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1H-MRS Measured Ectopic Fat in Liver and Muscle in Danish Lean and Obese Children and Adolescents.

https://arctichealth.org/en/permalink/ahliterature273208
Source
PLoS One. 2015;10(8):e0135018
Publication Type
Article
Date
2015
Author
Cilius Esmann Fonvig
Elizaveta Chabanova
Ehm Astrid Andersson
Johanne Dam Ohrt
Oluf Pedersen
Torben Hansen
Henrik S Thomsen
Jens-Christian Holm
Source
PLoS One. 2015;10(8):e0135018
Date
2015
Language
English
Publication Type
Article
Keywords
Adolescent
Anthropometry
Blood Glucose - analysis
Blood pressure
Body mass index
Body Weight
Cardiovascular Diseases - physiopathology
Child
Cross-Sectional Studies
Denmark
Dyslipidemias - blood
Fatty Liver - pathology
Female
Humans
Insulin - blood
Insulin Resistance
Intra-Abdominal Fat - pathology
Linear Models
Lipids - blood
Liver - metabolism - pathology
Male
Muscles - pathology
Overweight
Pediatric Obesity - blood - pathology
Proton Magnetic Resonance Spectroscopy
Puberty
Sex Factors
Subcutaneous Fat - pathology
Abstract
This cross sectional study aims to investigate the associations between ectopic lipid accumulation in liver and skeletal muscle and biochemical measures, estimates of insulin resistance, anthropometry, and blood pressure in lean and overweight/obese children.
Fasting plasma glucose, serum lipids, serum insulin, and expressions of insulin resistance, anthropometry, blood pressure, and magnetic resonance spectroscopy of liver and muscle fat were obtained in 327 Danish children and adolescents aged 8-18 years.
In 287 overweight/obese children, the prevalences of hepatic and muscular steatosis were 31% and 68%, respectively, whereas the prevalences in 40 lean children were 3% and 10%, respectively. A multiple regression analysis adjusted for age, sex, body mass index z-score (BMI SDS), and pubertal development showed that the OR of exhibiting dyslipidemia was 4.2 (95%CI: [1.8; 10.2], p = 0.0009) when hepatic steatosis was present. Comparing the simultaneous presence of hepatic and muscular steatosis with no presence of steatosis, the OR of exhibiting dyslipidemia was 5.8 (95%CI: [2.0; 18.6], p = 0.002). No significant associations between muscle fat and dyslipidemia, impaired fasting glucose, or blood pressure were observed. Liver and muscle fat, adjusted for age, sex, BMI SDS, and pubertal development, associated to BMI SDS and glycosylated hemoglobin, while only liver fat associated to visceral and subcutaneous adipose tissue and intramyocellular lipid associated inversely to high density lipoprotein cholesterol.
Hepatic steatosis is associated with dyslipidemia and liver and muscle fat depositions are linked to obesity-related metabolic dysfunctions, especially glycosylated hemoglobin, in children and adolescents, which suggest an increased cardiovascular disease risk.
Notes
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PubMed ID
26252778 View in PubMed
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Adoption of the children's obesity clinic's treatment (TCOCT) protocol into another Danish pediatric obesity treatment clinic.

https://arctichealth.org/en/permalink/ahliterature269068
Source
BMC Pediatr. 2015;15:13
Publication Type
Article
Date
2015
Author
Sebastian W Most
Birgitte Højgaard
Grete Teilmann
Jesper Andersen
Mette Valentiner
Michael Gamborg
Jens-Christian Holm
Source
BMC Pediatr. 2015;15:13
Date
2015
Language
English
Publication Type
Article
Keywords
Adolescent
Behavior Therapy
Body mass index
Child
Child, Preschool
Clinical Protocols
Denmark
Female
Humans
Male
Parenting
Pediatric Obesity - psychology - therapy
Professional-Family Relations
Prospective Studies
Sex Factors
Social Class
Treatment Outcome
Abstract
Treating severe childhood obesity has proven difficult with inconsistent treatment results. This study reports the results of the implementation of a childhood obesity chronic care treatment protocol.
Patients aged 5 to 18 years with a body mass index (BMI) above the 99th percentile for sex and age were eligible for inclusion. At baseline patients' height, weight, and tanner stages were measured, as well as parents' socioeconomic status (SES) and family structure. Parental weight and height were self-reported. An individualised treatment plan including numerous advices was developed in collaboration with the patient and the family. Patients' height and weight were measured at subsequent visits. There were no exclusion criteria.
Three-hundred-thirteen (141 boys) were seen in the clinic in the period of February 2010 to March 2013. At inclusion, the median age of patients was 11.1 years and the median BMI standard deviation score (SDS) was 3.24 in boys and 2.85 in girls. After 1 year of treatment, the mean BMI SDS difference was -0.30 (95% CI: -0.39; -0.21, p
Notes
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PubMed ID
25884714 View in PubMed
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An adult-based insulin resistance genetic risk score associates with insulin resistance, metabolic traits and altered fat distribution in Danish children and adolescents who are overweight or obese.

https://arctichealth.org/en/permalink/ahliterature297400
Source
Diabetologia. 2018 08; 61(8):1769-1779
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Date
08-2018
Author
Anne-Sofie Graae
Mette Hollensted
Julie T Kloppenborg
Yuvaraj Mahendran
Theresia M Schnurr
Emil Vincent R Appel
Johanne Rask
Tenna R H Nielsen
Mia Ø Johansen
Allan Linneberg
Marit E Jørgensen
Niels Grarup
Haja N Kadarmideen
Birgitte Holst
Oluf Pedersen
Jens-Christian Holm
Torben Hansen
Author Affiliation
Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Source
Diabetologia. 2018 08; 61(8):1769-1779
Date
08-2018
Language
English
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Keywords
Adolescent
Adult
Anthropometry
Body Composition
Child
Cholesterol, HDL - metabolism
Denmark
Diabetes Mellitus, Type 2
Genetic Predisposition to Disease
Genotype
Humans
Insulin Resistance
Linear Models
Metabolic Syndrome - metabolism
Middle Aged
Overweight - genetics
Pediatric Obesity - genetics
Phenotype
Risk
Abstract
A genetic risk score (GRS) consisting of 53 insulin resistance variants (GRS53) was recently demonstrated to associate with insulin resistance in adults. We speculated that the GRS53 might already associate with insulin resistance during childhood, and we therefore aimed to investigate this in populations of Danish children and adolescents. Furthermore, we aimed to address whether the GRS associates with components of the metabolic syndrome and altered body composition in children and adolescents.
We examined a total of 689 children and adolescents who were overweight or obese and 675 children and adolescents from a population-based study. Anthropometric data, dual-energy x-ray absorptiometry scans, BP, fasting plasma glucose, fasting serum insulin and fasting plasma lipid measurements were obtained, and HOMA-IR was calculated. The GRS53 was examined for association with metabolic traits in children by linear regressions using an additive genetic model.
In overweight/obese children and adolescents, the GRS53 associated with higher HOMA-IR (ß?=?0.109?±?0.050 (SE); p?=?2.73?×?10-2), fasting plasma glucose (ß?=?0.010?±?0.005 mmol/l; p?=?2.51?×?10-2) and systolic BP SD score (ß?=?0.026?±?0.012; p?=?3.32?×?10-2) as well as lower HDL-cholesterol (ß?=?-0.008?±?0.003 mmol/l; p?=?1.23?×?10-3), total fat-mass percentage (ß?=?-0.143?±?0.054%; p?=?9.15?×?10-3) and fat-mass percentage in the legs (ß?=?-0.197?±?0.055%; p?=?4.09?×?10-4). In the population-based sample of children, the GRS53 only associated with lower HDL-cholesterol concentrations (ß?=?-0.007?±?0.003 mmol/l; p?=?1.79?×?10-2).
An adult-based GRS comprising 53 insulin resistance susceptibility SNPs associates with insulin resistance, markers of the metabolic syndrome and altered fat distribution in a sample of Danish children and adolescents who were overweight or obese.
PubMed ID
29855666 View in PubMed
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Chronic care treatment of obese children and adolescents.

https://arctichealth.org/en/permalink/ahliterature134902
Source
Int J Pediatr Obes. 2011 Aug;6(3-4):188-96
Publication Type
Article
Date
Aug-2011
Author
Jens-Christian Holm
Michael Gamborg
Dorthe S Bille
Helle N Gr Nb K
Leigh C Ward
Jan Faerk
Author Affiliation
The Children's Obesity Clinic, Department of Pediatrics, Holb?k University Hospital , Holbaek , Denmark. jhom@regionsjaelland.dk
Source
Int J Pediatr Obes. 2011 Aug;6(3-4):188-96
Date
Aug-2011
Language
English
Publication Type
Article
Keywords
Adolescent
Adolescent Health Services
Body mass index
Child
Child Health Services
Child, Preschool
Chronic Disease
Clinical Protocols
Denmark
Female
Humans
Longitudinal Studies
Male
Obesity - diagnosis - physiopathology - psychology - therapy
Overweight - diagnosis - physiopathology - psychology - therapy
Program Evaluation
Time Factors
Treatment Outcome
Weight Loss
Young Adult
Abstract
Clinically-relevant protocols for the treatment of childhood obesity are lacking. This study report results for a clinic-based structured treatment program for chronic childhood obesity.
Patients were measured at baseline and for up to 24 months; there were no prior eligibility criteria. At baseline, height, weight, Tanner stages, testicular size, time of menarche, and social class of the parents were registered. A structured, tailored treatment plan including best-practice-based interventions was initiated. Height, weight, and pubertal development were measured at subsequent visits.
A total of 617 children or youths were included; 325 were girls and 292 were boys. At entry, the mean age was 11.6 years and the mean body mass index (BMI) standard deviation score (SDS) was 3.0. Seventy stopped treatment, 547 were in treatment, 125 had 1 examination, and 492 had two or more examinations, with a mean visit interval of six weeks. After 12 months, the mean BMI SDS decreased by 0.23 (P
PubMed ID
21529264 View in PubMed
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Common variants in LEPR, IL6, AMD1, and NAMPT do not associate with risk of juvenile and childhood obesity in Danes: a case-control study.

https://arctichealth.org/en/permalink/ahliterature272210
Source
BMC Med Genet. 2015;16:105
Publication Type
Article
Date
2015
Author
Mette Hollensted
Tarunveer S Ahluwalia
Christian Theil Have
Niels Grarup
Cilius Esmann Fonvig
Tenna Ruest Haarmark Nielsen
Cæcilie Trier
Lavinia Paternoster
Oluf Pedersen
Jens-Christian Holm
Thorkild I A Sørensen
Torben Hansen
Source
BMC Med Genet. 2015;16:105
Date
2015
Language
English
Publication Type
Article
Keywords
Adenosylmethionine Decarboxylase - genetics
Body mass index
Case-Control Studies
Cytokines - genetics
Denmark
Female
Genetic Predisposition to Disease
Humans
Interleukin-6 - genetics
Male
Middle Aged
Nicotinamide Phosphoribosyltransferase - genetics
Pediatric Obesity - genetics
Polymorphism, Single Nucleotide
Receptors, Leptin - genetics
Young Adult
Abstract
Childhood obesity is a highly heritable disorder, for which the underlying genetic architecture is largely unknown. Four common variants involved in inflammatory-adipokine triggering (IL6 rs2069845, LEPR rs1137100, NAMPT rs3801266, and AMD1 rs2796749) have recently been associated with obesity and related traits in Indian children. The current study aimed to examine the effect of these variants on risk of childhood/juvenile onset obesity and on obesity-related quantitative traits in two Danish cohorts.
Genotype information was obtained for 1461 young Caucasian men from the Genetics of Overweight Young Adults (GOYA) study (overweight/obese: 739 and normal weight: 722) and the Danish Childhood Obesity Biobank (TDCOB; overweight/obese: 1022 and normal weight: 650). Overweight/obesity was defined as having a body mass index (BMI) =25 kg/m(2); among children and youths, this cut-off was defined using age and sex-specific cut-offs corresponding to an adult body mass index =25 kg/m(2). Risk of obesity was assessed using a logistic regression model whereas obesity-related quantitative measures were analyzed using a general linear model (based on z-scores) stratifying on the case status and adjusting for age and gender. Meta-analyses were performed using the fixed effects model.
No statistically significant association with childhood/juvenile obesity was found for any of the four gene variants among the individual or combined analyses (rs2069845 OR: 0.94 CI: 0.85-1.04; rs1137100 OR: 1.01 CI: 0.90-1.14; rs3801266: 0.96 CI: 0.84-1.10; rs2796749 OR: 1.02 CI: 0.90-1.15; p?>?0.05). However, among normal weight children and juvenile men, the LEPR rs1137100 A-allele significantly associated with lower BMI (ß?=?-0.12, p?=?0.0026).
The IL6, LEPR, NAMPT, and AMD1 gene variants previously found to associate among Indian children did not associate with risk of obesity or obesity-related quantitative measures among Caucasian children and juvenile men from Denmark.
Notes
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PubMed ID
26558825 View in PubMed
Less detail
Source
Dan Med J. 2016 May;63(5)
Publication Type
Article
Date
May-2016
Author
Christina Gade
Gerd Mikus
Hanne Rolighed Christensen
Kim Peder Dalhoff
Jens-Christian Holm
Helle Holst
Source
Dan Med J. 2016 May;63(5)
Date
May-2016
Language
English
Publication Type
Article
Keywords
Adolescent
Caffeine - blood - pharmacokinetics - urine
Child
Chlorzoxazone - blood - pharmacokinetics - urine
Clinical Protocols
Cytochrome P-450 CYP1A2 - metabolism
Cytochrome P-450 CYP2E1 - metabolism
Cytochrome P-450 CYP3A - metabolism
Denmark
Female
Humans
Male
Midazolam - blood - pharmacokinetics - urine
Pediatric Obesity - metabolism
Abstract
In Denmark, it is estimated that 3-5% of children are obese. Obesity is associated with pathophysiological alterations that may lead to alterations in the pharmacokinetics of drugs. In adults, obesity was found to influence important drug-metabolising enzyme pathways. The impact of obesity-related alterations on drug metabolism and its consequences for drug dosing remains largely unknown in both children and adults. An altered drug metabolism may contribute significantly to therapeutic failure or toxicity. The aim of this trial is to investigate the in vivo activity of CYP3A4, CYP2E1 and CYP1A2 substrates in obese versus non-obese children.
The CYTONOX trial is an open-label explorative pharmacokinetic trial. We intend to include 50 obese and 50 non-obese children. The primary end points are: in vivo clearance of CYP3A4, CYP2E1 and CYP1A2 substrates, which will be defined by using well-tested probes; midazolam, chlorzoxazone and caffeine. Each of the probes will be administered as a single dose. Subsequently, blood and urine samples will be collected at pre-specified times.
The aim of the CYTONOX trial is to investigate the in vivo activity of CYP3A4, CYP2E1 and CYP1A2 in obese and non-obese children. The results are expected to be used in the future as a basis for drug dosing recommendations in obese children.
The study was funded by the Danish Regions' "Medicinpuljen". The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
EudraCT: 2014-004554-34.
PubMed ID
27127017 View in PubMed
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Danish clinical guidelines for examination and treatment of overweight and obese children and adolescents in a pediatric setting.

https://arctichealth.org/en/permalink/ahliterature270639
Source
Dan Med J. 2015 May;62(5)
Publication Type
Article
Date
May-2015
Author
Anders Johansen
Jens-Christian Holm
Seija Pearson
Mimi Kjærsgaard
Lone Marie Larsen
Birgitte Højgaard
Dina Cortes
Source
Dan Med J. 2015 May;62(5)
Date
May-2015
Language
English
Publication Type
Article
Keywords
Adolescent
Behavior Therapy - methods
Body mass index
Child
Denmark
Family
Humans
Overweight - diagnosis - therapy
Pediatric Obesity - diagnosis - therapy
Pediatrics - standards
Referral and Consultation - standards
Waist Circumference
Abstract
Overweight children are at an increased risk of becoming obese adults, which may lead to shorter life expectancies in the current generation of children as compared to their parents. Furthermore, being an overweight child has a negative psycho-social impact. We consider obesity in children and adolescents a chronic illness, which is in line with the American Medical Society. We summarize the evidence for the efficacy of a combination of diet, physical activity and behavior-focused interventions in a family-based setting. The present guidelines propose a multidisciplinary service implemented as a "chronic care model" based on "best clinical practice" inspired by an American expert committee and the daily practice of The Children's Obesity Clinic at Copenhagen University Hospital Holbaek. Children and adolescents should be referred for examination and treatment in a pediatric setting when BMI corresponds to an isoBMI of minimum 30 or BMI corresponds to an isoBMI of 25 and complex obesity is suspected. Obtaining a thorough medical history is pivotal. We propose a structured interview to ensure collection of all relevant information. We recommend physical examination focused on BMI, waist circumference, growth, pubertal stage, blood pressure, neurology and skin and provide comprehensive paraclinical investigations for obesity and obesity related conditions. Treatment of obesity in children and adolescents is fully dependent on the combined effort of the entire family. This cannot be overemphasized! The main principle of the treatment is developing an individual detailed plan for every patient to reduce caloric intake whilst increasing physical activity, leaving no ambiguity with the recommendations.
PubMed ID
26050836 View in PubMed
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Dyslipidemia and reference values for fasting plasma lipid concentrations in Danish/North-European White children and adolescents.

https://arctichealth.org/en/permalink/ahliterature289937
Source
BMC Pediatr. 2017 04 28; 17(1):116
Publication Type
Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Date
04-28-2017
Author
Tenna Ruest Haarmark Nielsen
Ulrik Lausten-Thomsen
Cilius Esmann Fonvig
Christine Bøjsøe
Lise Pedersen
Palle Skov Bratholm
Torben Hansen
Oluf Pedersen
Jens-Christian Holm
Author Affiliation
The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Smedelundsgade 60, DK 4300, Holbæk, Denmark. ter@regionsjaelland.dk.
Source
BMC Pediatr. 2017 04 28; 17(1):116
Date
04-28-2017
Language
English
Publication Type
Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Keywords
Adolescent
Biomarkers - blood
Case-Control Studies
Child
Cholesterol - blood
Cross-Sectional Studies
Denmark - epidemiology
Dyslipidemias - blood - complications - diagnosis - epidemiology
Europe - epidemiology
European Continental Ancestry Group
Fasting
Female
Humans
Logistic Models
Male
Pediatric Obesity - blood - complications - diagnosis - epidemiology
Prevalence
Reference Values
Triglycerides - blood
Young Adult
Abstract
Dyslipidemia is reported in 27 - 43% of children and adolescents with overweight/obesity and tracks into adulthood, increasing the risk of cardiovascular morbidity. Cut-off values for fasting plasma lipid concentrations are typically set at fixed levels throughout childhood. The objective of this cross-sectional study was to generate fasting plasma lipid references for a Danish/North-European White population-based cohort of children and adolescents, and investigate the prevalence of dyslipidemia in this cohort as well as in a cohort with overweight/obesity.
A population-based cohort of 2141 (1275 girls) children and adolescents aged 6 - 19 (median 11.5) years was recruited from 11 municipalities in Denmark. Additionally, a cohort of children and adolescents of 1421 (774 girls) with overweight/obesity aged 6 - 19 years (median 11.8) was recruited for the study. Height, weight, and fasting plasma lipid concentrations were measured on all participants. Smoothed reference curves and percentiles were generated using the Generalized Additive Models for Location Scale and Shape package in the statistical software R.
In the population-based cohort, plasma concentrations of total cholesterol (TC) (P 
Notes
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PubMed ID
28454530 View in PubMed
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A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents.

https://arctichealth.org/en/permalink/ahliterature285215
Source
PLoS One. 2017;12(3):e0174204
Publication Type
Article
Date
2017
Author
Tenna Ruest Haarmark Nielsen
Emil Vincent Rosenbaum Appel
Mathilde Svendstrup
Johanne Dam Ohrt
Maria Dahl
Cilius Esmann Fonvig
Mette Hollensted
Christian Theil Have
Haja N Kadarmideen
Oluf Pedersen
Torben Hansen
Jens-Christian Holm
Niels Grarup
Source
PLoS One. 2017;12(3):e0174204
Date
2017
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Age Factors
Body mass index
Child
Child, Preschool
Denmark
Female
Genetic Loci - genetics - physiology
Genetic Markers - genetics
Genetic Predisposition to Disease - genetics
Humans
Male
Pediatric Obesity - blood - genetics
Polymorphism, Single Nucleotide - genetics
Thyrotropin - blood
Thyroxine - blood
Young Adult
Abstract
Hypothyroidism is associated with obesity, and thyroid hormones are involved in the regulation of body composition, including fat mass. Genome-wide association studies (GWAS) in adults have identified 19 and 6 loci associated with plasma concentrations of thyroid stimulating hormone (TSH) and free thyroxine (fT4), respectively.
This study aimed to identify and characterize genetic variants associated with circulating TSH and fT4 in Danish children and adolescents and to examine whether these variants associate with obesity.
Genome-wide association analyses of imputed genotype data with fasting plasma concentrations of TSH and fT4 from a population-based sample of Danish children, adolescents, and young adults, and a group of children, adolescents, and young adults with overweight and obesity were performed (N = 1,764, mean age = 12.0 years [range 2.5-24.7]). Replication was performed in additional comparable samples (N = 2,097, mean age = 11.8 years [1.2-22.8]). Meta-analyses, using linear additive fixed-effect models, were performed on the results of the discovery and replication analyses.
No novel loci associated with TSH or fT4 were identified. Four loci previously associated with TSH in adults were confirmed in this study population (PDE10A (rs2983511: ß = 0.112SD, p = 4.8 · 10-16), FOXE1 (rs7847663: ß = 0.223SD, p = 1.5 · 10-20), NR3C2 (rs9968300: ß = 0.194SD), p = 2.4 · 10-11), VEGFA (rs2396083: ß = 0.088SD, p = 2.2 · 10-10)). Effect sizes of variants known to associate with TSH or fT4 in adults showed a similar direction of effect in our cohort of children and adolescents, 11 of which were associated with TSH or fT4 in our study (p
Notes
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PubMed ID
28333968 View in PubMed
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Impaired fasting glucose and the metabolic profile in Danish children and adolescents with normal weight, overweight, or obesity.

https://arctichealth.org/en/permalink/ahliterature295500
Source
Pediatr Diabetes. 2018 05; 19(3):356-365
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Date
05-2018
Author
Julie T Kloppenborg
Cilius E Fonvig
Tenna R H Nielsen
Pernille M Mollerup
Christine Bøjsøe
Oluf Pedersen
Jesper Johannesen
Torben Hansen
Jens-Christian Holm
Author Affiliation
The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbaek, Holbaek, Denmark.
Source
Pediatr Diabetes. 2018 05; 19(3):356-365
Date
05-2018
Language
English
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Keywords
Adolescent
Blood glucose
Child
Cross-Sectional Studies
Denmark - epidemiology
Female
Humans
Male
Obesity - blood - complications - epidemiology
Prediabetic State - blood - epidemiology - etiology
Prevalence
Abstract
Whether the definitions of impaired fasting glucose (IFG) from the American Diabetes Association (ADA) and the World Health Organization (WHO) differentially impact estimates of the metabolic profile and IFG-related comorbidities in Danish children and adolescents is unknown.
Two thousand one hundred and fifty four (979 boys) children and adolescents with overweight or obesity (median age 12 years) and 1824 (728 boys) children with normal weight (median age 12 years) from The Danish Childhood Obesity Biobank were studied. Anthropometrics, blood pressure, puberty, and fasting concentrations of glucose, insulin, glycosylated hemoglobin (HbA1c), and lipids were measured.
About 14.1% of participants with overweight or obesity exhibited IFG according to the ADA and 3.5% according to the WHO definition. Among individuals with normal weight, the corresponding prevalences were 4.3% and 0.3%. IFG was associated with a higher systolic blood pressure, higher concentrations of HbA1c, insulin, C-peptide (P?
PubMed ID
29193487 View in PubMed
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