Teresa Salazar

Relationship between Nocturnal Growth Hormone Concentrations, Serum IGF-I/IGFBP-3 Levels, Insulin Sensitivity and GH Receptor Allelic Variant in Small for Gestational Age Children

Growth hormone may help to increase final height in patients with short stature, but its efficacy is variable. It has been recently reported that the isoform of the GH receptor (GHR) that lacks exon 3 (d3-GHR) is associated with a greater growth response to GH therapy. We hypothesized that nocturnal growth hormone concentrations, basal IGF-I and IGFBP-3 levels, and insulin sensitivity might show variations among individuals depending on their GHR allelic variant. To test this hypothesis, we studied 38 prepubertal LBW children with nocturnal GH concentrations, IGF-I and IGFBP-3 levels and insulin sensitivity during OGTT and Insulin test. The GHR allelic variant was analyzed through multiplex PCR analysis in DNA from peripheral leukocytes. Characteristics of the overnight GH secretion [(mean GH: 6.8 ± 0.6 vs. 6.2 ± 0.5 ng/ml), (AUC: 3,227 ± 280 vs. 2,908 ± 212 ng/ml·min), (peak number: 4.4 ± 0.3 vs. 4.4 ± 0.2), (amplitude: 12 ± 1.1 vs. 10.8 ± 1.1 ng/ml)] did not differ between groups (f1/f1 vs. f1/d3 plus d3/d3). In addition, we did not observe any significant differences in serum IGF-I SDS (–0.49 ± 0.26 vs. –0.40 ± 0.35) or IGFBP-3 SDS (–1.21 ± 0.24 vs. –0.89 ± 0.21) nor in insulin sensitivity (WIBSI: 12 ± 1.2 vs. 10.8 ± 1.1) in LBW children with full length GHR compared to children carrying at least one GHRd3 allele. The distribution of the f1/f1 allelic variant and fi/d3 or d3/d3 was similar in the LBW children with or without catch-up growth. These results suggest that the GHR allelic variant does not play a significant role in the regulation of GH-IGF-I/BP3 axis or in insulin sensitivity in prepubertal LBW children.

Comparison of leptin levels, body composition and insulin sensitivity and secretion by OGTT in healthy, early pubertal girls born at either appropriate‐ or small‐for‐gestational age

Background  Small for gestational age (SGA) has been associated with decreased insulin sensitivity (IS). A possible mechanism is the postnatal development of a metabolically disadvantageous body composition (BC).

Differences in Body Composition and Energy Expenditure in Prepubertal Children Born Term or Preterm Appropriate or Small for Gestational Age

Small size at birth may result from fetal undernutrition which may occur at different times during gestation. Early postnatal catch-up growth and excess childhood weight gain are associated with an increased risk of adult cardiovascular disease and type 2 diabetes mellitus. The aim of this study was to assess the relative contributions of body composition and energy expenditure on fasting insulin sensitivity during late childhood. We took advantage of two previously described prospective cohorts of children born either at term or prematurely, with a wide range of birth weights adjusted for gestational age. Seventy-one prepubertal children (mean age 7.5 +/- 0.3 years) were examined: 23 term SGA (8 M, 15 F), 12 preterm SGA (7 M, 5 F), 16 term AGA (8 M, 8 F), and 20 preterm AGA (9 M, 11 F). Mean height SDS was -0.18 +/- 0.11 and mean BMI SDS was 0.27 +/- 0.03. Change in weight SDS was significantly higher in children born SGA compared to their AGA counterparts (p < 0.001). Change in weight SDS was highly correlated with fasting insulin (p < 0.03) and leptin (p < 0.001). Fasting insulin correlated only with serum leptin levels. Body composition appeared to be the main determinant of fasting leptin levels. No differences in lipid profile were observed between the different groups. There was a clear tendency to higher insulin and leptin levels in children born SGA compared with their AGA counterparts. IGF-I levels were significantly higher only in SGA term compared to AGA term. Resting energy expenditure (REE) was lower in SGA born at term and higher in SGA born preterm compared to their AGA counterparts. In conclusion, fasting insulin sensitivity is mainly determined by leptin levels which in turn are determined by body composition. IGF-I and REE showed a divergent pattern in SGA term compared to SGA preterm groups. IGF-I levels were determined only by weight change from birth to age 2 years, which may not be as pronounced in VLBW children compared to SGA term and thus may preclude a difference in IGF-I levels in the group of preterm children. The divergent effect in REE in SGA born at term compared to SGA born preterm compared to their AGA counterparts may explain the divergent effects on IGF-I. This difference might be a consequence of different timing in the exposure to intrauterine nutritional deficiency.

The IGF-I Response to Growth Hormone Is Related to Body Mass Index in Short Children with Normal Weight

Aim: We investigated whether the insulin-like growth factor (IGF)-I response to growth hormone (GH) is regulated by body mass index (BMI) in short children with normal weight. Methods: We studied 37 prepubertal children with idiopathic short stature (ISS), comparing children with high-normal BMI (standard deviation scores, SDS 1.23 ± 0.11, n = 20) and low-normal BMI (SDS –0.93 ± 0.12, n = 17). The IGF-I response to GH was determined with an abbreviated IGF-I generation test, by measuring serum IGF-I concentrations at baseline and 24 h after the administration of GH (0.033 mg/kg). Results: Children with high- and low-normal BMI had similar age (8.5 ± 0.7 vs. 8.7 ± 0.7 years) and height (–2.0 ± 0.1 vs. –2.2 ± 0.2 SDS). However, children with high-normal BMI exhibited higher mean basal IGF-I (191 ± 15 vs. 139 ± 11 ng/ml, p < 0.05), higher mean IGF-I levels 24 h after GH administration (261 ± 22 vs. 164 ± 14 ng/ml, p < 0.05) and a higher IGF-I percent increase after GH administration (37 ± 5 vs. 17 ± 4%, p < 0.05) compared with children with normal-low BMI. Conclusion: BMI modulates the IGF-I response to GH, suggesting that GH sensitivity may be influenced by the nutritional status in children with ISS and normal body weight.

Effects of the IGF-I/IGFBP-3 complex on GH and ghrelin nocturnal concentrations in low birth weight children.

Objective  There is limited information regarding the effects of IGF‐I and/or IGFBP‐3 on circulating ghrelin concentrations. To determine the effects of IGF‐I on GH and ghrelin concentrations, we examined the GH and ghrelin nocturnal profiles before and after the administration of the IGF‐I/–IGFBP‐3 complex (Iplex™) to low birth weight children.

Accelerated early pubertal progression, ovarian morphology, and ovarian function in prospectively followed low birth weight (LBW) girls

Abstract Aim: To compare pubertal development in age-matched healthy girls born with low birth weight (LBW) or appropriate birth weight for gestational age (AGA). Subjects and methods: Girls with breast in Tanner stage II and normal body mass index were followed for 3 years with a complete physical exam, bone age, pelvic ultrasound, and measurement of gonadal hormones using a leuprolide test. Results: Forty-one girls (AGA 25/LBW 16) were followed up for 3 years. By 3 years, they had similar bone age, adjusted height, and body composition. In LBW girls, breast Tanner stage advanced faster during the first 2 years of follow-up, which was associated with higher serum androgens. Hirsutism score, ovarian volume, and number of follicles between AGA and LBW were not different nor was age of menarche. By the third year, basal and poststimulated levels of gonadotropins and androgens anti-Müllerian hormone and inhibin B were similar in both groups and did not show differences related to birth weight or degree of catch-up growth. Conclusion: LBW recruits showed a slightly faster breast development but no differences in androgen excess signs, internal genitalia, and gonadal hormonal patterns.

E180splice mutation in the growth hormone receptor gene in a Chilean family with growth hormone insensitivity: a probable common Mediterranean ancestor.

Mutations in the GH receptor gene have been identified as the cause of growth hormone insensitivity syndrome (GHIS), a rare autosomal recessive disorder. We studied the clinical and biochemical characteristics and the coding sequence and intron-exon boundaries of the GH receptor gene in a consanguineous family with severe short stature which consisted of two patients, their parents and five siblings. The two adolescents had heights of -4.7 and -5.5 SDS, respectively, with elevated growth hormone associated with low IGF-I, IGFBP-3 and GHBP concentrations. Molecular analysis of the GH receptor gene revealed a mutation in exon 6, present in both patients This mutation, E180 splice, has been previously described in an Ecuadorian cohort, and in one Israeli and six Brazilian patients. We determined the GH receptor haplotypes based on six polymorphic sites in intron 9. Co-segregation of the E180splice mutation with haplotype I was found in this family, compatible with a common Mediterranean ancestor, as shown for previous cases with the E180splice mutation described to date.

Relationship between Insulin Sensitivity and IGF-I Sensitivity in Low Birth Weight Prepubertal Children

Background: Insulin-like growth factor-I (IGF-I) and insulin are structurally related proteins with similar receptors and signal transduction systems. Aim: We postulate that some low birth weight (LBW) children may have decreased sensitivity to both insulin and IGF-I. Methods: We studied 48 prepubertal LBW children aged 7.6 ± 2.4 years. Insulin sensitivity was determined using an oral glucose tolerance test, and IGF-I sensitivity was assessed by determining nocturnal GH concentrations at baseline and after administration of recombinant human IGF-I/IGFBP-3 complex. Results: Children were classified into quartiles of insulin sensitivity based on their glucose AUC/insulin AUC index. Children in the lowest quartile of insulin sensitivity exhibited a lower IGF-I sensitivity after administration of the rhIGF-I/rhIGFBP-3 complex compared to children in the highest quartile of insulin sensitivity (percent change in GH AUC: –44.2 ± 5.7 vs. –21.6 ± 6.8, p < 0.05). Conclusion: LBW children in the lowest quartile of insulin sensitivity exhibited a lower pituitary GH response to the administration of rhIGF-I/rhIGFBP-3. Our findings suggest that reduced sensitivity to insulin and IGF-I may coexist in some prepubertal LBW children.

Cytoplasmic and nuclear STAT3 in GH-stimulated fibroblasts of children with idiopathic short stature.

Background: STAT5, which plays an important role in GH signal transduction, has been studied extensively in children with growth retardation, but there is scarce information regarding STAT3. Aim: We determined total and phosphorylated STAT3 after GH stimulation in fibroblasts from children with idiopathic short stature (ISS) and control children with normal stature. Subjects and Methods: We studied 15 prepubertal children (age 7.6 ± 0.4 years) with short stature (height –2.8 ± 0.2 SDS), decreased growth velocity (10 ng/ml to the clonidine stimulation test and decreased serum IGF-I concentrations (<–1 SDS), and 19 control children with normal stature (age 6.7 ± 0.3 years). We determined the levels of total and phosphorylated STAT3 in the cytoplasmic and nuclear fractions of fibroblast cultures obtained from a skin biopsy, stimulated with GH (200 ng/ml) for 15–60 min. Results: We observed a reduction in nuclear pSTAT3 levels and a lower nuclear/cytoplasmic STAT3 phosphorylated ratio in 3 patients from the study group compared to the control children. Conclusion: These results suggest that some children with ISS may exhibit a reduction in the nuclear content of their phosphorylated STAT3.

Ala54Thr polymorphism of the fatty acid-binding protein 2 gene (intestinal-type FABP) is associated with changes in insulin sensitivity in SGA pubertal girls.

INTRODUCTION Associations between FABP2 Ala54Thr polymorphism and increased fasting insulin concentration, fasting fatty acid oxidation and reduced glucose uptake have been identified in several populations. The aim of this study was to evaluate the association of Ala54 Thr polymorphism of the FABP2 gene with insulin sensitivity in pubertal girls born small for gestational age (SGA). RESULTS The frequency of the Thr54 allele did not differ between AGA and SGA girls (0.52 vs 0.43). Girls born SGA positive for the Ala/Thr polymorphism were older at the beginning of puberty compared to girls born AGA with the Thr54 allele (p < 0.01). These girls had lower whole body insulin sensitivity index (WBISI) (4.1 +/- 1.7 vs 9.2+/-7.4, p < 0.05), higher leptin (17.3 +/- 5.9 vs 12.1 +/- 13.7, p < 0.02), insulin area under the curve (AUC) (64,272 +/- 9,209 vs 27,981 +/- 15,637, p < 0.001), proinsulin (17.3 +/- 5.4 vs 10.9 +/- 3.6, p < 0.01) and insulinogenic index (4.6 +/- 3.0 vs 2.9 +/- 5.9, p < 0.01). Conversely, girls born SGA positive for the Ala/Thr polymorphism were older at the beginning of puberty (ns) compared to girls born SGA positive for the Ala/Ala polymorphism. These girls had higher insulin AUC (64,272 +/- 9,209 vs 33,322 +/-7,533, p < 0.01), insulinogenic index (4.6 +/- 3.0 vs 2.5 +/- 3.6, p < 0.01) and lower WBISI (4.1 +/- 1.7 vs 6.3 +/- 1.8, p < 0.05). DISCUSSION Our results suggest that the Thr54 variant of the FABP2 gene could be associated with a synergic effect in the SGA group regarding higher leptin levels (p < 0.05), lower insulin sensitivity by WBISI (p < 0.05) and higher insulin secretion determined by higher insulinogenic index (p < 0.01), insulin AUC (p < 0.01) and beta-cell stress measured by higher proinsulin (p < 0.05). Our data suggest an involvement of genetic factors in the insulin resistance associated with reduced fetal growth and strengthen the hypothesis that this association could be the consequence of interactions between detrimental factors during fetal life and genetic susceptibility.