Elizabeth Crowne

Physical activity patterns in nonobese and obese children assessed using minute-by-minute accelerometry.

OBJECTIVE:To determine the levels and patterns of physical activity in a sample of obese (≥99th percentile body mass index (BMI)) and nonobese (<99th percentile BMI) children.DESIGN:Cross-sectional study.SETTING:Children were recruited from schools in Bristol and from the childhood obesity clinic, Bristol Royal Hospital for Children. Children were instructed in the use of the accelerometer either while at school or in the clinic, and wore the instrument while carrying out their normal daily activities for 7 days.PARTICIPANTS:A total of133 children (mean age 10.5±0.8 y). In all 11 (16.9%) of the 65 girls and 14 (20.6%) of the 68 boys were classified as obese (above the 99th percentile for BMI and corresponding to projected adult BMI of 30).MAIN OUTCOME MEASURES:Objectively measured physical activity volume, intensity and pattern.RESULTS:Obese children were significantly less physically active overall than their nonobese counterparts (31 844±13 200 vs 41 844±10 430 counts/h; 95% confidence interval 4407 to 15592; P=0.001). Similarly the obese children spent less time in physical activity of moderate or greater intensity than the nonobese children (9.9±3.9 vs 12.9±4.2 min/h; 95% confidence interval 1.15 to 4.80; P=0.002). Hourly patterns of activity indicated a tendency in obese children to be less active than nonobese children at times when activity was more likely to be determined by free choice, particularly outside of school time.CONCLUSIONS:Obese children demonstrated patterns of physical activity that may have contributed to and are likely to sustain their obesity. Minute-by-minute accelerometry is a valuable tool to investigate physical activity patterns in obese children. It can identify periods when intervention to increase activity may be most appropriate and provide an evidence base for specific exercise prescription in primary and secondary care.SPONSORSHIP:Health Education Authority, NHS R& D South–West

Symptomatic adrenal insufficiency presenting with hypoglycaemia in asthmatic children with asthma receiving high dose inhaled fluticasone propionateCommentary: Exogenous glucocorticoids influence adrenal function, but assessment can be difficult

Children taking high dose fluticasone propionate may present with hypoglycaemia secondary to iatrogenic adrenal suppression

KSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidation

Summary Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEK-ERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes. PaperFlick

Fatty acid‐induced defects in insulin signalling, in myotubes derived from children, are related to ceramide production from palmitate rather than the accumulation of intramyocellular lipid

The elevation of free fatty acids (FFAs), observed in childhood obesity results in intramyocellular lipid (IMCL) accumulation with consequent insulin resistance. Using in vitro differentiated myotubes from normal weight pre‐pubertal children (n = 8), we examined the effects of saturated (palmitate) and unsaturated (oleate) FFAs on insulin‐stimulated AKT phosphorylation (pAKT) and IMCL accumulation. Palmitate decreased pAKT (Mean [SEM] % change pAKT with palmitate 750 µM vs. control; pThr308 site −50.5% [28.7] and pSer473 site −38.7% [11.7]; P < 0.001) with no effect on IMCL formation. Equimolar bromopalmitate did not effect pAKT and blocking ceramide production abolished the palmitate‐induced reduction in signalling, suggesting that ceramide synthesis is critical for palmitates actions. Oleate did not effect pAKT (1,000 µM oleate; pSer473 site −3.4% [11.4]; P = NS) but increased IMCL accumulation (+32.3% [7.1%]; P < 0.001). Co‐administration of oleate diminished the reduction in pAKT seen with palmitate (+36.4% [23.6] vs. −13.3% [13.6]; P = 0.28), with similar IMCL levels to oleate alone. Co‐administration also caused a significant reduction in 14C‐ceramide synthesis from 14C‐palmitate (101.6 [21.6] vs. 371.5 [122.4] DPM/mg protein; P < 0.001). In summary, palmitate appears to cause insulin resistance in childrens myotubes via its metabolism to ceramide, and this process appears unrelated to IMCL formation and is ameliorated by oleate. J. Cell. Physiol. 211: 244–252, 2007.

Characterization of differentiated subcutaneous and visceral adipose tissue from children: the influences of TNF-alpha and IGF-I

The relationship between subcutaneous and visceral adipocyte metabolism and development has been extensively studied in adult but not in pediatric tissue. Our aim was to isolate, develop, characterize, and compare primary cell cultures of subcutaneous and visceral preadipocytes from 16 normal prepubertal children (10 male and 6 female). Subculture techniques were developed to increase cell number and allow differentiation using a chemically defined serum-free medium. Removal of insulin from the differentiation medium prevented adipogenesis in both subcutaneous and visceral preadipocytes, whereas coincubation with rosiglitazone markedly enhanced glycerol-3-phosphate dehydrogenase activity, peroxisome proliferator-activated receptor γ expression, and triglyceride accumulation in cells from both fat depots. Adiponectin secretion increased with differentiation from undetectable levels at day 0. Histological analyses demonstrated significant differences in lipid droplet number and size, with subcutaneous cells having fewer but larger vesicles compared with visceral cells. Downregulation and reorganization of the cytoskeleton appeared comparable. We further demonstrate regional differences in adipogenesis manipulation. Tumor necrosis factor-α was more effective at inhibiting differentiation in subcutaneous cells, whereas insulin-like growth factor-I stimulated differentiation more effectively in visceral cells. Insulin-like growth factor binding protein-3 enhanced differentiation equally. These observations may have important physiological and pharmacological implications for the development of obesity in later life.

Clinical measures of adiposity and percentage fat loss: which measure most accurately reflects fat loss and what should we aim for?

Objective: To determine which clinical measure of childhood obesity should be monitored to best reflect change in adiposity in a weight management programme and estimate the degree of change needed to be relatively certain of fat reduction. Subjects: 92 obese children with a mean (range) age of 12.8 (6.9–18.9) years and a mean body mass index standard deviation score (BMI SDS) of +3.38 (+2.27 to +4.47) attending a hospital-based clinic on a regular, 3 monthly basis. Measurements: Pairs of weight and height measured up to 2.41 years apart used to derive BMI as kg/m2, and adjusted for age and gender to give weight and BMI SDS (BMI-z score) using British 1990 Growth Reference Data. Contemporaneous adiposity estimated by fatness measured by a bioimpedance segmental body composition analyser. Results: Changes in BMI-z scores, compared to BMI, weight and weight SDS, most accurately reflected loss of fat. Reductions of 0.25, 0.5, 0.75, and 1 BMI SDS equate to expected mean falls in total body fat percentage of 2.9%, 5.8%, 8.7% and 11.6%. Approximate 95% prediction intervals indicated that a fall in BMI SDS of at least 0.6 over 6–12 months (or 0.5 over 0–6 months) is consistent with actual fat loss. Conclusion: Change in BMI-z score best reflects percentage fat loss compared to BMI, weight and weight SDS. The wide variation in likely percentage fat loss for a given BMI SDS reduction means a loss of 0.5–0.6 is required to be relatively certain of definite percentage fat reduction.

Fasting Nonesterified Fatty Acid Profiles in Childhood and Their Relationship With Adiposity, Insulin Sensitivity, and Lipid Levels

OBJECTIVE. The objective of this study was to examine the major constituent of nonesterified fatty acids in children with respect to auxologic parameters, insulin sensitivity, and lipid levels, because nonesterified fatty acid levels are elevated in obesity and are important in the development of comorbidities. METHODS. Fasting blood samples were obtained from 73 children (43 girls; 49 obese; median [range] age: 11.4 [0.9–17.6] years). Concentrations of the major circulating nonesterified fatty acids (myristate, palmitate, oleate, stearate, and arachidate) were determined by gas chromatography mass spectrometry, alongside measurement of insulin, adiponectin, and lipid profiles. RESULTS. The sum of all nonesterified fatty acids was significantly higher in obese versus normal-weight children, although gender (but not age or puberty) was an important determinant, with the difference remaining significant only in boys. Overall, obese children had higher concentrations of myristate, palmitate, and oleate but not stearate or arachidate. Age was an important determinant of myristate and arachidate, whereas gender proved more important for palmitate and stearate. Fasting insulin concentrations were not associated with either total nonesterified fatty acid concentrations or any of the individual nonesterified fatty acids, although a positive correlation was found between adiponectin and total nonesterified fatty acid concentrations that was independent of obesity status and that seemed mediated by changes in palmitate and stearate. Serum total cholesterol and low-density lipoprotein (but not high-density lipoprotein) levels seemed to correlate positively with circulating concentrations of palmitate, oleate, and stearate, whereas serum triacylglycerols correlated with myristate, palmitate, and oleate concentrations. CONCLUSIONS. Nonesterified fatty acid concentrations are elevated in obese children, primarily as a result of increases in myristate, palmitate, and oleate. Independent effects of nonesterified fatty acids on circulating adiponectin levels and lipid parameters were observed, although we found no relationship between nonesterified fatty acid concentrations and the insulin resistance identified with obesity.

Characterisation of morbidity in a UK, hospital based, obesity clinic

Aim: To identify clinical features which predict those most at risk of co-morbidities within an obesity clinic. Methods: Children attending an obesity clinic had fasting glucose, insulin, and lipids measured prior to a standard oral glucose tolerance test (OGTT). History and examination established birth weight, family history of type 2 diabetes/obesity, pubertal status, and presence of acanthosis nigricans. Central and total fat mass was estimated by bio-impedance. Results: Of the 126 children evaluated, 10.3% (n = 13) had impaired glucose tolerance (IGT); the majority (n = 11) of these would not have been identified on fasting glucose alone. Those with IGT were more likely to have a parental history of type 2 diabetes (relative risk 3.5). IGT was not associated with acanthosis nigricans. Twenty five per cent (n = 19) of those evaluated (n = 75) had evidence of the “metabolic syndrome” (MS). HDL cholesterol and triglyceride levels were related to insulin sensitivity (HOMA-R); HDL cholesterol was also related to birth weight SDS. We observed a trend for those with MS to have a lower birth weight SDS. The severity of obesity did not influence the likelihood of IGT or MS. Conclusions: Significant numbers of obese children have associated co-morbidities. Analysis of fasting blood glucose samples alone is not satisfactory to adequately evaluate glucose homoeostasis. The overall level of obesity does not predict co-morbidities. Special attention should be given to those with parental diabetes and a history of low birth weight who are more likely to have IGT and abnormal lipid profiles respectively.

The effect of the Talking Diabetes consulting skills intervention on glycaemic control and quality of life in children with type 1 diabetes: cluster randomised controlled trial (DEPICTED study)

Objective To evaluate the effectiveness on glycaemic control of a training programme in consultation skills for paediatric diabetes teams. Design Pragmatic cluster randomised controlled trial. Setting 26 UK secondary and tertiary care paediatric diabetes services. Participants 79 healthcare practitioners (13 teams) trained in the intervention (359 young people with type 1 diabetes aged 4-15 years and their main carers) and 13 teams allocated to the control group (334 children and their main carers). Intervention Talking Diabetes programme, which promotes shared agenda setting and guiding communication style, through flexible menu of consultation strategies to support patient led behaviour change. Main outcome measures The primary outcome was glycated haemoglobin (HbA1c) level one year after training. Secondary outcomes were clinical measures (hypoglycaemic episodes, body mass index, insulin regimen), general and diabetes specific quality of life, self reported and proxy reported self care and enablement, perceptions of the diabetes team, self reported and carer reported importance of, and confidence in, undertaking diabetes self management measured over one year. Analysis was by intention to treat. An integrated process evaluation included audio recording a sample of 86 routine consultations to assess skills shortly after training (intervention group) and at one year follow-up (intervention and control group). Two key domains of skill assessment were use of the guiding communication style and shared agenda setting. Results 660/693 patients (95.2%) provided blood samples at follow-up. Training diabetes care teams had no effect on HbA1c levels (intervention effect 0.01, 95% confidence interval −0.02 to 0.04, P=0.5), even after adjusting for age and sex of the participants. At follow-up, trained staff (n=29) were more capable than controls (n=29) in guiding (difference in means 1.14, P<0.001) and agenda setting (difference in proportions 0.45, 95% confidence interval 0.22 to 0.62). Although skills waned over time for the trained practitioners, the reduction was not significant for either guiding (difference in means −0.33, P=0.128) or use of agenda setting (difference in proportions −0.20, −0.42 to 0.05). 390 patients (56%) and 441 carers (64%) completed follow-up questionnaires. Some aspects of diabetes specific quality of life improved in controls: reduced problems with treatment barriers (mean difference −4.6, 95% confidence interval −8.5 to −0.6, P=0.03) and with treatment adherence (−3.1, −6.3 to −0.01, P=0.05). Short term ability to cope with diabetes increased in patients in intervention clinics (10.4, 0.5 to 20.4, P=0.04). Carers in the intervention arm reported greater excitement about clinic visits (1.9, 1.05 to 3.43, P=0.03) and improved continuity of care (0.2, 0.1 to 0.3, P=0.01). Conclusions Improving glycaemic control in children attending specialist diabetes clinics may not be possible through brief, team-wide training in consultation skills. Trial registration Current Controlled Trials ISRCTN61568050.

Communication skills of healthcare professionals in paediatric diabetes services

Aims  To identify training needs in communication skills and to assess training preferences of staff working in paediatric diabetes services, which will inform the development of a learning programme in behaviour change counselling for healthcare professionals.