leptin and Growth-Disorders

Stunting, which results from chronic malnutrition, is common in children from low- and middle-income countries. Several studies have reported an association between obesity and asthma. However, only a handful of studies have identified stunting as a significant risk factor for wheezing, a symptom of asthma, although the underlying mechanism remains unclear. This article aimed to review possible mechanisms underlying asthma in stunted children. Overall, changes in diet or nutritional status and deficiencies in certain nutrients, such as vitamin D, can increase the risk of developing asthma. Vitamin D deficiency can cause linear growth disorders such as stunting in children, with lower levels of 25(OH)D found in underweight and stunted children. Stunted children show a decreased lean body mass, which affects lung growth and function. Low leptin levels during undernutrition cause a Th1-Th2 imbalance toward Th2, resulting in increased interleukin (IL)-4 cytokine production and total immunoglobulin E (IgE). Studies in stunted underweight children have also found an increase in the proportion of the total number of B cells with low-affinity IgE receptors (CD23+). CD23+ plays an important role in allergen presentation that is facilitated by IgE to T cells and strongly activates allergen-specific T cells and the secretion of Th2-driving cytokines. Stunted children present with low vitamin D and leptin levels, impaired lung growth, decreased lung function, and increased IL-4 and CD23+ levels. All of these factors may be considered consequential in asthma in stunted children.

Topics: Allergens; Asthma; Child; Cytokines; Growth Disorders; Humans; Immunoglobulin E; Interleukin-4; Leptin; Receptors, IgE; Risk Factors; Thinness; Vitamin D; Vitamins

The availability of high-quality studies on the association between sleep-disordered breathing in children and delayed growth associated with the hormonal profile recorded before surgery and at follow-up is limited.. Medline PubMed, Scopus and WebOfScience databases were searched for relevant publications published between January 2008 to January 2020 and a total of 261 potentially eligible studies were identified.. Following review 19 papers were eligible for inclusion: seven reported a significant postsurgical increase in growth regardless of initial weight status, type of surgery, type of study design, and length of follow-up period. The only high-quality study was a randomized controlled trial that found an increased risk of obstructive sleep apnea syndrome relapse in overweight children. Twelve studies reported the significant increase in growth parameters showing that IGF-1, IGFBP-3, and ghrelin may boost growth after surgery.. The current systematic review demonstrates a scarcity of high-quality studies on growth delay in children with sleep-disordered breathing. Significant catch-up growth after surgery in the short term and changes in IGF-1, IGFBP-3, ghrelin, and leptin levels has been reported in most published studies.

Topics: Adenoidectomy; Adolescent; Adolescent Development; Age Factors; Biomarkers; Child; Child Development; Child, Preschool; Ghrelin; Growth Disorders; Humans; Infant; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Risk Assessment; Risk Factors; Sleep Apnea Syndromes; Tonsillectomy; Treatment Outcome

Malnutrition is considered a leading cause of growth attenuation in children. When food is replenished, spontaneous catch-up (CU) growth usually occurs, bringing the child back to its original growth trajectory. However, in some cases, the CU growth is not complete, leading to a permanent growth deficit. This review summarizes our current knowledge regarding the mechanism regulating nutrition and growth, including systemic factors, such as insulin, growth hormone, insulin- like growth factor-1, vitamin D, fibroblast growth factor-21, etc., and local mechanisms, including autophagy, as well as regulators of transcription, protein synthesis, miRNAs and epigenetics. Studying the molecular mechanisms regulating CU growth may lead to the establishment of better nutritional and therapeutic regimens for more effective CU growth in children with malnutrition and growth abnormalities. It will be fascinating to follow this research in the coming years and to translate the knowledge gained to clinical benefit.

Topics: Autophagy; Child; Epigenomics; Fibroblast Growth Factors; Glucocorticoids; Growth Disorders; Growth Hormone; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Infant; Insulin; Insulin-Like Growth Factor I; Leptin; Malnutrition; MicroRNAs; Nutritional Status; Thyroid Hormones; TOR Serine-Threonine Kinases; Vitamin D

The US Food and Drug Administration approved use of recombinant human growth hormone (GH) for the treatment of idiopathic short stature (ISS) in children; however, few studies have evaluated metabolic outcomes. This article addresses whether children with ISS treated with GH experience the same metabolic benefits as children with GH deficiency (GHD) treated with GH. A systematic review of all published studies of GH treatment in children with ISS that included data on metabolic outcomes identified five studies. No meta-analysis has been performed.Studies show a metabolic response to GH treatment in children with ISS similar to that observed in children with GHD; effects include a transient decrease in insulin sensitivity and a dose-dependent increase in insulin-like growth factor I. However, no increase in the risk of diabetes was found. Children with ISS seem to benefit from GH treatment in terms of height gain without any severe negative metabolic outcomes.

Topics: Adipose Tissue; Adolescent; Body Height; Child; Dwarfism; Dwarfism, Pituitary; Glucose; Growth Disorders; Human Growth Hormone; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Lipid Metabolism; Male; Recombinant Proteins

Depending on the definitions used, up to 10% of all live-born neonates are small for gestational age (SGA). Although the vast majority of these children show catch-up growth by 2 yr of age, one in 10 does not. It is increasingly recognized that those who are born SGA are at risk of developing metabolic disease later in life. Reduced fetal growth has been shown to be associated with an increased risk of insulin resistance, obesity, cardiovascular disease, and type 2 diabetes mellitus. The majority of pathology is seen in adults who show spontaneous catch-up growth as children. There is evidence to suggest that some of the metabolic consequences of intrauterine growth retardation in children born SGA can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain. Implicitly, this argument questions current infant formula feeding practices. The risk is less clear for individuals who do not show catch-up growth and who are treated with GH for short stature. Recent data, however, suggest that long-term treatment with GH does not increase the risk of type 2 diabetes mellitus and the metabolic syndrome in young adults born SGA.

Topics: Adult; Animals; Body Height; Child; Child Development; Fetal Development; Growth Disorders; Growth Hormone; Humans; Infant, Newborn; Infant, Small for Gestational Age; Leptin; Metabolic Syndrome; Models, Biological

Puberty is a crucial period of life during which dramatic hormonal changes induce notable modifications in linear growth, bone mass and body composition. These changes are associated with variations in some biochemical parameters such as markers of bone turnover and leptin, which may reflect changes in bone growth and fat mass, respectively. Children with growth hormone (GH) deficiency have reduced concentrations of bone markers, which increase during GH administration, while the levels of leptin decrease. There have been few studies analysing the behaviour of bone markers during puberty in GH-treated GH-deficient patients and no studies analysing the behaviour of leptin. Results from a longitudinal study showed that there was no change in serum osteocalcin, carboxy-terminal propeptide of type I procollagen, and cross-linked carboxy-terminal telopeptide of type I collagen levels during puberty in GH-treated GH-deficient children. Some studies have shown that changes in markers of bone turnover and leptin after short-term GH treatment may predict the growth response (at 6-12 months) to GH administration in GH-deficient children. At present, insufficient data are available for the clinical use of these parameters as markers of growth response during pubertal development and as predictors of long-term growth response to GH treatment in children with GH deficiency. Nevertheless, the use of more and possibly new markers might improve the accuracy of growth prediction models in the future.

Topics: Adolescent; Biomarkers; Bone and Bones; Child; Growth; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans; Leptin; Puberty

Intra-uterine growth retardation (IUGR), caused by maternal undernutrition or placental insufficiency, is usually associated with disproportionately large reductions in the growth of some fetal organs and tissues (thymus, liver, spleen, thyroid) and impaired cellular development of other tissues (small intestine, secondary wool follicles, skeletal muscle). Growth of other tissues, most notably brain, is relatively unimpaired. In our restudy of postnatal consequences of IUGR in the offspring of prolific ewes, growth-retarded newborn lambs tended to be hypoglycaemic and showed sluggish postnatal engagement of the growth hormone (GH)-insulin-like growth factor (IGF) system. When artificially reared in an optimum environment, low birth weight lambs grew at rates similar to those of normal lambs. However, low birth weight lambs were fatter at any given weight, apparently related to their high energy intakes, especially soon after birth, had low maintenance energy requirements, and limited capacity for bone and muscle growth. These growth characteristics were accompanied by higher plasma concentrations of GH and leptin, and lower concentrations of insulin-like growth factor I (IGF-I) during the first 2 weeks of postnatal life, and higher concentrations of insulin during subsequent growth up to 20 kg body weight. Emerging evidence indicates that in sheep, as in rodents, fetal programming of postnatal cardiovascular and metabolic dysfunctions is associated with IUGR and may be mediated partly by overexposure of the fetus to cortisol. Similar postnatal responses can be elicited by maternal undernutrition or cortisol treatment in early to mid-pregnancy without changing the growth of the fetus or placenta.

Topics: Animals; Animals, Newborn; Female; Fetal Growth Retardation; Growth Disorders; Growth Hormone; Hydrocortisone; Insulin; Insulin-Like Growth Factor I; Leptin; Malnutrition; Maternal Nutritional Physiological Phenomena; Placental Insufficiency; Pregnancy; Sheep; Sheep Diseases

Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses.. Short prepubertal children with either isolated GHD (39) or ISS (89) participated in a 2-year randomized trial of either individualized GH treatment with six different GH doses (range, 17-100 microg/kg/day) or a standard dose (43 microg/kg/day).. To evaluate if individualized GH treatment reduced the variance of the metabolic measures as shown for growth response and to compare changes in metabolic variables in children with ISS and GHD.. Individualized GH dose reduces the range of metabolic outcomes, and metabolic outcomes are similar in children with ISS and GHD.. We observed a narrower variation for fasting insulin (-34.2%) and for homoeostasis model assessment (HOMA) (-38.9%) after 2 years of individualized GH treatment in comparison with standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (Delta) height SDS correlated with Deltainsulin-like growth factor I (IGF-I), Deltaleptin and Deltabody composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [Deltalean body mass (LBM) SDS and DeltaIGF-I SDS] clustered together and correlated strongly with Deltaheight SDS and GH dose, whereas lipolytic variables [Deltafat mass (FM) SDS and Deltaleptin] were clustered separately from anabolic variables. Regression analysis showed GH dose dependency in ISS, and to a lesser degree in GHD, for DeltaLBM SDS and Deltaheight SDS, but not for changes in FM.. Individualized GH dosing during catch-up growth reduces the variance in insulin and HOMA and results in equal metabolic responses irrespective of the diagnosis of GHD or ISS.

Topics: Adiponectin; Analysis of Variance; Body Composition; Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Dwarfism, Pituitary; Female; Growth Disorders; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Principal Component Analysis; Prospective Studies; Time Factors; Treatment Outcome

GH replacement therapy in children with GH deficiency (GHD) mainly promotes linear growth. Not only have very few studies fully analyzed the metabolic consequences of GH therapy, but also the question as to whether GH may affect adipokine secretion has been insufficiently investigated. Our aim was to study the effects of GH replacement therapy on auxological data, lipid and glycemic profiles, insulin homeostasis (HOMA-IR) and serum adipokines in children.. This was a 1-year prospective study. Thirty-four GHD children (11.6 +/- 2.6 years) and thirty healthy matched controls were enrolled. Children affected by GHD were studied both before beginning continuous GH replacement therapy and again at 12 months.. At the beginning of the study, total and LDL cholesterol were higher in GHD children than in controls (P<0.001), whereas HDL cholesterol, triglycerides, insulin, HOMA-IR, leptin, and adiponectin were similar. At 12 months of continuous GH replacement therapy in the GHD group, there was a significant increase in both auxological data and IGF-I (P<0.001); total cholesterol (P<0.001), LDL (P<0.001), triglycerides (P<0.005), and leptin (P<0.001) decreased significantly; HDL (P<0.003), insulin (P<0.001), HOMA-IR (P<0.001) increased while adiponectin was unmodified. Furthermore, IGF-IDelta showed an inverse correlation with leptin Delta (rho = -0.398, P = 0.02).. In GHD children, the evaluation of metabolic parameters proves to be a useful tool for the evaluation of auxological parameters during GH replacement therapy. In our study, GH replacement therapy in GHD children improved final height, restored IGF-I levels, reduced leptin levels, and improved the lipid profile, without producing any unfavorable effects on glucose metabolism.

Topics: Adiponectin; Adolescent; Body Height; Body Mass Index; Body Weight; Child; Cholesterol, LDL; Female; Growth Disorders; Hormone Replacement Therapy; Human Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Time Factors; Treatment Outcome; Triglycerides

Pediatric patients with brain tumors can loose 1 SD of height prior to beginning growth hormone (GH) therapy. The objectives of this study were to characterize the early growth failure, identify contributing factors and propose interventions. Five children were followed quarterly for 2 years to monitor auxological parameters, nutritional indices, and endocrine measuremnts. GH stimulation tests were done every 6 months to determine the timing of the onset of GH deficiency. The nadir for height velocity (HV) occurred 6 months after diagnosis. Poor gains in height correlated with decreased calorie count (p <0.001), poor weight gain (p <0.001), decreased BMI (p <0.001) and lowered leptin levels (p <0.001). All patients were able to secrete GH normally during this nadir of growth. Children treated for brain tumors demonstrate an early triphasic pattern of growth. Growth failure due to cachexia occurs first, then a second transient phase of normal growth is observed followed by a third phase of growth failure due to GH deficiency. Phase 1 is characterized by decreased HV, BMI, leptin levels and calorie counts. With recognition of this profile, the early growth failure might be preventable with aggressive nutritional rehabilitation.

Topics: Antineoplastic Agents; Body Height; Brain Neoplasms; Cachexia; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Female; Follow-Up Studies; Growth Disorders; Hormone Replacement Therapy; Human Growth Hormone; Humans; Hypothalamus; Leptin; Male; Neoplasms, Neuroepithelial; Radiation Injuries; Survivors

Ghrelin is a recently discovered gastric peptide that increases appetite, glucose oxidation, and lipogenesis and stimulates the secretion of GH. In contrast to ghrelin, GH promotes lipolysis, glucose production, and insulin secretion. Both ghrelin and GH are suppressed by intake of nutrients, especially glucose. The role of GH in the regulation of ghrelin has not yet been established. We investigated the effect of GH on circulating levels of ghrelin in relation to its effects on glucose, insulin, body composition, and the adipocyte-derived peptides leptin and adiponectin. Thirty-six patients with adult-onset GH deficiency received recombinant human GH for 9 months in a placebo-controlled study. Body composition and fasting serum analytes were assessed at baseline and at the end of the study. The GH treatment was accompanied by increased serum levels of IGF-I, reduced body weight (-2%) and body fat (-27%), and increased serum concentrations of glucose (+10%) and insulin (+48%). Ghrelin levels decreased in 30 of 36 subjects by a mean of -29%, and leptin decreased by a mean of -24%. Adiponectin increased in the women only. The decreases in ghrelin and leptin correlated with changes in fat mass, fat-free mass, and IGF-I. The reductions in ghrelin were predicted independently of the changes in IGF-I and fat mass. It is likely that the reductions in ghrelin and leptin reflect the metabolic effects of GH on lipid mobilization and glucose production. Possibly, a suppression of ghrelin promotes loss of body fat in GH-deficient patients receiving treatment. The observed correlation between the changes in ghrelin and IGF-I may suggest that the GH/IGF-I axis has a negative feedback on ghrelin secretion.

Topics: Adiponectin; Adult; Blood Glucose; Body Composition; Body Weight; Female; Ghrelin; Growth Disorders; Human Growth Hormone; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Peptide Hormones; Proteins; Regression Analysis

To assess multiple dose-response relationships between three GH doses (1.5, 3.0 and 6.0 IU/m2) and nine different biochemical markers of GH sensitivity in a well-defined group of 17 children with idiopathic short stature (ISS).. Serum levels of IGF-I, IGF-II and IGFBP-3, and peripheral markers leptin, C-terminal propeptide of type I collagen (PICP) and N-terminal propeptide of type III collagen (PIIINP), alkaline phosphatase (AP) and osteocalcin (OC) were measured at the start and after 2 and 12 weeks of periods of no treatment, GH 1.5 IU/m2 and GH 3.0 IU/m2. Twelve-week washout periods were applied between the 12-week GH-treatment periods. High-dose GH treatment was given during the second year of study and all serum markers were measured at start, after 2 and 12 weeks and 1 year of GH 6.0 IU/m2. In 18 non-GH-treated children with ISS the same parameters were measured yearly. The bone resorption marker urinary deoxypyridinoline (DPD) was measured during 12-h day and night periods at start and after 2 weeks GH 1.5, 3.0 and 6.0 IU/m2.. All markers were GH dependent, but the timing of maximal response varied among different markers. Height SDS at start, age at start and IGF-II at baseline were inversely related to the first-year growth response (r = -0.73, P = 0.001; r = -0.53, P = 0.03; and r = -0.53, P = 0.03, respectively). Some statistically significant correlations between biochemical responses on low GH doses (1.5 or 3.0 IU/m2) and second-year growth response were found, but these showed no consistent pattern. However, all changes in IGF-I SDS after GH 6.0 IU/m2 measured either after 2 or 12 weeks or 1 year correlated significantly with the second-year growth response (r = 0.55, P = 0.02; r = 0.81, P = 0.001; and r = 0.86, P < 0.001, respectively). Baseline or GH-stimulated levels of peripheral markers did not correlate with the growth response.. The individual capacity of IGF-I generation after high-dose GH treatment (6.0 IU/m2) determines the growth response on high-dose GH treatment. Peripheral markers do not seem to play a role in growth prediction of children with ISS.

Topics: Biomarkers; Body Height; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Growth; Growth Disorders; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Male; Prognosis; Treatment Outcome

This study was planned in order to investigate the role of insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) and leptin, the product of the ob gene synthesized by fat tissue cells, in constitutional delay of growth and puberty (CDGP) which is the most frequent cause of short stature in children. This study was conducted on 80 children with CDGP aged 6-15 years, and 60 healthy children served as controls. Serum IGF-I, IGFBP-3, insulin and plasma leptin levels were measured by immunoradiometric assay. Mean IGF-I and leptin levels were significantly lower in the CDGP group compared with the controls, but the mean IGFBP-3 level was not different in the two groups. Mean leptin levels were 3.72 +/- 2.29 in CDGP and 4.68 +/- 3.08 in the control group (p <0.05). There was a statistically significant relationship between leptin levels and height, weight, and body mass index. Leptin levels were also correlated with chronological age, bone age and height age. When evaluated according to pubertal status, a significant difference was found in IGF-I, leptin and IGFBP-3 levels between prepubertal and pubertal groups. Leptin levels were significantly different in the prepubertal CDGP group compared with controls but in the pubertal CDGP group only IGF-I levels were significantly different from controls. As the weight of children with CDGP was lower than in the control group, it is postulated that the reason for short stature and pubertal delay may be this decrease in weight which is also the cause of low levels of leptin and IGF-I.

Topics: Adolescent; Body Height; Body Weight; Child; Female; Growth Disorders; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Radioimmunoassay

The aim of this study was to follow changes in body composition, estimated by dual-energy X-ray absorptiometry (DXA), in relation to changes in leptin during the first year of GH therapy in order to test the hypothesis that leptin is a metabolic signal involved in the regulation of GH secretion in children.. In total, 33 prepubertal children were investigated. Their mean (S.D.) chronological age at the start of GH treatment was 11.5 (1.6) years, and their mean height was -2.33 (0.38) S.D. scores (SDS). GH was administered subcutaneously at a daily dose of 0.1 (n=26) or 0.2 (n=7) IU/kg body weight. Ten children were in the Swedish National Registry for children with GH deficiency, and twenty-three children were involved in trials of GH treatment for idiopathic short stature. Spontaneous 24-h GH secretion was studied in 32 of the children. In the 24-h GH profiles, the maximum level of GH was determined and the secretion rate estimated by deconvolution analysis (GHt). Serum leptin levels were measured at the start of GH treatment and after 10 and 30 days and 3, 6 and 12 months of treatment. Body composition measurements, by DXA, were performed at baseline and 12 months after the onset of GH treatment.. After 12 months of GH treatment, mean height increased from -2.33 to -1.73 SDS and total body fat decreased significantly by 3.0 (3.3)%. Serum leptin levels were decreased significantly at all time points studied compared with baseline. There was a significant correlation between the change in total body fat and the change in serum leptin levels during the 12 months of GH treatment, whereas the leptin concentration per unit fat mass did not change. In a multiple stepwise linear regression analysis with 12 month change in leptin levels as the dependent variable, the percentage change in fat over 12 months, the baseline fat mass (%) of body mass and GHt accounted for 24.0%, 11.5% and 12.2% of the variability respectively.. There are significant correlations between changes in leptin and fat and endogenous GH secretion in short children with various GH secretory capacities. Leptin may be the messenger by which the adipose tissue affects hypothalamic regulation of GH secretion.

Topics: Adipose Tissue; Adolescent; Body Composition; Body Height; Child; Female; Growth Disorders; Growth Hormone; Hormones; Human Growth Hormone; Humans; Leptin; Linear Models; Male; Proteins

Undernutrition is responsible for up to 45% of deaths in children under five, with low- and middle-income countries disproportionately affected. Adipokines are known modulators of metabolism and have been linked to growth rates and neurocognition during infancy. We examined the relationship(s) between cord blood adiponectin and leptin and both longitudinal growth and cognition during the first year of life using generalized estimating equations. Infants were classified as underweight (weight-for-age z-score [WAZ]), stunted (height-for-age z-score [HAZ]) or wasted (weight-for-height z-score [WHZ]) using WHOAnthro software. Cord blood adiponectin and leptin levels were highly correlated (r = 0.35, P < 0.0001) and positively associated with birth WAZ (r = 0.34 and r = 0.45, P < 0.0001, respectively). Adipokines were independently, inversely associated with weight gain. Infants in the highest quintile of adipokine production had a lower risk of being stunted, while neither was associated with lower WAZ or WHZ in final adjusted models. Cognition was not found to be independently related to cord blood leptin or adiponectin. The negative association with adipokines and rate of weight gain during infancy may reflect heightened nutritional status at birth rather than a direct hormonal influence. The relationship between leptin or adiponectin and longitudinal length gains suggests that both adipokines may promote linear growth during infancy.

Topics: Adipokines; Adiponectin; Child; Fetal Blood; Growth Disorders; Humans; Infant; Infant, Newborn; Leptin; Weight Gain

Environmental enteric dysfunction (EED) limits the Sustainable Development Goals of improved childhood growth and survival. We applied mucosal genomics to advance our understanding of EED.. The Study of Environmental Enteropathy and Malnutrition (SEEM) followed 416 children from birth to 24 months in a rural district in Pakistan. Biomarkers were measured at 9 months and tested for association with growth at 24 months. The duodenal methylome and transcriptome were determined in 52 undernourished SEEM participants and 42 North American controls and patients with celiac disease.. After accounting for growth at study entry, circulating insulin-like growth factor-1 (IGF-1) and ferritin predicted linear growth, whereas leptin correlated with future weight gain. The EED transcriptome exhibited suppression of antioxidant, detoxification, and lipid metabolism genes, and induction of anti-microbial response, interferon, and lymphocyte activation genes. Relative to celiac disease, suppression of antioxidant and detoxification genes and induction of antimicrobial response genes were EED-specific. At the epigenetic level, EED showed hyper-methylation of epithelial metabolism and barrier function genes, and hypo-methylation of immune response and cell proliferation genes. Duodenal coexpression modules showed association between lymphocyte proliferation and epithelial metabolic genes and histologic severity, fecal energy loss, and wasting (weight-for-length/height Z < -2.0). Leptin was associated with expression of epithelial carbohydrate metabolism and stem cell renewal genes. Immune response genes were attenuated by giardia colonization.. Children with reduced circulating IGF-1 are more likely to experience stunting. Leptin and a gene signature for lymphocyte activation and dysregulated lipid metabolism are implicated in wasting, suggesting new approaches for EED refractory to nutritional intervention. ClinicalTrials.gov, Number: NCT03588013. (https://clinicaltrials.gov/ct2/show/NCT03588013).

Topics: Biomarkers; Case-Control Studies; Celiac Disease; Cell Proliferation; Child Development; Child, Preschool; Creatinine; DNA Methylation; Epigenome; Female; Ferritins; Genomics; Growth Disorders; Humans; Infant; Infant, Newborn; Insulin-Like Growth Factor I; Intestinal Diseases; Intestinal Mucosa; Leptin; Lipid Metabolism; Lymphocyte Activation; Lymphocytes; Male; Malnutrition; Oxidative Stress; Pakistan; Transcriptome

This study aimed to investigate the relationships between genetic polymorphisms of leptin/receptor genes and clinical/biochemical characteristics in children with growth hormone deficiency (GHD). Ninety-three GHD children and 69 age-matched normal controls were enrolled. Anthropometric measurements, bone age, and laboratory test results were obtained. Polymorphisms in the LEP gene promoter locus (LEP-2548, rs7799039) and LEPR genes (K109R, rs1137100 and Q223R, rs1137101) were analyzed using PCR-RFLP. The serum leptin levels were measured using an ELISA kit. The median height and BMI z-scores of all GHD subjects were -2.20 and -0.26, respectively, and those of normal controls were -0.30 and -0.13, respectively. The serum leptin levels were similar between GHD subjects and normal controls (p = 0.537), but those were different between the complete GHD (6.97 ng/mL) and partial GHD (4.22 ng/mL) groups (p = 0.047). There were no differences in the genotypic distributions of LEP-2548, LEPR K109R, and Q223R between GHD subjects and normal controls. However, GHD subjects with the G allele at LEP-2548 showed higher IGF-1 (p = 0.047) and IGFBP-3 SDSs (p = 0.027) than GHD subjects with the A allele. GHD subjects with the G allele at LEPR Q223R showed lower stimulated GH levels (p = 0.023) and greater height gain after 1 year of GH treatment (p = 0.034) than GHD subjects with the A allele. In conclusion, leptin/leptin receptor genes are suggested to have the role of growth-related factors, which can affect various growth responses in children who share the same disease entity.

Topics: Adolescent; Alleles; Body Height; Child; Child, Preschool; Female; Gene Frequency; Genotype; Growth Disorders; Hormone Replacement Therapy; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Polymorphism, Single Nucleotide; Receptors, Leptin; Treatment Outcome

Although bariatric surgery is approved for a woman of child-bearing age with an interest in subsequent pregnancy, reports of in utero growth issues during pregnancy have garnered a closer look at the impact of maternal surgical weight loss on the pre- and postpartum periods. Offspring of dams having received vertical sleeve gastrectomy (VSG) are born small-for-gestational age and have increased risk for metabolic syndrome later in life. Here, we aimed to determine whether the postnatal catch-up growth trajectory of bariatric offspring may be affected by milk composition. Milk samples were collected at postnatal day 15/16 from dams having received VSG surgery and fed a high-fat diet (HFD) (H-VSG), Sham surgery and fed chow (C-Sham), or Sham surgery and fed HFD (H-Sham). Milk obtained from H-VSG dams had elevated glucose (P < 0.05) and significantly reduced triglyceride content (P < 0.01). Milk from H-Sham dams had the lowest amount of milk protein (P < 0.05). Fatty acid composition measured by fractionation was largely not affected by surgery but rather maternal diet. No difference was observed in milk leptin levels; however, insulin, adiponectin, and growth hormone levels were significantly increased in milk from H-VSG animals. H-Sham had the lowest level of immunoglobulin (Ig)A, whereas IgG was significantly reduced in H-VSG. Taken together, the quality of milk from H-VSG dams suggests that milk composition could be a factor in reducing the rate of growth during the lactation period.

Topics: Adiponectin; Animals; Animals, Suckling; Bariatric Surgery; Diet, High-Fat; Disease Models, Animal; Female; Gastrectomy; Glucose; Growth Disorders; Growth Hormone; Humans; Insulin; Lactation; Leptin; Male; Milk; Nutrients; Obesity; Postoperative Period; Rats; Rats, Long-Evans; Weight Loss

Children born small for gestational age (SGA) are at a higher risk for metabolic disorders later in life. In this study, we aimed to characterize young SGA children without catch-up growth and evaluate the effects of GH treatment on endocrinological, metabolic, and immunological parameters. Study design is a one-year single hospital-based study included prospective observation of SGA patients during 12 months of GH treatment. Clinical and laboratory profiles of SGA children at baseline were compared with controls born appropriate size for age. Twenty-six SGA children (median age, 3.4 years) and 26 control children (median age, 3.8 years) were enrolled. Anthropometric, hematologic, biochemical, immunological, and endocrinological parameters were assessed at baseline and 1, 3, 6, 9, and 12 months after the start of GH treatment. As a result, median height SD score (SDS) of SGA children increased by +0.42 with 12-month GH treatment. Body mass index SDS was lower in SGA children than in controls. Serum apolipoprotein A1 increased, whereas apolipoprotein B decreased during GH treatment. Serum leptin and resistin levels, which were lower in SGA children than in controls at baseline, did not change remarkably with GH treatment. Monocyte counts, which were lower in SGA patients at baseline, increased after GH treatment. Neutrophil counts significantly increased after GH treatment. Natural killer cell ratios, which were higher in SGA patients, decreased after GH treatment. In conclusion, there was no evidence suggesting metabolic abnormalities in SGA children. Serum apolipoprotein changes might predict the beneficial role of GH treatment in lowering cardiometabolic risk.

Topics: Apolipoprotein A-I; Apolipoproteins B; Body Height; Child; Child, Preschool; Female; Growth Disorders; Human Growth Hormone; Humans; Infant, Small for Gestational Age; Leptin; Male; Prospective Studies; Resistin; Treatment Outcome

Variation in genes of the leptinergic-melanocortinergic system influence both body weight and height. Because short normal stature (SNS) is characterized by reduced body height, delayed maturation and leanness, allelic variation of genes in this pathway are hypothesized to affect this common condition.. We analyzed the coding regions of LEP, MC4R, MRAP2 and BDNF in 185 children with SNS (height < 5th percentile) to search for non-synonymous and frameshift variants. For association studies (two-sided χ. We detected eleven variants predicted to be protein-altering, four in MC4R, four in BDNF, and three in MRAP2. No variants were found in LEP. In vitro analysis implied reduced function for the MC4R variant p.Met215Ile. Loss-of-function is contrary to expectations based on obesity studies, and thus does not support that this variant is relevant for SNS. The minor SNP alleles at MC4R p.Val103Ile and BDNF p.Val66Met were nominally associated with SNS.. Taken together, although genes of the leptinergic-melanocortinergic system are important for normal growth, our data do not support the involvement of rare mutations in LEP, MC4R, MRAP2 or BDNF in short normal stature.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Body Height; Brain-Derived Neurotrophic Factor; Carrier Proteins; Child; Female; Frameshift Mutation; Gene Expression; Growth Disorders; Humans; Leptin; Male; Mutation; Polymorphism, Genetic; Receptor, Melanocortin, Type 4

Stimulant medication is known to cause transient weight loss and slowing down of growth, but whether it delays physical maturation is unclear. We studied growth and bone age over the first 3 years of treatment in children with attention-deficit/hyperactivity disorder (patients) compared with healthy siblings (controls). Bone age was estimated blindly by two independent radiologists using Tanner and Whitehouse version 3. Dexamphetamine or methylphenidate was titrated and continued when clinically indicated. Forty out of 73 patients, together with 22 controls, completed the study. There were no significant growth differences between the two groups at baseline. Despite slower growth on treatment [5.1 cm/year, 95% confidence interval (CI): 4.7-5.5, vs. 6.3 cm/year, 95% CI: 5.7-6.8, P=0.002; and 2.7 kg/year, 95% CI: 2.1-3.3, vs. 4.4 kg/year, 95% CI: 3.5-5.3, P=0.005], the patients showed no significant maturational delay (RUS score: 49 U/year, 95% CI: 44-55, vs. 55 U/year, 95% CI: 47-63, P=0.27). A subgroup of patients underwent serial biochemistry and dual-energy X-ray absorptiometry, recording a significant reduction in fat (5.61±3.56-4.22±3.09 kg, P<0.001) and leptin (3.88±2.87-2.57±1.94 ng/ml, P=0.017). The pattern of change in height z-score over time was modified by the dose of medication (P for interaction=0.024). We found no medication effect on the rate of maturation, which was instead predicted by baseline leptin (P=0.035 controlling for age and sex).

Topics: Absorptiometry, Photon; Adiposity; Age Factors; Anthropometry; Attention Deficit Disorder with Hyperactivity; Biomarkers; Body Height; Body Weight; Bone Development; Case-Control Studies; Central Nervous System Stimulants; Child; Child Development; Dextroamphetamine; Female; Growth Disorders; Humans; Leptin; Male; Methylphenidate; Prospective Studies; Time Factors; Treatment Outcome

The mechanisms linking sleep disordered breathing with impairment of sleep and bone metabolism/architecture are poorly understood. Here, we explored the role of the neuropeptide orexin, a respiratory homeostasis modulator, in growth retardation induced in an upper airway obstructed (AO) rat model.. The tracheae of 22-day-old rats were narrowed; AO and sham-control animals were monitored for 5 to 7 w. Growth parameters, food intake, sleep/wake activity, and serum hormones were measured. After euthanasia, growth plate (GP) histology, morphometry, orexin receptors (OXR), and related mediators were analyzed. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and GP histology were also investigated.. The AO group slept 32% less; the time spent in slow wave and paradoxical sleep during light period and slow wave activity was reduced. The AO group gained 46% less body weight compared to the control group, despite elevated food intake; plasma ghrelin increased by 275% and leptin level decreased by 44%. The impediment of bone elongation and bone mass was followed by a 200% increase in OX1R and 38% reduction of local GP ghrelin proteins and growth hormone secretagogue receptor 1a. Sry-related transcription factor nine (Sox9), a molecule mediating cartilage ossification, was downregulated and the level of transcription factor peroxisome proliferator-activated receptor gamma was upregulated, explaining the bone architecture abnormalities. Administration of almorexant restored sleep and improved GP width in AO animals.. In AO animals, enhanced expression of orexin and OX1R plays a role in respiratory induced sleep and growth abnormalities.

Topics: Acetamides; Animals; Body Weight; Bone Development; Eating; Ghrelin; Growth Disorders; Homeostasis; Isoquinolines; Leptin; Male; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Rats; Rats, Sprague-Dawley; Respiration; Sleep; Sleep Apnea Syndromes; Sleep, REM; Wakefulness

Neonatal growth restriction (nGR) leads to leptin deficiency and increases the risk of hypertension. Previous studies have shown nGR-related hypertension is normalized by neonatal leptin (nLep) and exacerbated by psychological stress. With recent studies linking leptin and angiotensin signaling, we hypothesized that nGR-induced nLep deficiency increases adult leptin sensitivity; leading to leptin- or stress-induced hypertension, through a pathway involving central angiotensin II type 1 receptors.. We randomized mice with incipient nGR, by virtue of their presence in large litters, to vehicle or physiologic nLep supplementation (80 ng/g/d). Adult caloric intake and arterial pressure were monitored at baseline, during intracerebroventricular losartan infusion and during systemic leptin administration.. nGR increased leptin-triggered renal sympathetic activation and hypertension with increased leptin receptor expression in the arcuate nucleus of the hypothalamus; all of those nGR-associated phenotypes were normalized by nLep. nGR mice also had stress-related hyperphagia and hypertension, but only the stress hypertension was blocked by central losartan infusion.. nGR leads to stress hypertension through a pathway that involves central angiotensin II receptors, and nGR-associated leptin deficiency increases leptin-triggered hypertension in adulthood. These data suggest potential roles for preservation of neonatal growth and nLep supplementation in the prevention of nGR-related hypertension.

Topics: Angiotensins; Animals; Blood Pressure; Disease Models, Animal; Growth Disorders; Hypertension; Leptin; Losartan; Male; Mice; Mice, Inbred C57BL; Random Allocation; Receptors, Angiotensin; Renin-Angiotensin System; Signal Transduction; Stress, Psychological; Sympathetic Nervous System

The effect of growth hormone (GH) on adipose tissue and the role of adipokines in modulating metabolism are documented, but with discordant data. Our aim was to evaluate the impact of GH treatment on a series of selected adipokines known to have a metabolic role and poorly investigated in this setting.. This is a prospective study. Thirty-one prepubertal children (25 M, 6 F; aged 8.5 ± 1.6 years) with isolated GH deficiency treated with GH for at least 12 months and 30 matched controls were evaluated. Auxological and metabolic parameters, insulin sensitivity indexes, leptin, soluble leptin receptor, adiponectin, visfatin, resistin, omentin, adipocyte fatty acid-binding protein and retinol-binding protein-4 were evaluated before and after 12 months of treatment.. At baseline, no significant difference in metabolic parameters was found between GHD children and controls, except for higher LDL cholesterol (p = 0.004) in the first group. At multivariate analysis, LDL cholesterol was independently associated with resistin (B 0.531; p = 0.002), while IGF-I was the only variable independently associated with visfatin (B 0.688; p < 0.001). After 12 months, a significant increase in fasting insulin (p = 0.008), Homa-IR (p = 0.007) and visfatin (p < 0.001) was found, with a concomitant decrease in LDL cholesterol (p = 0.015), QUICKI (p = 0.001), ISI Matsuda (p = 0.006), leptin (p = 0.015) and omentin (p = 0.003)]. At multivariate analysis, BMI was the only variable independently associated with leptin (B 0.485; p = 0.040).. GH treatment modifies adipokine secretion and the perturbation of some adipokine levels could contribute to the clinical and metabolic changes observed during the follow-up.

Topics: Biomarkers; Case-Control Studies; Child; Child, Preschool; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; GPI-Linked Proteins; Growth Disorders; Hormones; Human Growth Hormone; Humans; Lectins; Leptin; Male; Nicotinamide Phosphoribosyltransferase; Prospective Studies; Resistin

Wstęp. Peptydy produkowane w przewodzie pokarmowym, tkance tłuszczowej i w mózgu odgrywają ważną rolę w wydzielaniu hormonu wzrostu (GH) oraz regulacji przyjmowania posiłków. Zgodnie z hipotezą molekularnego podobieństwa antygeny mikroorganizmów bytujących w przewodzie pokarmowym mogą stać się mechanizmem spustowym dla produkcji przeciwciał, które reagują krzyżowo z peptydami regulatorowymi i modyfikują ich działanie. Celem pracy była ocena stężenia greliny, leptyny, oreksynyA i αMSH oraz poziomu przeciwciał skierowanych przeciwko wymienionym peptydom u dzieci z idiopatycznym niedoborem wzrostu (ISS) i niedoborem GH (GHD) w odniesieniu do infekcji Helicobacter pylori (H.pylori) i zasiedlenia Candida albicans (C.albicans). Materiał i metody. Analiza obejmowała 89 dzieci z niedoborem wzrostu (w wieku 10,24±3,52 lat): 64 z ISS i 25 z GHD oraz 36 dzieci prawidłowego wzrostu (grupa kontrolna) (w wieku 11,41±2,72 lat). U każdego dziecka oceniono w surowicy stężenie greliny, leptyny, oreksynyA i αMSH (alpha-melanocyte-stimulating hormone), poziom przeciwciał IgG skierowanych przeciwko wymienionym peptydom oraz przeciwko H.pylori, zaś obecność C.albicans na podstawie badania próbki kału. Grupa kontrolna została dobrana tak, aby częstość występowania infekcji H.pylori i zasiedlenia C.albicans była podobna do grupy badanej. Wyniki. Poziom przeciwciał IgG przeciwko grelinie i leptynie był znamiennie wyższy w grupie ISS niż w grupie kontrolnej. Stężenie greliny było istotnie wyższe u dzieci z GHD niż w grupie kontrolnej, zaś stężenie leptyny (jak również wskaźnik masy ciała) istotnie niższe w grupie ISS niż w grupach GHD i kontrolnej. Nie wykazano różnic pomiędzy grupami w odniesieniu do stężenia oreksynyA i αMSH ani przeciwciał skierowanych przeciwko nim. Wnioski. Podwyższony poziom przeciwciał skierowanych przeciwko grelinie i leptynie u dzieci z ISS jest związany z upośledzeniem wzrastania i gorszymi przyrostami masy ciała, prawdopodobnie poprzez modyfikację aktywności greliny i leptyny. Możliwe, że te przeciwciała reagują krzyżowo z peptydami na skutek molekularnego podobieństwa między wymienionymi peptydami a H.pylori i C.albicans, jednak potrzebne są dalsze badania wyjaśniające tę kwestię.

Topics: Adolescent; alpha-MSH; Autoantibodies; Candida albicans; Candidiasis; Child; Female; Ghrelin; Growth Disorders; Helicobacter Infections; Helicobacter pylori; Humans; Leptin; Male; Orexins

To investigate whether short children born very preterm (<32 weeks of gestation) exhibit features of growth hormone (GH) resistance compared to term peers.. We studied 26 prepubertal children (aged 7.0 ± 2.0 years) with short stature (height adjusted for parents' heights <10th percentile), who were born appropriate for gestational age and either very preterm (n = 11) or at term (n = 15). Children underwent insulin-like growth factor-1 (IGF-1) generation test via a daily recombinant human GH (rhGH) dose (0.05 mg/kg/day) over 4 consecutive days. Hormone and binding proteins were measured at baseline and day 5.. At baseline, preterm children had lower IGF-binding protein 1 (IGFBP-1; -22%; p = 0.049) and IGFBP-3 (-24%; p = 0.013) concentrations than term children. Preterm children also had insulin concentrations that tended to be 39% higher (p = 0.059) than term peers. After stimulation, IGF-1 and IGFBP-3 concentrations increased similarly in term and preterm groups, while GH-binding protein (GHBP) concentrations decreased in both groups. Preterm children had higher GHBP (+50%; p = 0.049), insulin (+86%; p = 0.005), and leptin (+107%; p = 0.020) but lower IGFBP-1 (-47%; p = 0.006) concentrations than term children following rhGH stimulation.. Preterm children who are short for genetic height potential show no evidence of GH resistance that would explain their short stature. However, there was indirect evidence of insulin resistance in the preterm children, as previously described in this group.

Topics: Body Height; Carrier Proteins; Child; Female; Growth Disorders; Human Growth Hormone; Humans; Infant, Extremely Premature; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Recombinant Proteins

Many of peptides synthesized in gastrointestinal tract (GI) and adipose tissues, regulate growth and food intake. The GI microflora is an antigenic source. Based on the molecular mimicry hypothesis, intestinal microbe-derived antigens may trigger the production of autoantibodies cross-reacting with some neuropeptides.. The aim of the study was to assess whether in idiopathic short stature (ISS) children with Candida albicans (C.albicans) colonisation and/or Helicobacter pylori (H.pylori) infection the autoantibodies (in positive levels) against selected neuropeptides [anti-NP Abs(+)]: ghrelin, leptin, orexin A, αMSH are more prevalent than in Controls.. The study group comprised 64 children with ISS and 36 children with normal height (Controls). In each child, IgG antibodies against H.pylori, ghrelin, leptin, orexin A and αMSH were assessed in serum, while presence of C.albicans - in stool samples.. The higher prevalence of anti-NP Abs(+) in ISS children with C.albicans and/or H.pylori than in normal height children with the colonization in question (34.4% vs 21.1%, p<0.01) was found. The prevalence of anti-NP Abs(+) in groups of children without C.albicans and H.pylori were low, anti-NP Abs(+) were detected in 9.4% of ISS children only, while in Controls they were not found.. In short children with C.albicans and/or H.pylori the incidence of autoantibodies against selected neuropeptides is high. It probably is connected with molecular mimicry between antigens of these microbiota and the mentioned peptides. It is tempting to speculate that presence of cross-reacting autoantibodies against regulatory neuropeptides may results in worse growth velocity. However, further studies are necessary to elucidate this issue.

Topics: Adolescent; alpha-MSH; Autoantibodies; Candida albicans; Candidiasis; Carrier State; Child; Child, Preschool; Cross Reactions; Female; Ghrelin; Growth Disorders; Helicobacter Infections; Helicobacter pylori; Humans; Leptin; Male; Molecular Mimicry; Neuropeptides; Orexins

Undernutrition in early life has been reported to be closely associated with the development of non-communicable diseases in adulthood. Adequate treatment is important for reversing these effects. In the present study, we investigated the effects of undernutrition and anthropometric recovery on the weights and heights of children in relation to the concentrations of leptin, adiponectin and plasminogen activator inhibitor-1 (PAI-1). A total of 119 children (aged 6-16 years) from the slums of São Paulo were selected according to their nutritional status and divided into three groups as follows: control (healthy without intervention, n 38) with a height-for-age Z score (HAZ) and a BMI-for-age Z score (BAZ) > -1·6; undernourished (HAZ and/or BAZ < -1·6, n 54); recovered from undernutrition (after treatment in a rehabilitation centre; HAZ and BAZ > -1·6, n 27). Blood samples were collected to determine insulin, glucose, leptin, adiponectin and PAI-1 concentrations. Leptin concentrations in the undernourished group were lower than those in the control and recovered groups (mean 0·92 (95% CI 0·67, 1·25), 2·03 (95% CI 1·46, 2·82) and 1·66 (95% CI 1·15, 2·44) ng/ml, P=0·003), which had similar leptin concentrations. There were no differences in adiponectin and PAI-1 concentrations among the groups. A positive correlation between waist circumference and leptin concentrations was observed in all the girls and boys of the control group (control: r 0·729, P<0·01; undernourished: r 0·490, P<0·05; and recovered: r 0·829, P<0·01; r 0·673, P<0·05). Stronger correlations between leptin and insulin concentrations were observed in the recovered group. The results of the present study indicate that normal leptin concentrations are found when normal height and weight are achieved.

Topics: Adiponectin; Adolescent; Adolescent Development; Body Height; Bone Development; Brazil; Child; Child Development; Cross-Sectional Studies; Female; Growth Disorders; Humans; Insulin; Leptin; Male; Malnutrition; Plasminogen Activator Inhibitor 1; Poverty Areas; Waist Circumference; Weight Gain

Leptin levels may regulate fat metabolism, skeletal growth, and puberty. Leptin gene variants affect risk of obesity, cancer, but their effect on onset of growth hormone deficiency (GHD) and idiopathic short stature (ISS) is unknown. We tested the hypothesis that the phenotype of GHD and ISS may be associated with polymorphism in the leptin gene. The prevalence of a single nucleotide polymorphism (SNP) in the leptin gene (LEP) promoter at -2548 and the leptin and insulin growth factor-1 (IGF-1) concentrations in GHD and ISS were compared to those of healthy controls. IGF-1 and leptin concentrations were significantly lower in both the GHD and ISS groups than in the control group. The ISS and GHD groups had a significantly different distribution of SNP alleles at the LEP -2548 (P = 0.010). Individuals with LEP -2548A/G or G/G genotype in ISS group (47.5%) showed a significantly lower weight and body mass index (BMI) (but not leptin levels) than individuals carrying the A/A genotype (52.5%). LEP -2548A/A in GHD patients (65.8%) was associated with lower weight, BMI, leptin concentrations than those of individuals carrying the A/G or G/G genotype (34.2%). These data suggest that the LEP -2548A polymorphism may associate with the weight and BMI of the children with ISS and GHD.

Topics: Age Determination by Skeleton; Age Factors; Body Height; Body Mass Index; Body Weight; Child; Dwarfism; Female; Gene Frequency; Growth Disorders; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Male; Polymorphism, Single Nucleotide

To study the effect of in-utero alcohol exposure on the insulin-like growth factor axis (IGF) and leptin during infancy and childhood, considering that exposed children may exhibit pre- and postnatal growth retardation.. We prospectively identified heavily drinking pregnant women who consumed on average 4 or more drinks of ethanol per day (≥ 48 g/day) and assessed growth in 69 of their offspring and an unexposed control group of 83 children, measuring serum IGF-I (radioimmunoassay), IGF-II (immunoradiometric assay, IRMA), insulin-like growth factor-binding protein 3 (IGFBP-3) (IRMA) and leptin (IRMA) at 1 month and 1, 2, 3, 4, and 5 years of age.. IGF-II levels increased with age in both groups, but the rate of increase was significantly higher in exposed children, and levels were significantly higher in ethanol-exposed children at 3, 4, and 5 years of age. In exposed children, IGF-I levels were higher at 3 and 4 years and leptin levels were significantly lower at 1 and 2 years. Exposed subjects showed a much lower correlation between IGF-I and growth parameters than unexposed subjects.. Exposure to ethanol during pregnancy increases IGF-I and IGF-II and decreases leptin during early childhood. The increase in serum IGF-II concentrations in ethanol-exposed children suggests that this hormone should be explored as a potential marker for prenatal alcohol exposure.

Topics: Alcohol Drinking; Biomarkers; Body Mass Index; Child Development; Child, Preschool; Female; Fetal Alcohol Spectrum Disorders; Growth Disorders; Humans; Infant; Infant, Newborn; Infant, Small for Gestational Age; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Male; Pregnancy; Prenatal Exposure Delayed Effects; Prospective Studies; Somatomedins

Constitutional delay of growth and puberty (CDGP) is a variation of the onset and timing of pubertal development without a defined endocrine abnormality. Recently published studies indicate that leptin and ghrelin play a role in puberty initiation and progress. They have been implicated in regulation of GnRH secretion, with ghrelin having inhibitory and leptin, facilitatory effects. We hypothesized that elevated ghrelin and reduced leptin concentrations could be implicated in altering the tempo of puberty in adolescents with CDGP. So in the current study we evaluate variations in leptin and ghrelin levels in adolescent boys with CDGP, the relationships between both hormones and reproductive hormones including LH, FSH and testosterone were also evaluated.. The study enrolled 23 adolescent boys with CDGP and 20 healthy controls matched for age and sex. Weight, height, BMI, testicular volume, bone age, bone age delay, serum FSH, LH, testosterone, leptin and ghrelin were assessed.. Adolescent boys with CDGP had significantly lower leptin and higher ghrelin than normal controls. Leptin was positively correlated with BMI, bone age, testicular volume, FSH, LH and testosterone and negatively correlated with delayed bone age and ghrelin. Ghrelin was negatively correlated with BMI, bone age, testicular volume, FSH, LH and testosterone. With multiple regression analysis BMI, FSH, LH, testosterone and ghrelin remained independently correlated with leptin while BMI, LH and testosterone remained independently correlated with ghrelin.. Elevated serum ghrelin and decreased leptin concentrations and their associations with reproductive hormones may explain the sexual immaturity in adolescent boys with CDGP.

Topics: Adolescent; Follicle Stimulating Hormone; Ghrelin; Growth Disorders; Humans; Leptin; Luteinizing Hormone; Male; Puberty; Puberty, Delayed; Testosterone

The aim of the study was to evaluate growth pattern of small- and appropriate-for-gestational-age children and to identify prenatal and postnatal risk factors for short stature and development of components of metabolic syndrome. A total of 109 small- and 239 appropriate-for-gestational-age infants were enrolled in the study. Within 24 hours after birth and at 2, 5, 9, 12, 18, 24 months, and 6 years of age, anthropometric data were recorded for study children. Cord blood samples from study infants were collected, and insulin-like growth factor-1 (IGF), IGF-binding protein-3, and leptin levels were measured. Birth weight and height (P<0.001) and insulin-like growth factor-1, IGF-binding protein-3, and leptin levels (P<0.05) were lower in children born small for gestational age vs. children born appropriate for gestational age. At 2, 5, 12, 18, and 24 months and 6 years of age, children born small for gestational age remained shorter and weighed less (P<0.001). Waist-to-hip ratio, heart rate at 6 years of age and gain in body mass index from birth up to 6 years of age was higher in children born small for gestational age. Height gain during the first year of life was mainly influenced by birth length and target height. Maternal weight before pregnancy and cord leptin levels were the most significant factors influencing postnatal weight gain during the first years of life.. During the first 6 years of life, children born small for gestational age remained shorter and lighter. A greater catch-up in body mass index and tendency towards central pattern of fat distribution during the first years of life might be predisposing factors for the development of long-term metabolic complications in these individuals.

Topics: Birth Weight; Body Mass Index; Chi-Square Distribution; Child; Child Development; Child, Preschool; Data Interpretation, Statistical; Female; Fetal Blood; Follow-Up Studies; Growth Disorders; Humans; Infant; Infant, Newborn; Infant, Small for Gestational Age; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Mothers; Pregnancy; Radioimmunoassay; Risk Factors; Time Factors

A puppy was evaluated for rapid growth and large stature. Extensive diagnostic evaluation suggested a growth hormone independent disorder. As the sole detected abnormality was elevated leptin concentration, an obesity syndrome causing leptin resistance was speculated to explain the puppy's condition but was not confirmed. Except for large body size, the puppy remained clinically normal.

Topics: Animals; Dogs; Female; Growth Disorders; Growth Hormone; Hydrocortisone; Insulin; Leptin; Thyroid Hormones

Topics: Animals; Dogs; Growth Disorders; Growth Hormone; Insulin-Like Growth Factor I; Leptin

Type 2 diabetes results from impaired insulin action and beta-cell dysfunction. There are at least two components to beta-cell dysfunction: impaired insulin secretion and decreased beta-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired beta-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, approximately 70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased beta-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as beta-cell mass gradually declined, indicating that replication-defective beta-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous beta-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of beta-cell dysfunction in type 2 diabetes should positively affect both aspects of beta-cell physiology.

Topics: Adaptation, Physiological; Adiponectin; Adipose Tissue; Animals; Animals, Newborn; Diabetes Mellitus; Glucose Tolerance Test; Growth Disorders; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin-Secreting Cells; Intracellular Signaling Peptides and Proteins; Leptin; Liver; Mice; Mice, Inbred Strains; Mice, Knockout; Muscle, Skeletal; Mutation; Organ Size; Osmolar Concentration; Phosphatidylinositol 3-Kinases; Phosphoproteins; Proto-Oncogene Proteins c-akt; Receptor, Insulin

The present study evaluated levels of growth factors and their associations with nutritional status with emphasis on stunting in children at 1 and 3 years of age. A follow-up study on a birth cohort (n 219) of children from villages in the central region of the Limpopo Province was undertaken. Of the original cohort, 156 and 162 could be traced and assessed at ages 1 and 3 years, respectively. Data collected included socio-demographic characteristics, anthropometric measurements, dietary intake and fasting blood (collected from 116 and 145 children at 1 and 3 years, respectively) for growth factor analysis (insulin-like growth factor (IGF)-1, IGF binding protein (BP)-1, IGFBP-3, leptin, glucose and insulin). At 1 year it was found that stunted children had lower leptin levels while their IGFBP-1 levels were higher than that in normal children. These differences were, however, not observed at 3 years. Furthermore at 1 year the biochemical parameters were more related to length measures whereas at 3 years the parameters were more associated with weight measures. The observed stunting in this group of children may be a result of chronic undernutrition resulting in long-term growth faltering which is already evident at 1 year. Thus the observed phenomenon might be an adaptive mechanism adopted by children's metabolic processes as they grow up in an environment with inadequate essential nutrients due to poor weaning practices and consumption of a diet of poor quality, resulting in them gaining more weight at the expense of linear growth.

Topics: Anthropometry; Body Height; Child, Preschool; Female; Growth Disorders; Humans; Infant; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Leptin; Male; Nutritional Status; Prevalence; Risk Factors; Rural Health; Socioeconomic Factors; South Africa

Topics: Anticonvulsants; Biomarkers; Growth Disorders; Humans; Leptin; Rett Syndrome; Valproic Acid

Abnormalities of the melanocortin system produce obesity and increased linear growth. While the obesity phenotype is well characterised, the mechanism responsible for increased linear growth is unclear. The somatotrophic axis was studied in the obese agouti (A(y)/a) mouse as a model of a perturbed melanocortin system.. Adult obese A(y)/a mice were compared to age- and sex-matched wild-type (WT) controls. Weight and body length (nose-anus) were recorded. Plasma growth hormone (GH), insulin-like growth factor-I (IGFI), insulin and leptin were measured using radioimmunoassay. Since ghrelin is a potent GH secretagogue, plasma ghrelin, stomach ghrelin peptide and stomach ghrelin mRNA expression were studied. Hypothalamic periventricular (PeVN) somatostatin neurones and arcuate (Arc) neuropeptide Y (NPY) neurones inhibit the growth axis, whereas Arc growth hormone-releasing hormone (GHRH) neurones are stimulatory. Therefore, specific hypothalamic expression of somatostatin, NPY and GHRH was measured using quantitative in situ hybridisation.. Obese A(y)/a mice were significantly heavier and longer than WT controls. Plasma IGFI concentrations were 30% greater in obese A(y)/a mice. Obese A(y) /a mice were hyperinsulinaemic and hyperleptinaemic, yet plasma ghrelin, and stomach ghrelin peptide and mRNA were significantly reduced. In obese A(y)/a mice, PeVN somatostatin and Arc NPY mRNA expression were reduced by 50% compared to WT controls, whereas Arc GHRH mRNA expression was unchanged.. Increased body length in adult obese A(y)/a mice may result from reduced Arc NPY and PeVN somatostatin mRNA expression, which in turn, may increase plasma IGFI concentrations and upregulate the somatotrophic axis.

Topics: Agouti Signaling Protein; Animals; Biometry; Body Weight; Gastric Mucosa; Gene Expression; Ghrelin; Growth Disorders; Growth Hormone; Hypothalamus; Insulin; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Leptin; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptide Hormones; Pituitary Gland, Anterior; RNA, Messenger; Signal Transduction; Somatostatin

Children with Cerebral Palsy (CP) are generally undernourished and growth retarded than normal children. The reasons of malnutrition are not only due to poor nutritional status but also nonnutritional factors including negative neurotrophic effects and indirect factor such as immobility, endocrinological abnormalities or spasticity that energy requirements might be contributing factors. Several studies indicated that leptin which is produced by adipocytes, might regulate energy intake and expenditure. The aim of this study is to determine serum leptin levels in children with CP and to investigate the relationship between nutritional status and anthropometric measurements.. Forty children with CP and 18 healthy controls were included in this study. The weight, height, body mass index (BMI), upper arm length (UAL) and triceps skinfold thickness (TST) was measured in all children. Serum leptin, growth hormone, C-peptide and cortisol levels were studied. Based on TST measurement CP patients were divided as DSF group (decreased subcutaneous fat) and non-DSF group (nondecreased subcutaneous fat).. UAL were shorter and TST measurements were thinner than control group (p<0.05, p<0.01). Group DSF had lower leptin concentrations compared to Group non-DSF and controls (p<0.001, p<0.001). On the other hand non DSF group had higher leptin levels than controls (p<0.05). There was a positive and significant correlation between leptin and anthropometric measurements, especially TST in children with CP. Serum leptin levels were also lower in non-ambulatory children than ambulatory children with CP (p<0.05).. This study has shown that triceps skinfold thickness is better index for the evaluation of nutritional status in children with CP. Serum leptin levels were lower in CP, especially in DSF group. The possible explanation of this finding may not only related with malnutrition, but also immobility related other factors such as bone metabolism and spasticity. We concluded that leptin which regulates energy intake might have a role of nutritional disorders in cerebral palsy. To better understand this relationship further studies are needed.

Topics: Adolescent; Anthropometry; C-Peptide; Cerebral Palsy; Child; Child Nutrition Disorders; Child, Preschool; Energy Metabolism; Female; Growth Disorders; Human Growth Hormone; Humans; Hydrocortisone; Leptin; Male; Nutritional Status

The aim of the study was to estimate the anthropometric parameters and their relationship to serum levels of IGF-I, IGF-II, IGFBP-3, IGFBP-2 and leptin before and during intensive antineoplastic treatment for acute lymphoblastic leukaemia in children.. In 46 children in median age 6.6 years (range from 1.6 to 16) we evaluated at the time of diagnosis, after protocol I and after intensive treatment, height, body mass index (BMI) and IGF-I, IGF-II, IGFBP-3, IGFBP-2 and leptin.. Height SDS lowered in successive points of analysis whereas BMI SDS rose after protocol II. IGF-I SDS was low and similar at each point, IGF-II SDS and IGFBP-3 SDS values augmented progressively and IGFBP-2 SDS was significantly elevated before treatment and lowered (but not normalized) during the therapy. Leptin SDS was elevated, especially after protocol I.. Leukaemia and its treatment affect directly growth factors, its binding proteins and leptin production leading to growth retardation and overweight.

Topics: Adolescent; Antineoplastic Agents; Body Constitution; Body Height; Child; Child, Preschool; Female; Growth Disorders; Humans; Infant; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Male; Overweight; Precursor Cell Lymphoblastic Leukemia-Lymphoma

To examine the influence of recombinant human growth hormone (rhGH) therapy on insulin sensitivity in short children born small for gestational age (SGA).. Twelve short (height standard deviation score, -3.2 +/- 0.1) non-GH-deficient children SGA (7 boys/5 girls) were studied at 9.3 +/- 1.0 years of age. The insulin sensitivity index was measured with Bergman's minimal model before (11 children) and during (12 children) rhGH therapy (21 +/- 6 months) administered daily at 20 IU/m(2) per week. No child had a change in pubertal status during the study. In addition, 5 children who remained prepubertal had insulin sensitivity remeasured 3 months after rhGH therapy was suspended.. With rhGH therapy, insulin sensitivity fell 44% +/- 10% (P =.018), with a compensatory rise in the acute insulin response of 123% +/- 59% (P <.009). Reassessment of insulin sensitivity in 5 children (3 boys/2 girls) 3 months after suspension of rhGH occurred at 9.9 +/- 0.7 years. Insulin sensitivity remained unchanged after rhGH therapy was stopped: 31.6 (20.5-42.3) before treatment, 11.5 (5.7-24.4) with treatment, and 10.7 (6.2-16.9) 10(-4). min(-1) microU/mL after treatment.. Children SGA are known to have reduced insulin sensitivity. There was a further reduction in insulin sensitivity with rhGH therapy that did not recover 3 months after rhGH therapy was stopped.

Topics: Blood Glucose; Body Height; Body Mass Index; Child; Drug Monitoring; Female; Growth Disorders; Growth Hormone; Humans; Infant, Newborn; Infant, Small for Gestational Age; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Male; Time Factors; Treatment Outcome

Catch-up growth is a risk factor for later obesity, type 2 diabetes, and cardiovascular diseases. We show here that after growth arrest by semistarvation, rats refed the same amount of a low-fat diet as controls show 1) lower energy expenditure due to diminished thermogenesis that favors accelerated fat deposition or catch-up fat and 2) normal glucose tolerance but higher plasma insulin after a glucose load at a time point when their body fat and plasma free fatty acids (FFAs) have not exceeded those of controls. Isocaloric refeeding on a high-fat diet resulted in even lower energy expenditure and thermogenesis and increased fat deposition and led to even higher plasma insulin and elevated plasma glucose after a glucose load. Stepwise regression analysis showed that plasma insulin and insulin-to-glucose ratio after the glucose load are predicted by variations in efficiency of energy use (i.e., in thermogenesis) rather than by the absolute amount of body fat or plasma FFAs. These studies suggest that suppression of thermogenesis per se may have a primary role in the development of hyperinsulinemia and insulin resistance during catch-up growth and underscore a role for suppressed thermogenesis directed specifically at catch-up fat in the link between catch-up growth and chronic metabolic diseases.

Topics: Adipose Tissue; Aging; Analysis of Variance; Animals; Blood Glucose; Body Weight; Diet, Fat-Restricted; Energy Metabolism; Fatty Acids, Nonesterified; Glucose Tolerance Test; Growth; Growth Disorders; Insulin; Leptin; Male; Rats; Rats, Sprague-Dawley; Regression Analysis; Thermogenesis

Transketolase (TKT) is a ubiquitous enzyme used in multiple metabolic pathways. We show here by gene targeting that TKT-null mouse embryos are not viable and that disruption of one TKT allele can cause growth retardation ( approximately 35%) and preferential reduction of adipose tissue ( approximately 77%). Other TKT(+/-) tissues had moderate ( approximately 33%; liver, gonads) or relatively little ( approximately 7 to 18%; eye, kidney, heart, brain) reductions in mass. These mice expressed a normal level of growth hormone and reduced leptin levels. No phenotype was observed in the TKT(+/-) cornea, where TKT is especially abundant in wild-type mice. The small female TKT(+/-) mice mated infrequently and had few progeny (with a male/female ratio of 1.4:1) when pregnant. Thus, TKT in normal mice appears to be carefully balanced at a threshold level for well-being. Our data suggest that TKT deficiency may have clinical significance in humans and raise the possibility that obesity may be treated by partial inhibition of TKT in adipose tissue.

Topics: Adipose Tissue; Alleles; Animals; Body Weight; Cornea; Disease Models, Animal; Embryonic and Fetal Development; Energy Metabolism; Eye Proteins; Female; Gene Targeting; Growth Disorders; Growth Hormone; Heterozygote; Infertility, Female; Introns; Leptin; Litter Size; Mice; Mice, Inbred C57BL; Mice, Knockout; Morula; Mutagenesis, Insertional; Organ Size; Phenotype; Pregnancy; Sexual Behavior, Animal; Transketolase

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are two closely related peptides that bind two homologous G protein-coupled receptors, VIP/PACAP receptor 1 (VPAC1R) and VIP/PACAP receptor II (VPAC2R), with equally high affinity. Recent reports suggest that VPAC2R plays a role in circadian rhythm and T cell functions. To further elucidate the functional activities of VPAC2R, we generated VPAC2R-deficient mice by deleting exons VIII-X of the VPAC2R gene. The VPAC2R-deficient mice showed retarded growth and had reduced serum IGF-I levels compared with gender-matched, wild-type siblings. The mutant mice appeared healthy and fertile at a young adult age. However, older male mutant mice exhibited diffuse seminiferous tubular degeneration with hypospermia and reduced fertility rate. The mutant mice appeared to have an increase in insulin sensitivity. VPAC2R-deficient mice had increased lean mass and decreased fat mass with reduced serum leptin levels. Indirect calorimetry experiments showed that the respiratory quotient values immediately following the transition into the dark cycle were significantly higher in male knockout mice for about 4 h. Additionally, male and female VPAC2R-deficient mice presented an increased basal metabolic rate (23% and 10%, respectively) compared with their wild-type siblings. Our results suggest that VPAC2R plays an important role in growth, basal energy expenditure, and male reproductive functions.

Topics: Amino Acid Sequence; Animals; Basal Metabolism; Body Composition; Female; Growth; Growth Disorders; Infertility, Male; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Knockout; Molecular Sequence Data; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Peptide, Type II; Reference Values; Seminiferous Tubules; Sex Characteristics; Sperm Count

To observe the effect of growth hormone on serum leptin levels, serum leptin concentrations were measured by enzyme immunoassay in 12 prebuttal children with growth hormone deficiency 1, 3 and 6 months before and after the treatment with recombinant human growth hormone (r-hGH). For comparison, 34 normal prepubertal children were also investigated. Relationship between leptin levels and body mass index (BMI) was observed at the same time. Our results showed that serum leptin level in normal prepubertal children was 1.22 +/- 0.34 ng/ml; the pretreatment serum leptin levels in GHD children was 3.08 +/- 2.41 ng/ml, which was significantly different from those 1, 3 and 6 months after GH treatment (i.e. 1.64 +/- 1.37 ng/ml, 1.57 +/- 1.40 ng/ml and 1.35 +/- 0.89 ng/ml respectively) (all P < 0.001). Our results suggested that r-hGH has a suppressive effect on leptin expression.

Topics: Adolescent; Body Mass Index; Child; Female; Growth Disorders; Growth Hormone; Humans; Leptin; Male

To develop and to characterize a human preadipocyte cell strain with high capacity for adipose differentiation serving as a model for studying human adipocyte development and metabolism in vitro.. Cells were derived from the stromal cells fraction of subcutaneous adipose tissue of an infant with Simpson-Golabi-Behmel syndrome (SGBS). Adipose differentiation was induced under serum-free culture conditions by exposure to 10 nM insulin, 200 pM triiodothyronine, 1 microM cortisol and 2 microM BRL 49653, a PPAR gamma agonist.. During the differentiation process SGBS cells developed a gene expression pattern similar to that found in differentiating human preadipocytes with a characteristic increase in fat cell-specific mRNAs encoding lipoprotein lipase (LPL), glycero-3-phosphate dehydrogenase (GPDH), GLUT4, leptin and others. Differentiated SGBS cells exhibited an increase in glucose uptake upon insulin stimulation and in glycerol release upon catecholamine exposure. SGBS adipocytes were morphologically, biochemically and functionally identical to in vitro differentiated adipocytes from healthy subjects. However, while preadipocytes from healthy control infants rapidly lost their capacity to differentiate after a few cell divisions in culture, SGBS cells maintained their differentiation capacity over many generations: upon appropriate stimulation 95% of SGBS cells of generation 30 developed into adipocytes. A mutation in the glypican 3 gene was not detected in the patient. Thus, it remains unclear whether the molecular alteration in SGBS cells is also responsible for the high differentiation capacity and further investigations are required.. The human cell strain described here provides an almost unlimited source of human preadipocytes with high capacity for adipose differentiation and may, therefore, represent a unique tool for studying human fat cell development and metabolism. International Journal of Obesity (2001) 25, 8-15

Topics: Adipocytes; Adipose Tissue; Cell Differentiation; Cell Division; Cells, Cultured; Female; Gene Expression; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Humans; Infant; Insulin; Karyotyping; Leptin; Male; Models, Biological; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Syndrome; Thiazoles; Thiazolidinediones; Transcription Factors

Serum IGF-I levels in GH-treated subjects demonstrate a wide range of responsiveness to GH. However, the factors influencing GH sensitivity are not well known. The aim of this work was 1) to test whether body composition (determined by dual energy x-ray absorptiometry) or factors related to body composition (fasting blood glucose, FFA, C-peptide, leptin, and insulin sensitivity determined by an insulin tolerance test) influence GH sensitivity; and 2) to study the effect of sex steroid priming on GH sensitivity. We measured serum IGF-I at baseline and 24 h after a single administration of GH (2 mg/m(2)) in 60 healthy prepubertal and early pubertal children (height, -2.1 +/- 1.0 SD score). GH sensitivity, as estimated by the increase in serum IGF-I after GH administration (difference between stimulated and baseline serum IGF-I = delta IGF-I), was also determined after a short-term administration of oral ethinyl E2 in girls and im T in boys. The serum IGF-I concentration was 297 +/- 114 microg/liter at baseline and increased to 429 +/- 160 microg/liter, corresponding to a 46 +/- 29% increase over the baseline value (P < 0.0001, stimulated vs. baseline serum IGF-I). delta IGF-I was not different between gender or pubertal stage. There were positive correlations (P < 0.001) between delta IGF-I and adiposity (total body fat, r = 0.62; trunk fat, r = 0.62), fasting leptin (r = 0.64), and C-peptide (r = 0.54), and a negative correlation with fasting FFA (r = -0.33; P < 0.05) even after adjustment for age, gender, and pubertal stage. These factors remained significant independent predictors of the absolute as well as the percent increase in serum IGF-I in multiple regression analyses. Priming with T and ethinyl E2 had a similar stimulating effect on the serum GH peak in response to the insulin tolerance test. In boys, serum baseline IGF-I increased by 60%, and delta IGF-I was similar after vs. before T administration. By contrast, in girls, serum baseline IGF-I was similar, and delta IGF-I was 60% less after vs. before ethinyl E2 administration. This study indicates that 1) GH sensitivity is determined by fat mass, serum fasting leptin, C-peptide, and FFA; and 2) oral ethinyl E2 and im T have divergent effects on the IGF-I response to a single administration of GH.

Topics: Adolescent; Body Composition; Body Height; Child; Ethinyl Estradiol; Fasting; Female; Forecasting; Gonadal Steroid Hormones; Growth Disorders; Human Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Puberty; Recombinant Proteins; Sex Characteristics; Testosterone

Topics: Deficiency Diseases; Drug Resistance; Female; Growth Disorders; Humans; Hypothyroidism; Leptin; Obesity; Risk Assessment

Serum IGF-I levels are monitored during GH replacement treatment in adults with GH deficiency (GHD) to guide GH dose adjustment and to minimize occurrence of GH-related side-effects. This is not routine practice in children treated with GH. The aim of this study was to evaluate changes in (1) serum IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio, and (2) serum leptin, an indirect marker of GH response, during the first year of GH treatment in children with disordered growth.. An observational prospective longitudinal study with serial measurements at five time points during the first year of GH treatment was carried out. Each patient served as his/her own control.. The study included 31 patients, grouped as (1) GHD (n = 20) and (2) non-GHD (Turner syndrome n = 7; Noonan syndrome n = 4), who had not previously received GH treatment.. Serum IGF-I, IGFBP-3 and leptin levels were measured before treatment and after 6 weeks, 3 months, 6 months and 12 months of GH treatment, with a mean dose of 0.5 IU/kg/wk in GHD and 0.7 IU/kg/wk in non-GHD groups. IGF-I, IGFBP-3 and the calculated IGF-I/IGFBP-3 molar ratio were expressed as SD scores using reference values from the local population.. In the GHD group, IGF-I SDS before treatment was lower compared with the non-GHD (-5.4+/-2.5 vs. -1.8+/-1.0; P<0.001). IGF-I (-1.8 SDS +/- 2.2) and IGFBP-3 (-1.1 SDS +/- 0.6) levels and their molar ratios were highest at 6 weeks and remained relatively constant thereafter. In the non-GHD group, IGF-I levels increased throughout the year and were maximum at 12 months (0.3 SDS +/- 1.4) while IGFBP-3 (1.1 SDS +/- 0.9) and IGF-I/IGFBP-3 molar ratio peaked at 6 months. In both groups, IGF-I SDS and IGF-I/IGFBP-3 during treatment correlated with the dose of GH expressed as IU/m2/week (r-values 0. 77 to 0.89; P = 0.005) but not as IU/kg/week. Serum leptin levels decreased significantly during GH treatment in the GHD (median before treatment 4.0 microg/l; median after 12 months treatment 2.4 microg/l; P = 0.02) but not the non-GHD (median before treatment 3.0 microg/l; median after 12 months treatment 2.6 microg/l). In the GHD group, serum leptin before treatment correlated with 12 month change in height SDS (r = 0.70, P = 0.02).. The pattern of IGF-I, IGFBP-3 and their molar ratio during the first year of GH treatment differed between the GHD and non-GHD groups. Calculation of GH dose by surface area may be preferable to calculating by body weight. As a GH dose-dependent increase in serum IGF-I and IGF-I/IGFBP-3 may be associated with adverse effects, serum IGF-I and IGFBP-3 should be monitored routinely during long-term GH treatment. Serum leptin was the only variable that correlated with first year growth response in GHD.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans; Infant; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Noonan Syndrome; Prospective Studies; Turner Syndrome

Nongenetic factors such as nutrition modulate the effects of genes responsible for overgrowth in animals. The goal of this study was to examine the importance of genotype x diet interactions on the effects of a major locus that regulates growth in the mouse. We have examined the phenotype of high growth (hg), a partially recessive autosomal locus that increases growth rate and mature body size. C57BL/6J (C57) and congenic C57BL/6J-hg/hg (HG) mice were fed three experimental diets differing in protein and energy content from 3 to 12 wk of age. HG mice grew faster and were, on average, 51% heavier than C57 at 12 wk of age. Feed intake was higher in HG mice but proportional to the increase in body weight. The magnitude of the differences in body size and composition between lines depended on the interaction between genotype and the protein/energy ratio of the diet. In C57, the diets modified the level of fatness without changing adult lean mass. However, in HG the diets differentially affected both linear growth and body composition. In general, HG had higher plasma levels of insulin-like growth factor I at 3 and 12 wk than C57. Plasma insulin did not differ between lines, but leptin was higher for C57 mice fed a high-energy diet. These results show that the effects of hg on growth are modulated by diet composition. Therefore, this mutation could be a valuable model with which to study the genetic and nutritional aspects of overgrowth disorders.

Topics: Animals; Blood Glucose; Body Composition; Dietary Proteins; Disease Models, Animal; Eating; Energy Intake; Food, Formulated; Growth Disorders; Homozygote; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Organ Size; Phenotype; Weight Gain

Short stature can be a severe side-effect of bone marrow transplantation (BMT). Because of the effect of weight changes on growth rate and on plasma insulin-like growth factor (IGF I), we analyzed changes in height and body mass index (BMI) in 53 patients given BMT. Group 1 (n = 22) was given 12 Gy total body irradiation (TBI) as six fractions, group 2 (n = 14) 10 Gy TBI (one dose), group 3 (n = 8) 6 Gy total lymphoid irradiation (one dose), and group 4 (n = 9) chemotherapy alone. At the first evaluation, 13/36 patients in groups 1 and 2 had low growth hormone (GH) peaks after stimulation. The mean plasma IGF I concentrations (z score) were similar in groups 1 (-2.9 +/- 0.3) and 2 (-2.5 +/- 0.3), and in groups 3 (-1.4 +/- 0.3) and 4 (-1.4 +/- 0.7), but those of group 1 were lower than those of groups 3 (P < 0.01) and 4 (P < 0.05), and those of group 2 than those of group 3 (P < 0.05). BMI during the 5 years after BMT did not change in groups 1 and 2, decreased in group 3, and increased in group 4. However, these changes were not significant. Most of the patients given TBI had BMI below the mean at 2 (66%) and 5 (57%) years later. Their BMI and leptin concentrations correlated positively with each other (P = 0.005), and negatively with GH peak (P = 0.02 for BMI and 0.007 for leptin). In conclusion, this study suggests that TBI actually decreases GH secretion and is followed by a persistent low BMI. The negative relationship between GH peak and leptin may indicate that both are markers of a TBI-induced hypothalamic-pituitary lesion.

Topics: Adolescent; Adult; Body Height; Body Mass Index; Body Weight; Bone Marrow Transplantation; Child; Child, Preschool; Female; Follow-Up Studies; Growth Disorders; Human Growth Hormone; Humans; Infant; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Transplantation Conditioning; Weight Loss; Whole-Body Irradiation

Serum leptin concentrations are higher in early adolescence compared with childhood and may play a facilitatory role in pubertal development. Constitutional delay in growth and puberty (CDGP) is a disorder of the tempo of physical maturation and may be associated with relative hypoleptinaemia. We have therefore compared serum leptin concentrations in normal boys with those in boys exhibiting constitutional delay of growth, controlling for pubertal status, age and body mass index (BMI).. 23 boys with constitutional delay in growth (n = 17, prepubertal) and puberty (n = 6, early pubertal) and 88 normal boys (n = 64 prepubertal, n = 24 Tanner stage 2).. Serum leptin was measured in a single, non-fasted morning serum sample by radioimmunoassay. Using the data from normal boys, leptin standard deviation scores (sds) were calculated, to account for the independent influences of age and body mass index (BMI) sds. Both chronological age and bone age were used in the calculation of leptin sds in those with delay.. BMIsds was significantly lower in prepubertal delays compared with controls but was not different in pubertal subjects. Leptin concentrations were higher in early puberty compared with prepuberty (P < 0.001) in normal boys but were not significantly elevated in pubertal boys with delay compared with prepubertal delays. Although leptin sds, for both chronological age and bone age, was similar in prepubertal controls and delays, it was significantly lower in the pubertal delay group (P < 0.05). In controls leptin sds did not correlate with age. However, in delays leptin sds was negatively correlated with both chronological age (r = - 0.43, P < 0.05) and bone age (r = - 0.68, P < 0.01), indicating that in the older delays leptin levels were lower than expected given their age and BMIsds.. These data indicate that significantly higher leptin levels in Tanner stage 2 compared with prepuberty are not a prerequisite for progression into puberty. However, the absence of elevated leptin concentrations may be associated with delayed puberty in boys.

Topics: Biomarkers; Body Mass Index; Case-Control Studies; Child; Child, Preschool; Growth Disorders; Humans; Leptin; Male; Proteins; Puberty, Delayed; Regression Analysis

The aim of this study was to investigate the relationship among GH secretion, leptin concentrations, and body composition measured with x-ray absorptiometry (DXA) in children. In total, 71 children were investigated, 51 males and 20 females. Their mean chronological age was 10.8 yr (range, 6.2-17.7 ys), and their mean height (SD) was -2.1 (0.63) SD scores. Their mean weight for height SD scores (WH(SDS)) was 0.2 (1.18). Body composition was investigated using DXA. Blood samples were taken for analysis of leptin, insulin-like growth factor I (IGF-I), IGF-binding protein-3, and 24-h GH secretion. A positive correlation was found between leptin and total body fat (r = 0.83; P < 0.0001) and when fat was expressed as a percentage of body weight (r = 0.86; P < 0.0001). There were significant (P < 0.0001) relationships between leptin and WH(SDS) (r = 0.45) and between leptin and body mass index (r = 0.69). A significant gender difference in leptin levels was found, but this disappeared after adjustment for body fat, as measured by DXA. There were significant (P < 0.001) inverse correlations between leptin and the AUCb for GH (r = -0.41), leptin, and GHmax (r = -0.38), where AUCb is the area under the curve above the calculated baseline, and GHmax is the maximum peak during the 24-h GH profile (percent fat and AUCb for GH, r = -0.43; percent fat and GHmax, r = -0.39). In a multiple stepwise forward regression analysis with leptin as the dependent variable, the percent trunk fat accounted for 77.7% of the leptin variation. With AUCb for GH as the dependent variable, the percent trunk fat accounted for 20.3% of the variation. With GHmax as the dependent variable, the percent trunk fat accounted for 18.8% of the variation, IGF-binding protein-3 for another 8.5%, and the percentage of fat from arms and legs for another 4.4%. We demonstrated a strong positive correlation between leptin levels and body fat, a significant negative correlation between leptin levels and GH secretion, and a significant negative correlation between body fat and GH secretion. We have also shown that specific regional fat depots have different relationships with leptin and particular markers of GH secretion.

Topics: Absorptiometry, Photon; Adipose Tissue; Body Composition; Body Height; Child; Female; Growth Disorders; Human Growth Hormone; Humans; Leptin; Male; Multivariate Analysis; Reference Values

The relationship between GH, body composition and leptin in children remains ill-defined. We have therefore examined the impact of severe GH deficiency (GHD) due to a mutation in the GHRH receptor on serum leptin concentrations and body composition in childhood.. 12 affected children and young people (GHD) (4 M:8F, age 5.4-20.1 years, 8 Tanner stage (TS) 1-2, 4 TS 3-5) and 40 healthy controls (C) from the same region (13 M:27F, age 5.3-18.4 years, 20 TS 1-2, 20 TS 3-5).. Percent body fat was determined by infra-red interactance, from which the amounts of fat mass (FM, kg) and fat free mass (FFM, kg) were derived. Serum leptin concentrations were measured in a single fasted, morning serum sample and results expressed as a concentration and as leptin per unit fat mass (L/FM, ng/ml/kg). To control for differences in sex and pubertal maturation, leptin standard deviation scores (leptin SDS) were calculated using normative data from UK children.. FFM was significantly lower in GHD children than in controls (TS 1-2 P < 0.05, TS 3-5 P < 0.001). FM did not differ significantly between the two groups. Serum leptin concentrations, leptin per unit fat mass and leptin SDS were significantly elevated in GHD children both peripubertal and pubertal compared with controls. Using all subjects, stepwise multiple linear regression with FM, FFM, age, puberty and sex as explanatory variables and leptin concentration as the dependent variable indicated that 59% of the variability in leptin could be accounted for by FM (+, 45%), FFM (-, 9%) and sex (+, 5%) (P < 0.001). However on inclusion of GH deficiency (coded GHD = 1, control = 2) as an explanatory variable 73% of the variability in leptin was explained by FM (+, 45%), GHD (-, 22%) and sex (+, 6%) (P < 0.001).. These data indicate that severe GH deficiency in children is associated with elevated leptin concentrations, irrespective of sex or pubertal stage. This increase is not associated with differences in fat mass but is related to reduced fat free mass in GH deficiency. Furthermore in this population there may be an additional effect of GH deficiency on leptin, independent of the influences of sex and body composition.

Topics: Adolescent; Adult; Body Composition; Child; Child, Preschool; Female; Growth Disorders; Growth Hormone; Humans; Leptin; Linear Models; Male; Mutation; Receptors, Leptin; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone