial fat are visceral fat depots surrounding the kidneys and the myocardium, respectively, which can be easily assessed by ultrasound. Their clinical relevance in children is largely unknown. This review describes studies relating perirenal and epicardial fat to cardiovascular disease or carotid intima-media thickness (cIMT), a well-established surrogate for subclinical atherosclerosis, and discusses this in context with our own data from children. In adults, both perirenal and epicardial fat are useful biological markers of visceral obesity. The former has been related to hypertension in overweight subjects and with atherosclerosis in patients with human immunodeficiency virus. The latter was associated with several metabolic syndrome components and with calcification of the carotid artery. In healthy prepubertal children, both epicardial and perirenal fat thickness, rather than total body fat mass, were related to cIMT. Ultrasonography measures of perirenal and epicardial fat are related to atherosclerosis in adults and may be convenient tools for the assessment of cardiometabolic risk in children.

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.

Undercarboxylated osteocalcin relates to cardiovascular risk markers in offspring of families with metabolic syndrome.

BACKGROUND: The undercarboxylated form of osteocalcin (ucOC) is an emerging marker of cardiovascular disease. It is unknown if ucOC in related to common cardiovascular risk markers in children. In offspring of families with and without metabolic syndrome (MetS+ and MetS- families), we assessed whether ucOC was related to a continuous metabolic syndrome score (MetS score) and to carotid intima-media thickness (cIMT). METHODS: ucOC and total OC, MetS score and cIMT were assessed in 203 asymptomatic prepubertal children (age 7.6 ± 0.1 yr; 49% girls), of whom 99 were from MetS+ families. RESULTS: In children from MetS+ families, percent ucOC was higher than in children from MetS- families (p < 0.01). In offspring from MetS+ families, higher ucOC and especially higher percent ucOC was independently associated with both the MetS score and cIMT (both p ≤ 0.01). CONCLUSIONS: The undercarboxylated form of OC is related to common cardiovascular risk markers in children at risk for cardiovascular disease.

Carotid intima-media thickness at 7 years of age: relationship to C-reactive protein rather than adiposity.

OBJECTIVE: According to the concept of adipose tissue expandability, the vascular complications of obesity are related less to the amount of stored fat than to the low-grade inflammation that excess fat storage may elicit. We tested this concept in 7-year-old children by assessing whether carotid intima-media thickness (cIMT) is related to obesity measures or to circulating highly sensitive C-reactive protein (hsCRP), as a marker of low-grade inflammation. STUDY DESIGN: The study group comprised 135 asymptomatic Caucasian children (72 girls and 63 boys; mean age, 7.1±1.1 years) with normal height and weight distributions. Relationships were assessed among cIMT, hsCRP, obesity measures (ie, body mass index [BMI], total fat by bioelectric impedance, and visceral fat by ultrasound), insulin resistance (by the homeostasis model assessment for insulin resistance), and fasting serum lipid levels. RESULTS: cIMT was correlated with hsCRP, but not with BMI or body fat; the regression coefficients between cIMT and hsCRP (adjusted for age, sex, BMI, body fat, and serum lipid levels) were fairly similar across all BMI categories (ß=0.370-0.411; all P<.001 to<.0001). Serum hsCRP increased with increasing BMI, total fat, and visceral fat (all P<.001). CONCLUSION: At age 7 years, cIMT is already associated with low-grade inflammation, as measured by hsCRP, but not with BMI or body fat. These findings imply that public health strategies aimed at early prevention of cardiovascular disease may need to target low-grade inflammation rather than only BMI or adiposity.

Relative hypoadiponectinemia, insulin resistance, and increased visceral fat in euthyroid prepubertal girls with low-normal serum free thyroxine.

A lower activity of the thyroid axis within the clinical reference range is related to a dysmetabolic phenotype in adult populations. We posited that such an association is already present as early as in prepubertal childhood. Serum thyroid stimulating hormone (TSH) and free T4, body fat (bioelectric impedance), insulin resistance (homeostasis model assessment of insulin resistance (HOMA(IR))), total and high molecular weight (HMW)-adiponectin and serum lipids were assessed in 234 euthyroid prepubertal children (113 boys and 121 girls) attending primary care clinics. Visceral fat (abdominal ultrasound) was measured in a subset of these subjects (n = 147; 74 boys and 73 girls). Explants of visceral adipose tissue from an additional six prepubertal children (three boys and three girls) were used to study the regulation of total and HMW-adiponectin by thyroid hormone. Serum free T4 was in girls independently associated with HMW-adiponectin, HOMA(IR) and visceral fat, so that circulating HMW-adiponectin decreased by 30% (ß = 0.305 P < 0.005, R(2) = 0.13) and HOMA(IR) and visceral fat increased, respectively, by 90% (ß = -0.255 P < 0.01, R(2) = 0.05) and 30% (ß = -0.369, P < 0.005, R(2) = 0.12) from the highest to the lowest tertile of serum free T4. Nonsignificant differences in these parameters were found in boys. Treatment of visceral fat explants with thyroid hormone increased total and HMW-adiponectin by 70% and 53%, respectively, above control values (P < 0.01). In conclusion, a dysmetabolic phenotype, consisting of relative hypoadiponectinemia, insulin resistance and increased visceral fat, is associated with low-normal serum free thyroxine in euthyroid prepubertal girls. These associations may be partly explained by a positive regulation of HMW-adiponectin secretion by thyroid hormone.

Physiological concentrations of serum cortisol are related to vascular risk markers in prepubertal children.

There is increasing evidence that cortisol contributes to cardiovascular risk. It is unclear whether physiological concentrations of serum cortisol are related to vascular risk markers in children. The cross-sectional associations between morning serum cortisol and cardiovascular risk markers: blood pressure (BP) and carotid intima-media thickness (IMT), were examined in a sample of healthy prepubertal children (age, 6.8 ± 0.1 y) attending primary care clinics. Serum cortisol was associated with increased systolic BP (SBP; n = 223; p < 0.001) and carotid IMT (n = 91; p < 0.0001). These associations were independent from age, BMI, body fat, waist, insulin resistance, serum lipids, and heart rate (HR). No gender interactions were apparent in these associations. In summary, a higher morning serum cortisol within the physiological range is in prepubertal children associated with vascular risk markers. Because childhood risk factors predict adult risk for cardiovascular disease, these observations may have implications in the prevention of cardiovascular disease early in life.