Wayne S. Cutfield

Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment

BACKGROUND Growth hormone (GH) contributes to insulin resistance, but whether children treated with GH are at increased risk of diabetes has not been established. We undertook a retrospective analysis of data from an international pharmacoepidemiological survey of children treated with GH to find out the incidence of impaired glucose tolerance and types 1 and 2 diabetes mellitus. METHODS Reports to the survey of abnormal glucose metabolism were investigated and classified. The incidence and age-distribution of type 1 diabetes were compared with values from a model of reference data. The incidence of type 2 diabetes was compared with data from two reports of children not treated with GH. FINDINGS 85 (0.36%) of 23333 children were reported with abnormal glucose metabolism. After investigation, 43 had confirmed glucose disorders (11 with type 1 diabetes, 18 with type 2 diabetes, and 14 with impaired glucose tolerance). The incidence and age at diagnosis of type 1 diabetes in children treated with GH did not differ from expected values. The incidence of type 2 diabetes was 34.4 cases per 100000 years of GH treatment which was six-fold higher than reported in children not treated with GH. Type 2 diabetes did not resolve after GH therapy was stopped. INTERPRETATION GH treatment did not affect the incidence of type 1 diabetes mellitus in any age group. We postulate that the higher than expected incidence of type 2 diabetes mellitus with GH treatment may be an acceleration of the disorder in predisposed individuals.

Insulin resistance in children: Consensus, perspective, and future directions

OBJECTIVE Emerging data indicate that insulin resistance is common among children and adolescents and is related to cardiometabolic risk, therefore requiring consideration early in life. However, there is still confusion on how to define insulin resistance, how to measure it, what its risk factors are, and whether there are effective strategies to prevent and treat it. A consensus conference was organized in order to clarify these points. PARTICIPANTS The consensus was internationally supported by all the major scientific societies in pediatric endocrinology and 37 participants. EVIDENCE An independent and systematic search of the literature was conducted to identify key articles relating to insulin resistance in children. CONSENSUS PROCESS The conference was divided into five themes and working groups: background and definition; methods of measurement and screening; risk factors and consequences; prevention; and treatment. Each group selected key issues, searched the literature, and developed a draft document. During a 3-d meeting, these papers were debated and finalized by each group before presenting them to the full forum for further discussion and agreement. CONCLUSIONS Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases.

Exercise Training in Pregnancy Reduces Offspring Size without Changes in Maternal Insulin Sensitivity

CONTEXT Epidemiological studies have identified the importance of the in utero environment in providing a healthy start to life. Previous studies have suggested that the maternal environment, in particular a reduction in maternal insulin sensitivity, contributes significantly to fetal growth. Regular aerobic exercise, through an effect on maternal insulin sensitivity, may influence offspring size by regulating nutrient supply to the fetus. OBJECTIVE The aim of the study was to determine the effects of aerobic exercise training in the second half of pregnancy on maternal insulin sensitivity and neonatal outcomes. DESIGN AND SETTING We conducted a community-based, randomized, controlled trial of exercise in pregnancy. PARTICIPANTS Eighty-four healthy nulliparous women (mean +/- sd, age, 30 +/- 4 yr; body mass index, 25.5 +/- 4 kg/m(2)) participated in the study. INTERVENTION Subjects participated in a home-based stationary cycling program from 20 wk gestation to delivery. MAIN OUTCOME MEASURES Maternal insulin sensitivity, neonatal auxology, body composition, and growth-related peptides in cord blood were measured. RESULTS Offspring of exercisers had lower birth weight (sd score, control, 0.23 +/- 0.8; exercise, -0.19 +/- 0.9; P = 0.03) and body mass index at birth (sd score, control, 0.40 +/- 0.9; exercise, -0.01 +/- 0.09; P = 0.04). The reduction in maternal insulin sensitivity in late gestation was not affected by exercise (P = 0.45) and was unrelated to offspring size. Exercise offspring had lower cord serum IGF-I (P = 0.03) and IGF-II (P = 0.04). CONCLUSIONS Regular exercise was associated with lower birth weights and reduced cord concentrations of growth-related peptides, suggesting an influence of exercise on endocrine regulation of fetal growth. These effects on offspring growth were not associated with an exercise training effect on maternal insulin sensitivity.

Foot-to-foot bioelectrical impedance analysis: a valuable tool for the measurement of body composition in children.

OBJECTIVE: To determine the accuracy of foot-to-foot bioelectrical impedance analysis (BIA) and anthropometric indices as measures of body composition in children.DESIGN: Comparison of foot-to-foot BIA and anthropometry to dual-energy X-ray absorptiometry (DEXA)-derived body composition in a multi-ethnic group of children.SUBJECTS: Eighty-two European, NZ Maori and Pacific Island children aged 4.9–10.9 y.MEASUREMENTS: DEXA body composition, foot-to-foot bioelectrical impedance, height, weight, hip and waist measurements.RESULTS: Using a BIA prediction equation derived from our study population we found a high correlation between DEXA and BIA in the estimation of fat-free mass (FFM), fat mass (FM) and percentage body fat (PBF) (r=0.98, 0.98 and 0.94, respectively). BIA-FFM underestimated DEXA-FFM by a mean of 0.75 kg, BIA-FM overestimated DEXA-FM by a mean of 1.02 kg and BIA-PBF overestimated DEXA-PBF by a mean of 2.53%. The correlation between six anthropometric indices (body mass index (BMI), ponderal index, Chinns weight-for-height index, BMI standard deviation score, weight-for-length index and Coles weight-for-height index) and DEXA were also examined. The correlation of these indices with PBF was remarkably similar (r=0.85–0.87), more variable with FM (r=0.77–0.94) and poor with FFM (r=0.41–0.75).CONCLUSIONS: BIA correlated better than anthropometric indices in the estimation of FFM, FM and PBF. Foot-to-foot BIA is an accurate technique in the measurement of body composition.

Congenital idiopathic growth hormone deficiency associated with prenatal and early postnatal growth failure

To assess the role of growth hormone in fetal and infant growth, we analyzed the pretreatment data on 52 patients with a diagnosis of congenital growth hormone deficiency before 2 years of age, obtained from the Kabi Pharmacia International Growth Study. These infants had reduced birth-length standard deviation scores, an excess of birth weight relative to length, and progressive growth failure. We conclude that congenital growth hormone deficiency may cause impaired growth in utero and early infancy, and that growth hormone plays an important role in perinatal and infantile growth.

Evaluation of HOMA and QUICKI as measures of insulin sensitivity in prepubertal children

Abstract:  Background: Simple fasting sample methods to measure insulin sensitivity (SI) such as homeostasis model assessment (HOMA) and quantitative insulin‐sensitivity check index (QUICKI) have been widely promoted in adult studies but have not been formally evaluated in children. The aim of this study was to compare HOMA and QUICKI to the minimal model as measures of SI in prepubertal children.

Reduced insulin sensitivity and the presence of cardiovascular risk factors in short prepubertal children born small for gestational age (SGA)

Background  Epidemiological studies have shown that the metabolic syndrome, a combination of type 2 diabetes mellitus, hypertension, dyslipidaemia and a high body mass index (BMI), occurs more frequently among adults who were born with a low birth weight. Because insulin is thought to play a key role in the pathogenesis of this syndrome we investigated insulin sensitivity and risk factors for cardiovascular disease in short prepubertal children born small for gestational age (SGA).

FINAL HEIGHT IN IDIOPATHIC GROWTH HORMONE DEFICIENCY : THE KIGS EXPERIENCE

Cutfield W, Lindberg A, Albertsson Wikland K, Chatelain P, Ranke MB, Wilton P, on behalf of the KIGS International Board. Final height in idiopathic growth hormone deficiency: the KIGS experience. Acta Pædiatr 1999; Suppl 428: 72–5. Stockholm. ISSN 0803–5326

The Impact of Early Nutrition in Premature Infants on Later Childhood Insulin Sensitivity and Growth

OBJECTIVES. Children born prematurely have decreased insulin sensitivity. The etiology of this insulin resistance is unknown. The aim of this study was to evaluate infant nutrition and its influence on insulin sensitivity and postnatal growth in children born ≤32 weeks’ gestation. METHODS. A total of 56 healthy, developmentally normal, prepubertal children, aged 4 to 10 years were recruited. Thirty-seven were born ≤32 weeks’ gestation, and 19 were control subjects born at term with a birth weight >10th percentile. Insulin sensitivity (10−4 min−1 μU/mL) was calculated from a 90-minute frequently sampled intravenous glucose tolerance test. Perinatal, nutritional, and growth data were obtained retrospectively from both neonatal and early infancy records in the premature cohort. RESULTS. Children born prematurely had decreased insulin sensitivity when compared with those born at term (13.8 vs 30.6). Neonatal nutrition was not correlated with insulin sensitivity; however, all of the infants had inadequate protein in the first month followed by excessive fat intake thereafter. Premature children with greater weight gain had lower insulin sensitivity. Higher carbohydrate intake in the first month of life was associated with greater weight gain from birth. No relationship was seen between weight gain and either protein or lipid intake. CONCLUSIONS. Prematurely born children are insulin resistant and have suboptimal neonatal nutrition. Greater childhood weight gain magnifies this reduction in insulin sensitivity and seems to be associated with early nutrition. We speculate that a high carbohydrate neonatal diet may lead to greater weight gain and a greater reduction in insulin sensitivity in this group.

Could Epigenetics Play a Role in the Developmental Origins of Health and Disease

Following Barkers observations of an association between birth size and later adult diseases, considerable efforts have been made to define the characteristics of low birth weight groups in childhood. In this review, the phenotypic and biochemical characteristics during childhood of three low birth weight groups are summarized: children born following inviter fertilization (IVF), small for gestational age (SGA), or very premature. Each of these groups is likely to have been exposed to an adverse environment at different developmental stages. The triggers and mechanisms leading to programmed changes in growth, development, and metabolism of these groups of children have yet to be identified. Epigenetics has been proposed as a potential mechanism for these programmed changes through environmentally induced changes in gene expression. Data from animal models in which environmental, particularly nutritional, manipulation leads to changes in DNA methylation are presented. The relevance of these animal studies to IVF, SGA, and very premature children are discussed as are potential candidate genes that may have undergone epigenetic modification to alter growth and metabolism.