Hillarie Slater

IGF-1 and IGF-Binding Proteins and Bone Mass, Geometry, and Strength: Relation to Metabolic Control in Adolescent Girls With Type 1 Diabetes

Children and adolescents with poorly controlled type 1 diabetes mellitus (T1DM) are at risk for decreased bone mass. Growth hormone (GH) and its mediator, IGF‐1, promote skeletal growth. Recent observations have suggested that children and adolescents with T1DM are at risk for decreased bone mineral acquisition. We examined the relationships between metabolic control, IGF‐1 and its binding proteins (IGFBP‐1, ‐3, ‐5), and bone mass in T1DM in adolescent girls 12–15 yr of age with T1DM (n = 11) and matched controls (n = 10). Subjects were admitted overnight and given a standardized diet. Periodic blood samples were obtained, and bone measurements were performed. Serum GH, IGFBP‐1 and ‐5, glycosylated hemoglobin (HbA1c), glucose, and urine magnesium levels were higher and IGF‐1 values were lower in T1DM compared with controls (p < 0.05). Whole body BMC/bone area (BA), femoral neck areal BMD (aBMD) and bone mineral apparent density (BMAD), and tibia cortical BMC were lower in T1DM (p < 0.05). Poor diabetes control predicted lower IGF‐1 (r2 = 0.21) and greater IGFBP‐1 (r2 = 0.39), IGFBP‐5 (r2 = 0.38), and bone‐specific alkaline phosphatase (BALP; r2 = 0.41, p < 0.05). Higher urine magnesium excretion predicted an overall shorter, lighter skeleton, and lower tibia cortical bone size, mineral, and density (r2 = 0.44–0.75, p < 0.05). In the T1DM cohort, earlier age at diagnosis was predictive of lower IGF‐1, higher urine magnesium excretion, and lighter, thinner cortical bone (r2 ⩽ 0.45, p < 0.01). We conclude that poor metabolic control alters the GH/IGF‐1 axis, whereas greater urine magnesium excretion may reflect subtle changes in renal function and/or glucosuria leading to altered bone size and density in adolescent girls with T1DM.

Newborn Adiposity Measured by Plethysmography Is Not Predicted by Late Gestation Two-Dimensional Ultrasound Measures of Fetal Growth

Noninvasive measures of fetal and neonatal body composition may provide early identification of children at risk for obesity. Air displacement plethysmography provides a safe, precise measure of adiposity and has recently been validated in infants. Therefore, we explored relationships between term newborn percent body fat (%BF) measured by air displacement plethysmography to 2-dimensional ultrasound (2-D US) biometric measures of fetal growth and maternal and umbilical cord endocrine activity. A total of 47 mother/infant pairs were studied. Fetal biometrics by 2-D US and maternal blood samples were collected during late gestation (35 wk postmenstrual age); infants were measured within 72 h of birth. Fetal biometrics included biparietal diameter, femur length, head circumference, abdominal circumference (AC), and estimated fetal weight (EFW). Serum insulin, insulin-like growth factor (IGF) 1, IGF binding protein-3, and leptin concentrations were measured in umbilical cord and maternal serum. The mean %BF determined by plethysmography was 10.9 +/- 4.8%. EFW and fetal AC had the largest correlations with newborn %BF (R(2) = 0.14 and 0.10, respectively; P < 0.05); however, stepwise linear regression modeling did not identify any fetal biometric parameters as a significant predictor of newborn %BF. Newborn mid-thigh circumference (MTC; cm) and ponderal index (PI; weight, kg/length, cm(3)) explained 21.8 and 14.4% of the variability in %BF, respectively, and gave the best stepwise linear regression model (%BF = 0.446 MTC + 0.347 PI -29.692; P < 0.001). We conclude that fetal growth biometrics determined by 2-D US do not provide a reliable assessment of %BF in term infants.

Mechanical-tactile stimulation (MTS) intervention in a neonatal stress model alters adult adipose tissue deposition and prevents hyperinsulinemia in male rats

Preterm infants are exposed to numerous stressors during hospitalization and by term corrected gestational age they have lower body weight but a greater proportion of total body as well as abdominal visceral adipose tissue (VAT) accumulation. Greater abdominal VAT stores have a known association with metabolic syndrome. Mechanical-tactile stimulation (MTS) improves modulation of stress response in both humans and rodents. We hypothesize that MTS, administered during an established model of neonatal stress, would decrease stress-driven adiposity and prevent associated metabolic imbalances in adult rats. Neonatal stress, administered to rat pups from postnatal days 5 to P9, consisted of needle puncture and hypoxic/hyperoxic challenge during 60 min of maternal separation (STRESS; n=20). Mechanical-tactile stimulation (MTS; n=20) was administered to rat pups for 10 min during maternal separation in the stress protocol. Control animals received standard care (CTL; n=20). MRI measured adult (P120) abdominal total fat mass, subcutaneous (SAT) and visceral adipose tissue (VAT). Body weight and fasting serum adiponectin, leptin, glucose, insulin, and corticosterone were also measured. STRESS results in elevated VAT/SAT ratio compared to CTL but lower abdominal total fat mass and abdominal SAT. STRESS males experience hyperinsulinemia. Both STRESS and MTS had elevated leptin with lower adiponectin and corticosterone compared to CTL. In summary, neonatal stress promotes greater abdominal VAT accumulation and, in males, caused hyperinsulinemia and hypoadiponectinemia. Importantly, MTS normalized the VAT/SAT ratio and prevented hyperinsulinemia. We speculate that MTS ameliorates some of the negative metabolic consequences of early life perturbations due to neonatal stress exposure.

Mechanical-tactile stimulation (MTS) during neonatal stress prevents hyperinsulinemia despite stress-induced adiposity in weanling rat pups

Stress in early life negatively influences growth quality through perturbations in body composition including increased fat mass. At term (40 weeks) preterm infants have greater fat mass and abdominal visceral adipose tissue than term-born infants. Mechanical-tactile stimulation (MTS) attenuates the stress response in preterm infants and rodents. We tested the hypothesis that MTS, administered during an established model of neonatal stress, would decrease stress-driven adiposity and prevent associated metabolic imbalances in rat pups. Pups received one of three treatments from postnatal days 5 to P9: Neonatal Stress (Stress; n=20) = painful stimulus and hypoxic/hyperoxic challenge during 60 min of maternal separation; MTS (n=20) = neonatal stress+10 min of MTS; or Control (n=20). Body weight, DXA whole body fat mass (g), MRI subcutaneous and visceral adipose tissue, and fasting adiponectin, leptin, glucose, insulin, and corticosterone were measured at weaning (P21). Stress and MTS weight gain (g/d) were accelerated following neonatal stress with greater fat mass, abdominal subcutaneous adipose tissue, serum adiponectin, leptin, and fasting glucose at weaning (P21). Male Stress and MTS pups had greater visceral adipose tissue depot. Male and female Stress pups were hyperinsulinemic. In summary, neonatal stress compromised body composition by increasing fat mass and abdominal subcutaneous adipose tissue depot, and in males, visceral adipose tissue depot. Importantly, MTS prevented hyperinsulinemia despite of stress-induced adiposity. We conclude that MTS during neonatal stress has the potential to minimize metabolic consequences associated with stress-driven perturbations in fat mass and abdominal adipose depots.

Heart rate variability during caregiving and sleep after massage therapy in preterm infants.

BACKGROUND Preterm birth impairs the infants stress response due to interruption of autonomic nervous system (ANS) development. Preterm infants demonstrate a prolonged and aberrant sympathetic response to stressors. ANS development may be promoted by massage therapy (MT), which has been shown to improve stress response in preterm infants. AIMS The aim of this study was to compare preterm infant ANS function and stress response during sleep and caregiving epochs, as measured by heart rate variability (HRV), after two weeks of twice-daily MT. STUDY DESIGN A subset of participants from a larger randomized, masked, controlled trial was used. SUBJECTS Twenty-one infants (8 males and 13 females) from a larger study of 37 medically stable preterm infants were studied. The infants were receiving full volume enteral feedings with a mean post-menstrual age of 31.4 (MT) and 30.9 (control) weeks. OUTCOME MEASURES Low to high frequency (LF:HF) ratio of HRV was the outcome of interest. RESULTS There was a significant group×time×sex interaction effect (p<.05). Male control infants demonstrated a significant decline in LF:HF ratio from baseline to the second caregiving epoch, suggesting decreased mobilization of sympathetic nervous system response when exposed to stressors. Male MT infants demonstrated increased LF:HF ratio during caregiving and decreased LF:HF ratio during sleep epochs, suggesting improved ANS function, although this was not statistically significant. LF:HF ratio was similar in female MT and female control infants during caregiving and sleep. CONCLUSIONS Control males had decreased HRV compared to MT males. There was no difference in HRV between MT and control females.

Tibial geometry in individuals with neurofibromatosis type 1 without anterolateral bowing of the lower leg using peripheral quantitative computed tomography.

INTRODUCTION Lower leg bowing with tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1). The objective of the study is to determine if the geometry of the lower limb in individuals with neurofibromatosis type 1 (NF1) differs from controls, and to characterize the osseous components of the tibia in NF1. METHODS Peripheral quantitative computed tomography (pQCT) of the lower limb was performed (90 individuals with NF1 without tibial and/or fibular dysplasia: 474 healthy individuals without NF1). Subjects were 4-18 years of age. Individuals with NF1 were compared to controls using an analysis-of-covariance with a fixed set of covariates (age, weight, height, Tanner stage, and gender). RESULTS Using pQCT, NF1 individuals without bowing of the lower leg have smaller periosteal circumferences (p<0.0001), smaller cortical area (p<0.0001), and decreased tibial cortical and trabecular bone mineral content (BMC) (p<0.0001) compared to controls. DISCUSSION Individuals with NF1 have a different geometry of the lower leg compared to healthy controls suggesting that NF1 haploinsufficiency impacts bone homeostasis although not resulting in overt anterolateral bowing of the lower leg.

Mid-arm circumference is a reliable method to estimate adiposity in preterm and term infants

Background:Premature birth is associated with increased adipose deposition after birth. Standard anthropometry (body weight, length, and head circumference) may not adequately assess fat deposition. Validated methods to assess adiposity are needed to optimize growth quality in preterm infants. The purpose of this study was to identify covariates of infant body fat.Methods:Air displacement plethysmography (ADP), standard anthropometry, and body circumferences were measured at hospital discharge in preterm (n = 28; 31–35 wk postmenstrual age (PMA)) and term (n = 28; 38–41 wks PMA) infants.Results:Body weight, length, and head circumference were lower for preterm infants (P < 0.05) at hospital discharge compared with that of term infants. Despite smaller body size and younger PMA, preterm infant percent body fat (%BF) by ADP was 12.33 ± 4.15% vs. 9.64 ± 4.01% in term infants (P = 0.01). Mid-arm circumference (MAC) is a covariate of %BF in both preterm and term infants (adjusted R2 = 0.49; P < 0.001). In preterm infants alone, MAC accounted for 60.4% of the variability of percent body fat (%BF) by ADP (P < 0.01).Conclusions:Preterm infants have increased body fat deposition as they approach term-corrected age, and MAC is a reliable, low-cost measure for monitoring infant body fat deposition in preterm and term infants.

Tactile/kinesthetic stimulation (TKS) increases tibial speed of sound and urinary osteocalcin (U-MidOC and unOC) in premature infants (29-32weeks PMA).

Preterm delivery (<37 weeks post-menstrual age) is associated with suboptimal bone mass. We hypothesized that tactile/kinesthetic stimulation (TKS), a form of infant massage that incorporates kinesthetic movement, would increase bone strength and markers of bone accretion in preterm infants. Preterm, AGA infants (29-32 weeks) were randomly assigned to TKS (N=20) or Control (N=20). Twice daily TKS was provided 6 days per week for 2 weeks. Control infants received the same care without TKS treatment. Treatment was masked to parents, health care providers, and study personnel. Baseline and week two measures were collected for tibial speed of sound (tSOS, m/sec), a surrogate for bone strength, by quantitative ultrasound (Sunlight8000) and urine markers of bone metabolism, pyridinium crosslinks and osteocalcin (U-MidOC and unOC). Infant characteristics at birth and study entry as well as energy/nutrient intake were similar between TKS and Control. TKS intervention attenuated the decrease in tSOS observed in Control infants (p<0.05). Urinary pyridinium crosslinks decreased over time in both TKS and CTL (p<0.005). TKS infants experienced greater increases in urinary osteocalcin (U-MidOC, p<0.001 and unOC, p<0.05). We conclude that TKS improves bone strength in premature infants by attenuating the decrease that normally follows preterm birth. Further, biomarkers of bone metabolism suggest a modification in bone turnover in TKS infants in favor of bone accretion. Taken together, we speculate that TKS improves bone mineralization.

Analysis of radiographic characteristics of anterolateral bowing of the leg before fracture in neurofibromatosis type 1.

Background: Anterolateral leg bowing is associated with neurofibromatosis type 1 (NF1) frequently leading to fracture and nonunion of the tibia. The objective of the study was to characterize the radiographic findings of tibial dysplasia in NF1. Methods: This study is a retrospective review of radiographs of tibial dysplasia obtained within 52 years, between 1950 and 2002, from the Shriners Hospitals for Children, Salt Lake City, and of peripheral quantitative computed tomographic images of 3 individuals with anterolateral bowing of the leg without fracture compared with age- and sex-matched controls. Results: Individuals with NF1 with bowing of the leg have the appearance of thicker cortices with medullary narrowing on plain film radiographs. The peripheral quantitative computed tomographic images of individuals with NF1 with anterolateral bowing show an unusual configuration of the tibia. Conclusions: Anterolateral bowing of the leg in NF1 is associated with the appearance of thicker cortices with medullary narrowing rather than thinning of the long bone cortex on plain film radiographs as currently used as a qualifier in the sixth diagnostic criterion for the clinical diagnosis of NF1. Individuals with NF1 who have anterolateral bowing of the leg have differences in tibial geometry compared with age- and sex-matched controls. Clinical Relevance: The characterization of the radiographic findings of long bone bowing in NF1 helps clarify the NF1 clinical diagnostic criteria.

Validity and reliability of perinatal biomarkers of adiposity after storage as dried blood spots on paper

To validate use of chip‐based immunoaffinity capillary electrophoresis on dried blood spot samples (DBSS) to measure obesity‐related hormones.