Terence J. Wilkin

Effectiveness of intervention on physical activity of children: systematic review and meta-analysis of controlled trials with objectively measured outcomes (EarlyBird 54)

Objective To determine whether, and to what extent, physical activity interventions affect the overall activity levels of children. Design Systematic review and meta-analysis. Data sources Electronic databases (Embase, Medline, PsycINFO, SPORTDiscus) and reference lists of included studies and of relevant review articles. Study selection Design: randomised controlled trials or controlled clinical trials (cluster and individual) published in peer reviewed journals. Intervention: incorporated a component designed to increase the physical activity of children/adolescents and was at least four weeks in duration. Outcomes: measured whole day physical activity objectively with accelerometers either before or immediately after the end of the intervention period. Data analysis Intervention effects (standardised mean differences) were calculated for total physical activity, time spent in moderate or vigorous physical activity, or both for each study and pooled using a weighted random effects model. Meta-regression explored the heterogeneity of intervention effects in relation to study participants, design, intervention type, and methodological quality. Results Thirty studies (involving 14 326 participants; 6153 with accelerometer measured physical activity) met the inclusion criteria and all were eligible for meta-analysis/meta-regression. The pooled intervention effect across all studies was small to negligible for total physical activity (standardised mean difference 0.12, 95% confidence interval 0.04 to 0.20; P<0.01) and small for moderate or vigorous activity (0.16, 0.08 to 0.24; P<0.001). Meta-regression indicated that the pooled intervention effect did not differ significantly between any of the subgroups (for example, for total physical activity, standardised mean differences were 0.07 for age <10 years and 0.16 for ≥10 years, P=0.19; 0.07 for body mass index across the entire range and 0.22 for exclusively overweight/obese children, P=0.07; 0.12 for study duration ≤6 months and 0.09 for >6 months, P=0.71; 0.15 for home/family based intervention and 0.10 for school based intervention, P=0.53; and 0.09 for higher quality studies and 0.14 for lower quality studies, P=0.52). Conclusions This review provides strong evidence that physical activity interventions have had only a small effect (approximately 4 minutes more walking or running per day) on children’s overall activity levels. This finding may explain, in part, why such interventions have had limited success in reducing the body mass index or body fat of children.

Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes

The transcription factor insulin promoter factor-1 (IPF-1) plays a central role in both the development of the pancreas and the regulation of insulin gene expression in the mature pancreatic β cell. A dominant-negative frameshift mutation in the IPF-l gene was identified in a single family and shown to cause pancreatic agenesis when homozygous and maturity-onset diabetes of the young (MODY) when heterozygous. We studied the role of IPF-1 in Caucasian diabetic and nondiabetic subjects from the United Kingdom. Three novel IPF-1 missense mutations (C18R, D76N, and R197H) were identified in patients with type 2 diabetes. Functional analyses of these mutations demonstrated decreased binding activity to the human insulin gene promoter and reduced activation of the insulin gene in response to hyperglycemia in the human β-cell line Nes2y. These mutations are present in 1% of the population and predisposed the subject to type 2 diabetes with a relative risk of 3.0. They were not highly penetrant MODY mutations, as there were nondiabetic mutation carriers 25‐53 years of age. We conclude that mutations in the IPF-1 gene may predispose to type 2 diabetes and are a rare cause of MODY and pancreatic agenesis, with the phenotype depending upon the severity of the mutation. J. Clin. Invest. 104:R33-R39 (1999).

Contribution of Early Weight Gain to Childhood Overweight and Metabolic Health: A Longitudinal Study (EarlyBird 36)

BACKGROUND. Early weight gain (0–5 years) is thought to be an important contributor to childhood obesity and consequently metabolic risk. There is a scarcity of longitudinal studies in contemporary children reporting the impact of early weight gain on metabolic health. OBJECTIVE. We aimed to assess the impact of early weight gain on metabolic health at 9 years of age. METHOD. Two hundred thirty-three children (134 boys, 99 girls) with a gestational age of >37 weeks were assessed at birth, 5 years of age, and 9 years of age. Measures included weight SD scores at each time point and excess weight gained (Δ weight SD score) between them. The outcome measure included composite metabolic score (sum of internally derived z scores of insulin resistance, mean blood pressure, triglyceride level, and total cholesterol/high-density lipoprotein cholesterol ratio). RESULTS. Weight SD score increased by 0.29 SD score in girls and 0.26 SD score in boys from 0 to 5 years of age and by 0.03 SD score in girls and 0.11 SD score in boys from 5 to 9 years of age. Weight SD score correlated poorly to moderately before 5 years of age but strongly after 5 years of age. Birth weight SD score predicted (girls/boys) 2.4%/0% of the variability in composite metabolic score at 9 years of age. Adding Δ weight SD score (0–5 years old) contributed (girls/boys) 11.2%/7.0% to the score, and adding Δ weight SD score (5–9 years old) additionally contributed (girls/boys) 26.4%/16.5%. Importantly, once weight SD score at 9 years of age was known, predictive strength was changed little by adding Δ weight SD score. CONCLUSIONS. Most excess weight before puberty is gained before 5 years of age. Weight at 5 years of age bears little relation to birth weight but closely predicts weight at 9 years of age. Single measures of current weight are predictive of metabolic health, whereas weight gain within a specific period adds little. A single measure of weight at 5 years of age provides a pointer to future health for the individual. If metabolic status at 9 years of age means future risk, diabetes/cardiovascular prevention strategies might better focus on preschool-aged children, because the die seems to be largely cast by 5 years of age, and a healthy weight early in childhood may be maintained at least into puberty.

Studies of Association between the Gene for Calpain-10 and Type 2 Diabetes Mellitus in the United Kingdom

Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.

VALUE OF INSULIN AUTOANTIBODIES AS SERUM MARKERS FOR INSULIN-DEPENDENT DIABETES MELLITUS

Insulin autoantibodies (IAA) were studied in newly diagnosed insulin-dependent diabetics before the start of insulin treatment and in unaffected identical twins of insulin-dependent diabetics. In 15 of the 40 (38%) diabetics and 27 of the 58 (47%) twins IAA levels exceeded those of 100 controls. Frequency of IAA in unaffected twins was not related to duration of diabetes in their affected twin. In 11 unaffected twins, IAA levels differed in two samples taken 1-12 years apart; IAA were detected at least once in all twins and in one on both occasions. IAA in the twins were not related to the presence of islet-cell antibodies or to HLA-DR 3 or 4. As the unaffected twins of longstanding diabetics are unlikely to develop diabetes, these observations suggest that IAA do not always presage diabetes and are probably not a consequence of the disease; they may reflect an inherited autoimmune tendency to diabetes.

Contribution of timetabled physical education to total physical activity in primary school children: cross sectional study.

A recent survey of children at primary schools in England found a marked decline in timetabled physical education between 1994 and 1999.1 Sport England expressed concern about the impact of competing priorities, such as numeracy and literacy, on curricular physical education and concluded that children from poorer backgrounds would be worst affected. We used accelerometers to measure the impact of timetabled physical education at school on overall physical activity in children. We monitored physical activity during waking hours for seven days using accelerometers (Manufacturing Technology, Fort Walton Beach, FL2) in 215 children (120 boys and 95 girls aged 7.0-10.5 (mean 9.0) years) from three schools with different sporting facilities and opportunity for physical education in the curriculum. School 1, a private preparatory school with some boarding pupils, had extensive facilities and 9.0 hours a week of physical education in the curriculum. School 2, a village school awarded Activemark gold status …

Physical activity at the government-recommended level and obesity-related health outcomes: a longitudinal study (Early Bird 37)

Background: In the UK and USA, government guidelines for childhood physical activity have been set (⩾60 min/day at ⩾3 metabolic equivalents of thermogenesis (METs)), and body mass index (BMI) chosen as the outcome measure. Aim: To determine the extent to which physical activity at the government-recommended intensity is associated with change in body mass/fat and metabolic health in pre-pubertal children. Methods: Non-intervention longitudinal study of 113 boys and 99 girls (born 1995/96) recruited from 54 schools. Physical activity (Actigraph accelerometers), changes in body mass (raw and age/gender-standardised BMI), fatness (skin-fold thickness and waist circumference) and metabolic status (insulin resistance, triglycerides, cholesterol/HDL ratio and blood pressure – separately and as a composite metabolic z score) were measured on four annual occasions (5, 6, 7 and 8 years). Results: Mean physical activity did not change over time in either sex. Averaging the 7-day recordings from four time points rather than one increased the reliability of characterising a child’s activity from 71% to 90%. Some 42% of boys and 11% of girls met the guideline. There were no associations between physical activity and changes in any measurement of body mass or fatness over time in either sex (eg, BMI standard deviation scores: r = −0.02, p = 0.76). However, there was a small to moderate inverse association between physical activity and change in composite metabolic score (r = −0.19, p<0.01). Mixed effects modelling showed that the improvement in metabolic score among the more active compared to the less active children was linear with time (−0.08 z scores/year, p = 0.001). Conclusions: In children, physical activity above the government-recommended intensity of 3 METs is associated with a progressive improvement in metabolic health but not with a change in BMI or fatness. Girls habitually undertake less physical activity than boys, questioning whether girls in particular should be encouraged to do more, or the recommendations adjusted for girls.

Age Before Stage: Insulin Resistance Rises Before the Onset of Puberty: A 9-year longitudinal study (EarlyBird 26)

OBJECTIVE Insulin resistance (IR) is associated with diabetes. IR is higher during puberty in both sexes, with some studies showing the increase to be independent of changes in adiposity. Few longitudinal studies have reported on children, and it remains unclear when the rise in IR that is often attributed to puberty really begins. We sought to establish from longitudinal data its relationship to pubertal onset, and interactions with age, sex, adiposity, and IGF-1. RESEARCH DESIGN AND METHODS The EarlyBird Diabetes study is a longitudinal prospective cohort study of healthy children aged 5–14 years. Homeostasis model assessment (HOMA-IR), skinfolds (SSF), adiposity (percent fat, measured by dual-energy X-ray absorptiometry), serum leptin, and IGF-1 were measured annually in 235 children (134 boys). Pubertal onset was adduced from Tanner stage (TS) and from the age at which luteinizing hormone (LH) first became serially detectable (≥0.2 international units/L). RESULTS IR rose progressively from age 7 years, 3–4 years before TS2 was reached or LH became detectable. Rising adiposity and IGF-1 together explained 34% of the variance in IR in boys and 35% in girls (both P < 0.001) over the 3 years preceding pubertal onset. The contribution of IGF-1 to IR was greater in boys, despite their comparatively lower IGF-1 levels. CONCLUSIONS IR starts to rise in mid-childhood, some years before puberty. Its emergence relates more to the age of the child than to pubertal onset. More than 60% of the variation in IR prior to puberty was unexplained. The demography of childhood diabetes is changing, and prepubertal IR may be important.

The gender insulin hypothesis: why girls are born lighter than boys, and the implications for insulin resistance

Girls are born lighter than boys. The consistency of this observation across different populations is striking, suggesting that it may have fundamental significance for those conditions linked with lower birth weight, such as diabetes. Previous hypotheses relating low birth weight to subsequent diabetes have addressed differences in insulin resistance within the sexes, not between them. Here, we propose that gender-specific genes affecting insulin sensitivity are responsible for the gender difference in birth weight – the genetically more insulin resistant female fetus is less responsive to the trophic effects of insulin and is therefore smaller. These genes also render female subjects more susceptible to diabetes, explaining why reports of type 2 diabetes (T2D) in younger populations show a female preponderance. Consistent with our proposal, concentrations of insulin and/or its propeptides are higher at birth in female populations and they are intrinsically more insulin resistant throughout life, with attendant impact on their metabolism, and the regressions describing the relationship between insulin resistance and adiposity in female and male subjects have similar gradients, but different constants. These gender-specific genes have a demonstrable impact on fetal growth and insulin resistance. Diabetes and cardiovascular disease are thought to be driven by insulin resistance, and the observations reported here may help to focus the search for genes that control it.

Adiponectin in childhood

Adiponectin, a hormone produced and secreted by adipocytes, is present in circulation in high circulating concentrations, suggesting an important physiological role. An indirect regulator of glucose metabolism, adiponectin increases insulin sensitivity, improves glucose tolerance and inhibits inflammation. Plasma adiponectin relates inversely to adiposity and, importantly, reflects the sequelae of accumulation of excess adiposity. The role of adiponectin in adults has been explored in detail. Studies in children are now available and, given the increasing rates of childhood obesity, it is important to establish the role of adiponectin in mediating insulin resistance and cardiovascular disease in this age group. This paper reviews the regulation of adiponectin, its effect on body mass, glucose metabolism and cardiovascular risk in infants, children and adolescents. It demonstrates clear links between adiponectin and features of the metabolic syndrome in obese children and adolescents. However, adiponectins role as a predictor of metabolic dysfunction in healthy, normal-weight youngsters is less clear.