Background
It is imperative to develop markers for risk stratification and detection of cardiometabolic comorbidities in children with obesity. The adipokines leptin and adiponectin are both involved ...in fat mass regulation and the development of obesity‐related disorders; furthermore, their ratio (leptin/adiponectin ratio) is suggested to be associated with insulin resistance and cardiometabolic risk.
Objective
To evaluate associations between fasting serum concentrations of the adipokines (total leptin and adiponectin as well as the L/A ratio) and cardiometabolic comorbidities in children with overweight/obesity.
Methods
A total of 2258 children with overweight/obesity or normal weight aged 6 to 18 years were studied. Differences in anthropometrics and adipokine concentrations were tested using Wilcoxon rank‐sum test. Associations between the adipokines and cardiometabolic risk were tested using Spearman's correlation and logistic regression, adjusted for age and body mass index SD score (BMI‐SDS).
Results
Compared to normal weight children; children with overweight/obesity exhibited higher leptin concentrations, lower adiponectin concentrations, and higher L/A ratios. After adjusting for age and degree of obesity, girls with overweight/obesity in the upper quartile range for the L/A ratio, when compared with girls in the lower quartile range, were more likely to have insulin resistance (odds ratio OR: 7.78 95% confidence interval CI, 3.78‐16.65), dysglycemia (OR: 3.08 95% CI, 1.35‐7.31), and dyslipidemia (OR: 2.53 95% CI, 1.18‐5.59); while boys were more likely to have insulin resistance (OR: 4.45 95% CI, 2.03‐10.10).
Conclusions
Independent of the degree of obesity, leptin, adiponectin, and the L/A ratio were associated with insulin resistance and other cardiometabolic comorbidities in children with overweight/obesity, but the L/A ratio exhibited stronger associations than the respective adipokines.
Background
Alterations in glucose metabolism that lead to the development of metabolic and cardiovascular disease may begin already in childhood.
Objective
This study aims to generate pediatric age ...and sex‐specific reference values for fasting concentrations of glucose, hemoglobin A1c (HbA1c), insulin, C‐peptide, and homeostasis model assessment: insulin resistance (HOMA‐IR) in Danish/North‐European white children and adolescents from a population‐based cohort and to compare values from children and adolescents with overweight/obesity with this reference.
Methods
The population‐ and obesity clinic‐based cohorts consisted of 2451 and 1935 children and adolescents between 6 and 18 years of age. Anthropometric measurements and blood samples were obtained and percentile curves were calculated.
Results
In the population‐based cohort, glucose, insulin, and HOMA‐IR values increased before the expected onset of puberty (P < .05). Thereafter, all variables decreased in girls (P < .05) and HbA1c decreased in boys (P < .05). Concentrations of all measured markers of glucose metabolism were higher in the obesity clinic‐based cohort than the population‐based cohort (both sexes P < .001). Specifically, insulin and HOMA‐IR continued to increase to 18 years in the clinic‐based cohort, particularly among boys.
Conclusions
Fasting glucose, insulin, and HOMA‐IR change during childhood, making pediatric reference values essential for timely identification of derangements in glucose metabolism. Children and adolescents with obesity exhibit increased concentrations of these biomarkers.
To determine the prevalence of Melanocortin-4 Receptor (MC4R) mutations in a cohort of children and adolescents with overweight or obesity and to determine whether treatment responses differed ...between carriers and noncarriers.
Using target region capture sequencing, an MC4R mutation screen was performed in 1261 Danish children and adolescents enrolled at a tertiary multidisciplinary childhood obesity treatment center. Measurements of anthropometrics, blood pressure, fasting blood biochemistry including lipid and hormone levels, and dual-energy X-ray absorptiometry were performed at baseline and throughout treatment.
Of 1209 children and adolescents that met all criteria to be included in the described analyses, 30 (2.5%) carried damaging or unresolved MC4R mutations. At baseline, mutation carriers exhibited higher concentrations of plasma thyroid-stimulating hormone (p = 0.003), and lower concentrations of plasma thyroxine (p = 0.010) compared to noncarriers. After a median of 1 year of treatment (range 0.5-4.0 years), body mass index (BMI) standard deviation score (SDS) was reduced in noncarriers but not in carriers, and this difference in treatment response was statistically significant (p = 0.005). Furthermore, HDL cholesterol was reduced in carriers, a response significantly different from that of noncarriers (p = 0.017).
Among Danish children and adolescents with overweight or obesity entering a tertiary lifestyle intervention, 2.5% carried damaging or unresolved MC4R mutations. In contrast to noncarriers, carriers of damaging or unresolved MC4R mutations failed to reduce their BMI SDS during obesity treatment, indicating a need for personalized treatment based on the MC4R genotype.
Abstract
Background
Elevated plasma concentrations of liver enzymes are routinely used as markers of liver injury in adults and children. Currently, the age- and sex-specific effects of adiposity on ...pediatric liver enzyme concentrations are unclear.
Methods
We included participants from 2 cohorts of Danish children and adolescents: 1858 from a population-based cohort and 2155 with overweight or obesity, aged from 6 to 18 years. Age- and sex-specific percentile curves were calculated for fasting plasma concentrations of alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), bilirubin, and alkaline phosphatase (ALP) in both cohorts. Hepatic fat content was assessed by proton magnetic resonance spectroscopy in 458 participants.
Results
Concentrations of ALT, AST, LDH, and ALP decreased with age in both girls and boys, while GGT and bilirubin were comparable across age groups in girls and increased slightly with age in boys. Children and adolescents with overweight or obesity exhibited higher concentrations of ALT in all age groups. Concentrations of ALT, and to a lesser degree GGT, increased with age in boys with overweight or obesity. Optimal ALT cut-points for diagnosing hepatic steatosis (liver fat content > 5%) was 24.5 U/L for girls (sensitivity: 55.6%, specificity: 84.0%), and 34.5 U/L for boys (sensitivity: 83.7%, specificity: 68.2%).
Conclusions
Pediatric normal values of liver enzymes vary with both age and sex. Overweight and obesity is associated with elevated biochemical markers of liver damage. These findings emphasize the need for prevention and treatment of overweight and obesity in children and adolescents. (J Clin Endocrinol Metab XX: 0-0, 2019)
Human milk oligosaccharides (HMOs) impact the intestinal microbiota by increasing beneficial bacteria in infants and adults, and are safe and well tolerated in these age groups. Effects on intestinal ...microbiota, safety, and digestive tolerance in children have not been, however, assessed. The aims of this trial were to evaluate if HMOs are able to specifically modulate the intestinal microbiota in children, and to assess safety and digestive tolerance.
In this randomized, double-blinded, placebo-controlled trial, 75 children with overweight (including obesity) ages 6 to 12 years were randomized to receive 2'-fucosyllactose (2'FL), a mix of 2'FL and lacto-N-neotetraose (Mix), or a glucose placebo orally administrated once per day for 8 weeks.
The relative abundance of bifidobacteria increased significantly after 4 (P < 0.001) and 8 (P = 0.025) weeks of intervention in the 2'FL-group and after 4 weeks (P = 0.033) in the Mix-group, whereas no change was observed in the placebo group. Compared with placebo, the 2'FL-group had a significant increase in bifidobacteria abundance after 4 weeks (P < 0.001) and 8 weeks (P = 0.010) and the Mix-group showed a tendency to increased bifidobacteria abundance after 4 (P = 0.071) and 8 weeks (P = 0.071). Bifidobacterium adolescentis drove the bifidogenic effect in the 2 groups. Biochemical markers indicated no safety concerns, and the products did not induce digestive tolerance issues as assessed by Gastrointestinal Symptoms Rating Scale and Bristol Stool Form Scale.
Both 2'FL and the Mix beneficially modulate intestinal microbiota by increasing bifidobacteria. Furthermore, supplementation with either 2'FL alone or a Mix is safe and well tolerated in children.
Abstract
Context
The importance of fasting glucagon-like peptide-1 (GLP-1) in altered metabolic outcomes has been questioned.
Objective
This work aimed to assess whether fasting GLP-1 differs in ...children and adolescents with overweight/obesity compared to a population-based reference, and whether concentrations predict cardiometabolic risk (CMR) factors.
Methods
Analyses were based on The Danish Childhood Obesity Data- and Biobank, a cross-sectional study including children and adolescents, aged 6 to 19 years, from an obesity clinic group (n = 1978) and from a population-based group (n = 2334). Fasting concentrations of plasma total GLP-1 and quantitative CMR factors were assessed. The effects of GLP-1 as a predictor of CMR risk outcomes were examined by multiple linear and logistic regression modeling.
Results
The obesity clinic group had higher fasting GLP-1 concentrations (median 3.3 pmol/L; interquartile range, 2.3-4.3 pmol/L) than the population-based group (2.8 pmol/L; interquartile range, 2.1-3.8 pmol/L; P < 2.2E-16). Body mass index SD score (SDS), waist circumference, and total body fat percentage were significant predictors of fasting GLP-1 concentrations in boys and girls. Fasting GLP-1 concentrations were positively associated with homeostasis model assessment of insulin resistance, fasting values of insulin, high-sensitivity C-reactive protein, C-peptide, triglycerides, alanine transaminase (ALT), glycated hemoglobin A1c, and SDS of diastolic and systolic blood pressure. A 1-SD increase in fasting GLP-1 was associated with an increased risk of insulin resistance (odds ratio OR 1.59), dyslipidemia (OR 1.16), increased ALT (OR 1.14), hyperglycemia (OR 1.12) and hypertension (OR 1.12).
Conclusion
Overweight/obesity in children and adolescents is associated with increased fasting plasma total GLP-1 concentrations, which was predictive of higher CMR factors.
Pediatric obesity is characterized by insulin resistance, yet it remains unclear whether insulin resistance contributes to abnormalities in glucagon and incretin secretion.
To examine whether fasting ...and stimulated glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) concentrations differ between children and adolescents with obesity and insulin resistance (OIR), obesity and normal insulin sensitivity (OIS), and controls with normal weight (NW).
80 (34 boys) children and adolescents, aged 7-17 years with OIR (n = 22), OIS (n = 22), and NW (n = 36) underwent an oral glucose tolerance test with measurements of serum insulin, plasma glucose, glucagon, total GLP-1, and total GIP. Homeostatic model assessment of insulin resistance (HOMA-IR), single point insulin sensitivity estimator (SPISE), Matsuda index, insulinogenic index (IGI), and oral disposition index (ODI) were calculated.
Fasting concentrations of glucagon and GLP-1 were higher in the OIR group, with no significant differences for GIP. The OIR group had higher glucagon total area under the curve (tAUC0-120) and lower GLP-1 incremental AUC (iAUC0-120), with no significant differences in GIP iAUC0-120. Higher fasting glucagon was associated with higher HOMA-IR, lower Matsuda index, lower SPISE, higher IGI, and higher plasma alanine transaminase, whereas higher fasting GLP-1 was associated with higher HOMA-IR, lower Matsuda index, and lower ODI. Higher glucagon tAUC0-120 was associated lower SPISE and lower Matsuda index, whereas lower GLP-1 iAUC0-120 was associated with a higher HOMA-IR, lower Matsuda index, and lower ODI.
Children and adolescents with OIR have elevated fasting concentrations of glucagon and GLP-1, higher glucagon and lower GLP-1 responses during an OGTT compared to those with OIS and NW. In contrast, individuals with OIS have similar hormone responses to those with NW.
Objective
This study aimed to investigate the effect of a genetic risk score (GRS) comprising 15 single‐nucleotide polymorphisms, previously shown to associate with childhood BMI, on the baseline ...cardiometabolic traits and the response to a lifestyle intervention in Danish children and adolescents.
Methods
Children and adolescents with overweight or obesity (n = 920) and a population‐based control sample (n = 698) were recruited. Anthropometric and biochemical measures were obtained at baseline and in a subgroup of children and adolescents with overweight or obesity again after 6 to 24 months of lifestyle intervention (n = 754). The effects of the GRS were examined by multiple linear regressions using additive genetic models.
Results
At baseline, the GRS associated with BMI standard deviation score (SDS) both in children and adolescents with overweight or obesity (β = 0.033 SE = 0.01; P = 0.001) and in the population‐based sample (β = 0.065 SE = 0.02; P = 0.001). No associations were observed for cardiometabolic traits. The GRS did not influence changes in BMI SDS or cardiometabolic traits following lifestyle intervention.
Conclusions
A GRS for childhood BMI was associated with BMI SDS but not with other cardiometabolic traits in Danish children and adolescents. The GRS did not influence treatment response following lifestyle intervention.
To investigate the relationship between in utero growth conditions, as indicated by neonatal anthropometric measures, and childhood obesity treatment response, to examine the potential usefulness of ...neonatal anthropometrics as a potential childhood obesity treatment stratification tool.
The study included 2474 children and adolescents with obesity (mean age, 11.2 years; range, 5.0-18.9 years) treated at the Children's Obesity Clinic in Holbæk, Denmark. Treatment response was registered prospectively, and neonatal data were collected from national electronic registers.
Birth weight, birth length, birth weight for gestational age, and large for gestational age status were positively associated with the degree of obesity at treatment initiation. After a mean (SD) of 1.27 (0.69) years of enrollment in obesity treatment, the children exhibited a mean reduction of −0.32 (0.50) in body mass index SD score. No significant associations between neonatal anthropometric measures and childhood obesity treatment response were detected.
Neonatal anthropometric measures were positively associated with the degree of obesity at treatment initiation but not with response to multidisciplinary treatment of childhood obesity. Individualization of obesity treatment based on neonatal anthropometry does not seem warranted.
Pediatric obesity associates with both low-grade inflammation and cardiometabolic risk on the population level. Yet on an individual patient level, overweight/obesity does not always equal increased ...cardiometabolic risk. In this study, we examine whether low-grade inflammation associates with cardiometabolic risk in Danish children, independent of degree of adiposity. We further assess the value of integrating multiple inflammation markers to identify children with very-high cardiometabolic risk profiles.
We studied 2192 children and adolescents aged 6–18 years from an obesity clinic cohort and a population-based cohort, in a cross-sectional study design. Anthropometry, blood pressure, pubertal stage and body composition by dual-energy X-ray absorptiometry were assessed, and biomarkers including fasting serum high sensitivity C-reactive protein (hsCRP), white blood cells (WBC), resistin, lipid profile and glucose metabolism were measured. Adjusted correlation analysis and odds ratios were calculated. We found that, independent of degree of adiposity, having high-normal inflammation marker concentrations associated with increased cardiometabolic risk: for girls, hsCRP >0.57–9.98 mg/L (mid/upper tertile) associated with ~2-fold higher odds of dyslipidemia and hepatic steatosis (vs. lower tertile). For both sexes, WBC >7.0–12.4 109/L (upper tertile) associated with 2.5-fold higher odds of insulin resistance. Lastly, children with multiple inflammation markers in the high-normal range exhibited the most severe cardiometabolic risk profile.
Low-grade inflammation associates with cardiometabolic risk in children independent of degree of adiposity. The associations vary with sex and inflammation marker measured. Finally, integrating multiple low-grade inflammation markers identifies a very-high-risk subgroup of children with overweight/obesity and may have clinical value.
•Children with obesity exhibit more low-grade inflammation than normal weight peers.•High-normal inflammation markers independently associate with cardiometabolic risk.•Associations with cardiometabolic risk differ with sex and the biomarker examined.•Combining multiple inflammation markers identifies a very-high risk subgroup.
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