Awareness of body weight by mothers and their children: repeated measures in a single cohort (EarlyBird 64).

BACKGROUND: Mothers often do not realize when their child is overweight. We aimed to compare mothers' perceptions of children's weight before and during puberty, and to explore factors at 7 years predicting recognition of overweight at 16 years. METHODS: Mothers of 237 children (136 boys) from the EarlyBird study estimated their own weight category and that of their child aged 7 years and 16 years. The children estimated their own weight category at 16 years. Annual measures: body mass index standard deviation score (BMIsds), per cent fat, physical activity. Pubertal development assessed by age at peak height velocity (APHV). MATERNAL MEASURES: BMI, education, socio-economic status. RESULTS: At 7 years 21% of girls and 16% of boys were overweight or obese, rising to 27% and 22% respectively at 16 years. The accuracy of the mother's perception of her child's weight category improved from 44% at 7 years to 74% at 16 years, but they were less able to judge overweight in sons than daughters. The mothers' level of concern about overweight was greater for girls than boys, and increased for girls (52% mothers of overweight/obese girls were worried at 7 years, 62% at 16 years), but remained static in the boys (42% vs. 39%). Over 80% of the youngsters realized when they were overweight, but 25% normal-weight girls also classed themselves as overweight. Only BMI predicted a mother's ability to correctly perceive her child's weight. Neither her awareness, nor concern, about the child's weight at 7 years had any impact on the trajectory of the child's BMI from 7 years to 16 years. CONCLUSIONS: Parents are central to any successful weight reduction programme in their children, but will not engage while they remain ignorant of the problem. Crucially, any concern mothers may have about their child's excess weight at 7 years appears to have no impact on subsequent weight change.

The convergence of type 1 and type 2 diabetes in childhood: the accelerator hypothesis.

It seems likely that type 1 and type 2 diabetes lie at different points of the same spectrum, separated by the misunderstanding that one belongs to childhood and the other to adulthood. The spectrum is that of tempo--the rate at which beta cell function is lost over time. A combination of beta cell up-regulation (insulin demand, largely determined by obesity) and the genetically-determined immune response to it ('autoimmunity') determines tempo, ranging from slow to fast with every variant in between. There is good evidence that people who go on to develop type 1 (fast) diabetes are, like those who develop type 2 (slow diabetes), insulin resistant, and overwhelming evidence that body mass plays a key role. The prevention of type 1 diabetes may lie in weight restriction from an early age.

Can we modulate physical activity in children? No.

Intuition tells us that physical activity is central to weight reduction in obese children. Evidence, on the other hand, suggests that increases in physical activity are difficult to achieve in the short term, and may not be possible in the long term. One explanation could be an 'activitystat', a feedback loop in the child's brain that controls physical activity according to a set point. This brief article, which argues that it may not be possible to modulate the activity of children, reviews the principles of feedback control as they apply to physical activity, discusses evidence for its central control, and demonstrates how a physical activity control loop might operate to defend the set point. Studies restricted to objective measurement suggest that the physical activity of children varies in a systematic, rather than random manner. It varies little from environment to environment, from year to year or from place to place. Where children undertake more activity at one time of day, they appear to compensate at another. Systematic variation of this kind implies control, and the control of physical activity appears to lie with the child, not with his environment. Perturbation (temporary change in response to disturbance) during short-term physical activity interventions may be mistaken for modulation (permanent change in set point), a fundamentally different response. Perturbation lasts no longer than the disturbance that causes it, and there is little evidence that interventions raise activity long term, if at all.

BMI was right all along: taller children really are fatter (implications of making childhood BMI independent of height) EarlyBird 48.

OBJECTIVE: Several studies suggest that taller children may be wrongly labelled as 'overweight' because body mass index (BMI) is not independent of height (Ht) in childhood, and recommend adjustment to render the index Ht independent. We used objective measures of %body fat and hormonal/metabolic markers of fatness to investigate whether BMI and the corresponding fat mass index (FMI) mislead in childhood, or whether taller children really are fatter. DESIGN: Longitudinal observational study measuring children annually from age 7 to 12 years. SUBJECTS: Two hundred and eighty healthy children (56% boys) from the EarlyBird study. MEASUREMENTS: BMI (body mass (BM)/Ht(2)), FMI (fat mass (FM)/Ht(2)), %body fat ((FM/BM) × 100, where FM was measured by dual-energy X-ray absorptiometry), fasting leptin (a hormonal measure of body fatness) and insulin resistance (a metabolic marker derived from the validated homeostasis model assessment program for insulin resistance--HOMA2-IR) were all analysed in relation to Ht. Alternative Ht-independent indices of BM and FM were compared with BMI and FMI as indicators of true fatness and related health risk. RESULTS: BMI and FMI correlated with Ht at each annual time point (r~0.47 and 0.46, respectively), yet these correlations were similar in strength to those between Ht and %fat (r~0.47), leptin (r~0.41) and insulin resistance (r~0.40). Also, children who grew the most between 7 and 12 years showed greater increases in BMI, FMI, leptin and insulin resistance (tertile 1 vs 3, all p<0.05). BMI and FMI explained ~20% more of the variation in %fat, ~15% more in leptin and ~10% more in insulin resistance than the respective Ht-independent reformulations (BM/Ht(3.5) and FM/Ht(7), both p<0.001). CONCLUSION: Taller children really are fatter than their shorter peers, have higher leptin levels and are more insulin resistant. Attempts to render indices of BM or FM independent of Ht in children seem inappropriate if the object of the index is to convey health risk.

The impact of school-time activity on total physical activity: the activitystat hypothesis (EarlyBird 46).

OBJECTIVES: To explore the activitystat hypothesis in primary school children by asking whether more physical activity (PA) in school time is compensated for by less PA at other times. STUDY DESIGN: Observational, repeated measures (four consecutive occasions over a 12-month period). SETTING: South-west England. PARTICIPANTS: A total of 206 children (115 boys, aged 8-10 years) from 3 primary schools (S1, S2 and S3), which recorded large differences in PA during school time. MEASUREMENTS: Total PA (TPA) and its moderate-and-vigorous component were recorded weekly by accelerometry, in school and out of school, and adjusted for local daily rainfall and daylight hours. Habitual PA was assessed by linear mixed-effects modelling on repeated measures. RESULTS: S1 children recorded 64% more in-school PA, but S2 and S3 children compensated with correspondingly more out-of-school PA, so that TPA between the three schools was no different: 35.6 (34.3-36.9), 37.3 (36.0-38.6) and 36.2 (34.9-37.5) Units, respectively (P=0.38). CONCLUSIONS: The PA of children seems to compensate in such a way that more activity at one time is met with less activity at another. The failure of PA programmes to reduce childhood obesity could be attributable to this compensation.

Reliability of energy expenditure prediction equations in the weight management clinic.

BACKGROUND: Few weight management clinics have access to indirect calorimetry with which to measure energy expenditure. Instead, they use energy expenditure prediction equations, which were not designed for use in obesity. We aimed to establish the extent to which such equations overestimate and underestimate resting energy expenditure (REE) in overweight and obese individuals. METHODS: We compared the Schofield, Harris & Benedict, James & Lean and World Health Organisation (WHO) REE prediction equations with the clinical gold standard of indirect calorimetry in 28 males and 168 females, with a mean (SD) age of 28.9 (6.4) years and body mass index (BMI) of 19-67 kg m(-2). RESULTS: The mean REE estimated by indirect calorimetry, and the Schofield, Harris & Benedict, James & Lean and WHO equations were 8.09, 8.30, 8.09, 8.37 and 8.23 MJ day(-1) (1934, 1983, 1933, 2001 and 1966 kcal day(-1)), respectively. Although rising BMI exerted only a small effect on the mean differences between indirect calorimetry and the predicted REE [Schofield: +272 kJ (+65 kcal)/10 units BMI, P = 0.02; Harris & Benedict: +42 kJ (+10 kcal)/10 units BMI, P = 0.69; James & Lean: +217 kJ (+52 kcal) 10 units BMI, P = 0.06 and WHO: +42 kJ (+10 kcal) BMI, P = 0.11], the variance among overweight and obese patients of BMI >25 was substantially higher compared to that among normal weight subjects of BMI <25, on whom the equations were based. The estimated REE by Schofield for an individual of BMI 35 kg m(-2), for example, could lie anywhere from 2.78 MJ (661 kcal) above the indirect calorimetry value to 2.59 MJ (618) kcal below it. CONCLUSIONS: Prediction equations offer a quick assessment of energy needs for hypocaloric diets although, in reality, they run the random risk of excessive restriction or further weight gain.

The accelerator hypothesis: a review of the evidence for insulin resistance as the basis for type I as well as type II diabetes.

Although some 40 years have passed since type I diabetes was first defined, its cause remains unknown. The autoimmunity paradigm of immune dysregulation has not offered an explanation for its rising incidence, nor means of preventing it, and there is arguably good reason to consider alternatives. The accelerator hypothesis is a singular, unifying concept that argues that type I and type II diabetes are the same disorder of insulin resistance, set against different genetic backgrounds. The hypothesis does not deny the role of autoimmuniy, only its primacy in the process. It distinguishes type I and type II diabetes only by tempo, the faster tempo reflecting the more susceptible genotype and (inevitably) earlier presentation. Insulin resistance is closely related to the rise in overweight and obesity, a trend that the hypothesis deems central to the rising incidence of all diabetes in the developed and developing world. Rather than overlap between the two types of diabetes, the accelerator hypothesis envisages overlay-each a subset of the general population differing from each other only by genotype. Indeed, it views type I and type II diabetes as a continuum, where the infinitely variable interaction between insulin resistance and genetic response determines the age at which beta-cell loss becomes critical. Adult diabetes is not viewed as an entity, but rather as diabetes presenting in adulthood. Childhood diabetes, similarly, is diabetes presenting in childhood. The increasing incidence of both is primarily the result of lifestyle change and the rise in body weight that has resulted.

Assortative weight gain in mother-daughter and father-son pairs: an emerging source of childhood obesity. Longitudinal study of trios (EarlyBird 43).

OBJECTIVE: To look for same-sex (gender assortative) association of body mass index (BMI) in healthy trios (mother, father and child) from a contemporary birth cohort, which might imply shared environment rather than shared genes because selective mother-daughter and father-son gene transmission is not a common Mendelian trait. DESIGN: Prospective (longitudinal) cohort study with four annual time points, from 5 to 8 years. SUBJECTS: 226 healthy trios from a 1995 to 1996 birth cohort randomly selected in the city of Plymouth, UK. MEASUREMENTS: Average BMI of the two parents and maternal/paternal BMI separately related to the BMI-SDS (standard deviation score) of all offspring and to the BMI-SDS of the sons and the daughters separately. RESULTS: There were big differences in BMI-SDS among the daughters grouped according to mothers' category of BMI (effect size 1.37 SDS), but not their sons (effect size 0.16 SDS, gender interaction P<0.004), and among the sons grouped according to their fathers' BMI (effect size 1.28 SDS), but not their daughters (effect size 0.17, gender interaction P=0.02). Children whose same-sex parents were of normal weight, weighed either close to (girls+0.20 BMI-SDS) or less than (boys,-0.34 BMI-SDS) children of 20 years ago, and did not change from 5 to 8 years. In contrast, the risks of obesity at 8 years were 10-fold greater (girls 41%, P<0.001) or sixfold greater (boys 18%, P<0.05) if the same-sex parent was obese. Longitudinal linear mixed effects (multilevel) modelling showed a marked influence of maternal and paternal BMI on the rate of weight gain, which was unaffected by birth weight of the child. We report perhaps the largest effect sizes so far recorded in childhood obesity. CONCLUSIONS: Childhood obesity today seems to be largely confined to those whose same-sex parents are obese, and the link does not seem to be genetic. Parental obesity, like smoking, might be targeted in the interests of the child.

Children from low-income families have less access to sports facilities, but are no less physically active: cross-sectional study (EarlyBird 35).

BACKGROUND: Rising levels of childhood obesity have led to an increasing number of Government sponsored initiatives attempting to stem the problem. Much of the focus to date has been on physical activity and out-of-school activity in particular. There is an assumption that children from low-income families suffer most where there is a lack of structured physical education in school. Accordingly, provision of additional facilities for sport and other forms of active recreation tend to target areas of socio-economic deprivation. AIM: We have assessed the relationship between parental income, the use of out-of-school sports facilities and the overall physical activity of young children across a wide socio-economic range. METHODS: Total weekly physical activity was measured, objectively, over 7 days both at 7 years and 8 years in a healthy cohort of 121 boys and 93 girls using actigraph accelerometers. Questionnaires were used to establish parental income and parents reported the child's weekly use of out-of-school facilities for structured physical activity. RESULTS: Children from low-income families attended significantly fewer sessions of structured out-of-school activities than those from wealthier families (r = 0.39), with a clear dose-response relationship across income groups. Nevertheless, total physical activity, measured objectively over seven continuous days, showed no relationship between parental income and the mean activity level of the children (r = -0.08). Nor did we find a relationship between parental income and time spent in higher intensity activity (r = -0.04). CONCLUSION: Social inequality appears to have little impact on physical activity in young children. Those from poorer families make less use of facilities for structured activity out-of-school but they nevertheless record the same overall level of activity as others. What they lack in opportunity they appear to make up in the form of unstructured exercise. Improving provision for sport may not lead to the expected rise in activity levels in young children.

Increased urinary dopamine excretion in association with bilateral carotid body tumours-- clinical, biochemical and genetic findings.

This report describes a rare case of a patient with increased urinary dopamine excretion in association with bilateral carotid body tumours. Excretion of adrenaline, noradrenaline, metadrenaline, normetadrenaline and 4-hydroxy-3-methoxymandelic acid (HMMA) were within the reference ranges, and an (123)I-meta-iodobenzylguanidine (MIBG) scan showed uptake in the neck masses, with no other abnormal uptake anywhere else in the body. The patient is being managed conservatively as the tumours are not amenable to resection on account of their size and vascularity. There are only four previous case reports of dopamine-secreting tumours of the carotid body described in the literature, all of whom were women. The tumours were unilateral in three cases and bilateral in the fourth case. Familial cases of carotid body tumours have a higher prevalence of bilateral tumours than non-familial cases. Recent reports in the literature have suggested that a significant number of patients with extra-adrenal catecholamine-secreting paragangliomas have a genetic mutation in one of the identified susceptibility genes for catecholamine-secreting tumours, despite having no other affected family members, and a mutation has been found in the succinate dehydrogenase gene for this patient.

Increased preproinsulin mRNA in pancreatic islets incubated with islet cell-stimulating antibodies from serums of type I diabetic patients.

We recently described autoantibodies that stimulate the release of insulin from pancreatic beta-cells both in vitro and in vivo. The aim of this study was to establish whether islet cell-stimulating antibodies (ICSTAs) also increase islet cell preproinsulin mRNA content. Wistar rat islets, isolated by collagenase digestion, were exposed to 2.7 and 11.1 mM glucose. Insulin release increased 10-fold in response to the higher glucose concentration, and dot-blot analysis of islet mRNA with a rat preproinsulin cDNA probe showed a concomitant increase in mRNA levels. The globulin fractions of four test serums, three from patients with type I (insulin-dependent) diabetes and one from a patient with the insulin autoimmune syndrome, showed clear (5- to 8-fold) stimulation of insulin release. The nonglobulin fractions of these serums and both fractions of three control serums failed to stimulate secretion of insulin. The insulin mRNA content of islets incubated with the ICSTA globulin fractions was greatly increased compared with levels observed in islets treated with control serum globulin fractions. We conclude that ICSTAs not only can stimulate the release of insulin but also increase the preproinsulin mRNA content of islet cells.

The pharmacokinetics of nicotinamide in humans and rodents.

Nicotinamide, a derivative of the B vitamin niacin, is currently under trial for the prevention of insulin-dependent diabetes mellitus after success in the NOD mouse. However, the dose, route of administration, and formulation of nicotinamide given to humans is quite different from those used successfully in animals, and the aim of this study was to investigate the plasma pharmacokinetics of oral nicotinamide in humans in two doses and in two different formulations (standard and the long-acting Enduramide). There were no significant differences in the kinetics of the low dose of standard nicotinamide (2.5 mg/kg) and low-dose Enduramide (6.7 mg/kg) in young adult men. Nonlinear kinetics were found with both formulations at higher doses, e.g., a 10-fold increase in the dose of the standard nicotinamide produced a 62-fold increase in the area under the plasma concentration-time curve (AUC). The high dose of standard nicotinamide (25 mg/kg body wt) produced a mean peak plasma concentration 75% higher than that achieved with the sustained release nicotinamide preparation given in a dose similar to that currently used in prevention trials (2 g identical to 26.6 mg/kg body wt for a 75-kg subject). The AUC was also significantly greater with the standard formulation, indicating a higher bioavailability. Long-term plasma levels for high doses of both formulations were modeled from the single-dose kinetics by computer program. The AUC for standard nicotinamide was 1.7 times higher than that for Enduramide.(ABSTRACT TRUNCATED AT 250 WORDS)

Systematic variation and differences in insulin-autoantibody measurements.

Insulin autoantibodies (IAAs) are currently the subject of intensive investigation as potential markers for autoimmune insulitis. However, the results of different reports vary widely. In an attempt to elucidate the reasons for the discrepant reports and to initiate standardization procedures, the International Diabetes Workshop (IDW) undertook two studies in which 22 centers worldwide measured IAA in coded samples. The variance in binding signal from the 49 sera in study 1 was considerable, even when results were standardized, but was largely systematic and attributable to basic differences in assay type (liquid phase versus solid phase) and to differences in the ligand used (human vs. nonhuman insulin). In study 2, 5 sera were prepared and presented blindly to compare dilution curves, insulin-species specificity, interference from irrelevant serum proteins, precision, and dose-dependent displaceability. Many assays, both liquid and solid phase, were influenced by marked and unpredictable nonspecific binding, revealed by loss of parallelism between dilution curves in pooled normal serum and buffer, by variable binding signals with different normal sera, and by difficulty in distinguishing human insulin-specific from cross-reactive IAA sera. It was concluded from the experience of both studies that variance could probably be reduced by using a standard curve with derived common units, a single species of ligand, and methodology to minimize the effect of nonspecific binding. Variation related to assay type was probably due to liquid- versus solid-phase systems being differentially more sensitive to certain aspects of antigen-antibody binding; this issue will be addressed in future serum exchanges and workshops.

Antibody markers for type 1 diabetes: the issues.

The detection of islet-cell-specific autoantibodies before clinical onset may mean that diabetes mellitus can be predicted, with important implications for targeting those to whom preventive treatment might be given. A large number of such markers have been proposed, but only high-titer islet cell antibodies have so far demonstrated the specificity and sensitivity to be of potential clinical value.

Testing the accelerator hypothesis: the relationship between body mass and age at diagnosis of type 1 diabetes.

OBJECTIVE: Previous reports have predicted greater risk of type 1 diabetes among people who were heavier as young children. The Accelerator Hypothesis predicts earlier onset in heavier people, without necessarily a change in risk, and views type 1 and type 2 diabetes as the same disorder of insulin resistance, set against different genetic backgrounds. Insulin resistance is a function of fat mass, and increasing body weight in the industrialized world has been accompanied by earlier presentation (i.e., acceleration) of type 2 diabetes. We wanted to establish whether increasing body weight was also associated with the earlier presentation of type 1 diabetes, as the Accelerator Hypothesis would predict. RESEARCH DESIGN AND METHODS: The relationships between fatness and age at diagnosis were examined in context of birth weight, weight change since birth, weight at diagnosis, BMI at diagnosis, and BMI 12 months later in 94 children aged 1-16 years (49 boys and 45 girls) presenting for management of acute-onset type 1 diabetes. RESULTS: BMI standard deviation score (SDS) at diagnosis, weight SDS change since birth, and BMI SDS 12 months later were all inversely related to age at presentation (r = -0.39 to -0.40, P < 0.001). The boys were significantly fatter than the girls (BMI SDS 0.56 vs. -0.08, respectively; P = 0.006) and presented with diabetes at a significantly younger age (6.74 vs. 8.32 years, respectively; P < 0.05). The sex difference in age at diagnosis, however, disappeared when corrected for BMI (P = 0.31), suggesting that fatness or something related to it was the responsible factor. CONCLUSIONS: The data are consistent with the hypothesis that the age at presentation of type 1 diabetes is associated with fatness. The implications for prevention of type 1 diabetes may be important.

Spontaneous hypoglycemia associated with autoimmunity specific to human insulin.

A 55-yr-old woman with a history of Graves' disease experienced attacks of postprandial hypoglycemia for 6 yr. An insulinoma could not be confirmed by repeated fasting tests and by surgical pancreas revision. Extracted pancreatic insulin was chemically normal. Fasting plasma total insulin (1.22 nM = 183 microU/ml) and proinsulin (0.48 nM) were elevated and greatly increased after oral glucose. Glucose-clamp studies revealed delayed insulin clearance. Plasma free-insulin levels were normal. Insulin-binding antibodies were detected by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay with human insulin as ligand but not with pork or beef insulins. Analysis with a modified ELISA suggested a monotypic and monoclonal human insulin autoantibody, which showed a restriction to the lambda-light chain. T-lymphocytes (predominantly helper) demonstrated increased responsiveness to beef, pork, and human insulins by proliferation assay. A T-lymphocyte line showed exclusively human insulin specificity. All this indicated cellular and humoral anti-human insulin autoimmunities. Clinically, the cause of hypoglycemia associated with elevated total insulin and proinsulin was misdiagnosed as atypical insulinoma. The study of total and free plasma insulin levels and sensitive antibody assays specific to human insulin were necessary to correctly diagnose autoimmune hypoglycemia.

An avidin-biotin amplified ELISA for thyrotropin in human serum. Its implication for routine determination of thyrotropin in developing countries.

In developing countries the acquisition and use of radioisotopes with their short shelf lives poses enormous problems. The objective of this study was to develop a simple, sensitive, non-isotopic method for the measurement of TSH in human serum. A conventional sandwich enzyme-linked immunosorbent assay (ELISA) technique was modified to incorporate the avidin-biotin complex (ABC) in order to enhance the sensitivity of a solid-phase micro-ELISA for TSH. The lower limit of TSH detectability was 0.2 mIU/l. TSH levels ranged from 0.3 to 5.1 mIU/l in euthyroid subjects, 11.5-98.0 mIU/l in hypothyroid subjects and less than 0.2-2.1 mIU/l in hyperthyroid subjects. Sera from euthyroid post-menopausal or pregnant women yielded TSH levels within the normal range. The correlation between the TSH values obtained in the ELISA-ABC and a sensitive commercial immunoradiometric method was high (n = 59, r = 0.980, P less than 0.01). The simplicity and relatively high sensitivity of the procedure should make it a method of choice for TSH determination in small hospitals and those in developing countries.

An enzyme-linked immunosorbent assay (ELISA) for urinary growth hormone suitable for use in the routine laboratory. The Wessex Growth Study.

An avidin-biotin enzyme-linked immunoassay was developed to measure human growth hormone (hGH) in urine. The assay was validated in terms of sensitivity, specificity and reproducibility. Parallelism was demonstrated between the standard curve (4-500 pg/ml) and serially concentrated urine. There was no interference from 125 ng/ml of adrenocorticotrophin, follicle stimulating hormone, luteinising hormone, prolactin or thyroid stimulating hormone. Recovery of exogenous human growth hormone in urine ranged from 91 to 103%. Intra- and interassay variations were less than 10% and sensitivity was 1.4 pg/ml. Application to timed overnight urine samples from both normal and short children or from acromegalic patients suggests the assay may be useful for simple, non-invasive assessment of growth hormone secretion. Moreover, use of standard laboratory equipment and commercially available components, together with the avoidance of radioisotopes, facilitate its use as a routine screening assay.

A comparison of spleen and lymph node cells as fusion partners for the raising of monoclonal antibodies after different routes of immunisation.

Administration of antigen (human insulin) via the rear footpads of BALB/c mice with subsequent fusion of popliteal and inguinal lymph node lymphocytes induced a higher frequency of hybridomas (100%) secreting specific antibody than either intradermal immunisation and lymph node cell fusion (53%) or conventional subcutaneous immunisation and intraperitoneal boost followed by splenic lymphocyte fusion (8%). The rank order of serum antibody titres was found to correlate with the order of fusion efficiencies. Lymph node cell fusions also produced a greater spectrum of antibody specificities. Such differences in fusion efficiencies were also observed using bovine intestinal alkaline phosphatase.