Patterns of Catch-Up Growth

Developmen

Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat

Growth hormone (GH) therapy is often associated with adverse side effects, including impaired insulin sensitivity. GH treatment of children with idiopathic short stature does not lead to an optimized final adult height. It has been demonstrated that FFA reduction induced by pharmacological antilipolysis can stimulate GH secretion per se in both normal subjects and those with GH deficiency. However, to date, no investigation has been undertaken to establish efficacy of combination treatment with GH and FFA regulators on linear body growth. Using a model of maternal undernutrition in the rat to induce growth-restricted offspring, we investigated the hypothesis that combination treatment with GH and FFA regulators can enhance linear body growth above that of GH alone. At postnatal day 28, male offspring of normally nourished mothers (controls) and offspring born with low birth weight [small for gestational age (SGA)] were treated with saline, GH, or GH (5 mg.kg(-1).day(-1)) in combination with acipimox (GH + acipimox, 20 mg.kg(-1).day(-1)) or fenofibrate (GH + fenofibrate, 30 mg.kg(-1).day(-1)) for 40 days. GH plus acipimox treatment significantly enhanced linear body growth in the control and SGA animals above that of GH, as quantified by tibial and total body length. Treatment with GH significantly increased fasting plasma insulin, insulin-to-glucose ratio, and plasma volumes in control and SGA animals but was not significantly different between saline and GH-plus-acipimox-treated animals. GH-induced lipolysis was blocked by GH plus acipimox treatment in both control and SGA animals, concomitant with a significant reduction in fasting plasma FFA and insulin concentrations. This is the first study to show that GH plus acipimox combination therapy, via pharmacological blocking of lipolysis during GH exposure, can significantly enhance the efficacy of GH in linear growth promotion and ameliorate unwanted metabolic side effect

Insulin resistance in healthy prepubertal twins

Objectives: To evaluate insulin sensitivity (SI) in prepubertal twins and to examine the relation to reduced birth weight, prematurity, and peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) polymorphism. Study design: Fifty twins (birth weight SDS, −0.7 ± 0.2; gestation, 33.5 ± 0.5 weeks; and body mass index SDS, −0.04 ± 0.2) were studied at 8.2 ± 0.3 years. SI was measured by Bergman's minimal model from a 90 minutes frequently sampled intravenous glucose test. Twenty control children (height SDS, −1.7 ± 0.3; birth weight SDS, −0.3 ± 0.2; and gestation of 39.2 ± 0.7 weeks) were also evaluated at 7.0 ± 0.4 years. The PPAR{gamma} T-variant polymorphism was evaluated in 41 twins. Values are expressed as mean ± SEM, or 95% confidence intervals. Results: SI was reduced in twins compared with control subjects, (12.7 [11-15] versus 23.0 [16.8-31.4] 10−4 min−1 {my}U/mL, respectively, P = .005). The reduction in SI was independent of prematurity and birth weight and zygosity (P20% difference in birth weight (P = .9). The PPAR{gamma} heterozygote T-variant polymorphism was present in 7 of 41, with a further reduction in SI (P = .03) and a later gestation (P = .03). These twins also had increased fat mass (P = .02) but with similar fat free mass (P = .14). Conclusions: Twin children, independent of prematurity or birth weight, had a marked reduction in SI. To use twins as a model to study the fetal origins of adult diseases for glucose homeostasis is not valid

Repeat antenatal betamethasone and cardiometabolic outcomes

BACKGROUND: Repeat dose(s) of antenatal betamethasone are recommended for women at <32 weeks with ongoing risk of preterm birth. However, there is concern that use of repeat dose(s) in fetal growth restriction (FGR) may increase the risk of later cardiometabolic disease. METHODS: We undertook secondary analysis of data from the Australasian Collaborative Trial of Repeat Doses of Corticosteroids Midchildhood Outcome Study to determine if FGR influences the effect of repeat betamethasone on growth and cardiometabolic function. At 6 to 8 years, children underwent anthropometry, dual energy x-ray absorptiometry, intravenous glucose tolerance testing, ambulatory blood pressure monitoring, and spirometry. FGR was defined as severe FGR at entry, cesarean delivery for FGR, or customized birth weight below the third centile. RESULTS: Of 266 children assessed, FGR occurred in 43 of 127 (34%) exposed to repeat betamethasone and 44 of 139 (32%) exposed to placebo. There was an interaction between FGR and repeat betamethasone treatment for the effect on height (z score mean difference [95% confidence interval]; FGR: 0.59 [0.01 to 1.17]; non-FGR: −0.29 [−0.69 to 0.10]; P = .01). However, FGR did not influence the effect of repeat betamethasone on cardiometabolic function, which was similar in treatment groups, both in FGR and non-FGR subgroups. CONCLUSIONS: Repeat antenatal betamethasone treatment had no adverse effects on cardiometabolic function, even in the presence of FGR. It may have a positive effect on height in FGR. Clinicians should use repeat doses of antenatal corticosteroids when indicated before preterm birth, regardless of FGR, in view of the associated neonatal benefits.Robert D. Cartwright, Jane E. Harding, Caroline A. Crowther, Wayne S. Cutfield, Malcolm R. Battin, Stuart R. Dalziel, Christopher J.D. McKinlay, on behalf of the ACTORDS Follow-up Grou

Repeat antenatal betamethasone and cardiometabolic outcomes

Antenatal corticosteroid therapy is one of the most effective interventions for preterm birth, resulting in rapid maturation of fetal organ systems. The Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) revealed that neonatal benefit is greatest when antenatal corticosteroids are administered in repeat doses, which can be used to reduce the incidence and severity of preterm lung disease and other serious neonatal morbidity, with absolute benefits similar to that of an initial course of antenatal corticosteroids.Robert D. Cartwright, Jane E. Harding, Caroline A. Crowther, Wayne S. Cutfield, Malcolm R. Battin, Stuart R. Dalziel, Christopher J.D. McKinlay, on behalf of the ACTORDS Follow-up Grou

Neonatal leptin treatment reverses developmental programming

An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity and insulin resistance. Although the mechanisms are unclear, this programming has generally been considered an irreversible change in developmental trajectory. Adult offspring of rats subjected to undernutrition during pregnancy develop obesity, hyperinsulinemia, and hyperleptinemia, especially in the presence of a high-fat diet. Reduced locomotor activity and hyperphagia contribute to the increased fat mass. Using this model of maternal undernutrition, we investigated the effects of neonatal leptin treatment on the metabolic phenotype of adult female offspring. Leptin treatment (rec-rat leptin, 2.5 µg/g·d, sc) from postnatal d 3–13 resulted in a transient slowing of neonatal weight gain, particularly in programmed offspring, and normalized caloric intake, locomotor activity, body weight, fat mass, and fasting plasma glucose, insulin, and leptin concentrations in programmed offspring in adult life in contrast to saline-treated offspring of undernourished mothers who developed all these features on a high-fat diet. Neonatal leptin had no demonstrable effects on the adult offspring of normally fed mothers. This study suggests that developmental metabolic programming is potentially reversible by an intervention late in the phase of developmental plasticity. The complete normalization of the programmed phenotype by neonatal leptin treatment implies that leptin has effects that reverse the prenatal adaptations resulting from relative fetal undernutrition

The developmental origins of adult disease

Epidemiological and clinical observations have led to the hypothesis that the risk of developing some chronic diseases in adulthood is influenced not only by genetic and adult lifestyle factors, but also by environmental factors acting in early life. These factors act through the processes of developmental plasticity and possibly epigenetic modification, and can be distinguished from developmental disruption. The concept of predictive adaptation has been developed to explain the relationship between early life events and the risk of later disease. At its base, the model suggests that a mismatch between fetal expectation of its postnatal environment and actual postnatal environment contribute to later adult disease risk. This mismatch is exacerbated, in part, by the phenomenon of 'maternal constraint' on fetal growth, which implicitly provides an upper limit of postnatal nutritional environment that humans have adapted for and is now frequently exceeded. These experimental, clinical and conceptual considerations have important implications for prevention and intervention in the current epidemic of childhood obesity and adult metabolic and cardiovascular disorders