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Retinol-binding protein 4, fetal overgrowth and fetal growth factors.
Yang, MN, Zhang, GH, Du, K, Wang, WJ, Dong, Y, He, H, Chiu, HC, Guo, YN, Ouyang, F, Zhang, J, et al
Pediatric research. 2020;(5):946-951
Abstract
BACKGROUND Retinol-binding protein 4 (RBP-4) is an adipokine involved in regulating insulin sensitivity which would affect fetal growth. It is unclear whether RBP-4 is associated with fetal overgrowth, and unexplored which fetal growth factor(s) may mediate the association. METHODS In the Shanghai Birth Cohort, we studied 125 pairs of larger-for-gestational-age (LGA, birth weight >90th percentile, an indicator of fetal overgrowth) and optimal-for-gestational-age (OGA, 25-75th percentiles) control infants matched by sex and gestational age. We measured cord blood concentrations of RBP-4, insulin, proinsulin, insulin-like growth factor-I (IGF-I), and IGF-II. RESULTS Cord blood RBP-4 concentrations were elevated in LGA vs. OGA infants (21.9 ± 6.2 vs. 20.2 ± 5.1 µg/ml, P = 0.011), and positively correlated with birth weight z score (r = 0.19, P = 0.003), cord blood proinsulin (r = 0.21, P < 0.001), IGF-I (r = 0.24, P < 0.001), and IGF-II (r = 0.15, P = 0.016). Adjusting for maternal and neonatal characteristics, each SD increment in cord blood RBP-4 was associated with a 0.28 (0.12-0.45) increase in birth weight z score (P < 0.001). Mediation analyses showed that IGF-I could account for 31.7% of the variation in birth weight z score in association with RBP-4 (P = 0.01), while IGF-II was not an effect mediator. CONCLUSIONS RBP-4 was positively associated with fetal overgrowth. IGF-I (but not IGF-II) may mediate this association.
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The GH Axis in Relation to Accepting an Early Macronutrient Deficit and Outcome of Critically Ill Patients.
Van Dyck, L, Derese, I, Vander Perre, S, Wouters, PJ, Casaer, MP, Hermans, G, Van den Berghe, G, Vanhorebeek, I
The Journal of clinical endocrinology and metabolism. 2019;(11):5507-5518
Abstract
CONTEXT Changes in the GH axis during critical illness resemble fasting in healthy adults and contribute to hypercatabolism, which potentially affects outcome. Accepting macronutrient deficits by withholding parenteral nutrition (PN) during the first week in the intensive care unit (ICU; late PN) reduced complications and accelerated recovery as compared with early use of PN (early PN). OBJECTIVE To investigate how late PN affects the GH axis in relation to its clinical outcome benefits. DESIGN Preplanned subanalysis of the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients randomized controlled trial. PARTICIPANTS A total of 1128 patients for time-course study, 20 patients investigated for nocturnal GH pulsatility, and 600 patients investigated for muscle weakness, with early PN and late PN patients having comparable baseline characteristics. INTERVENTION Withholding PN during the first ICU week (late PN) vs early PN. MAIN OUTCOME MEASURES Changes in serum GH, IGF-I, IGF-binding protein (IGFBP) 3, and IGFBP1 concentrations from ICU admission to day 4 or last ICU day for patients with a shorter ICU stay (d4/LD) and association in multivariable analyses with likelihood of earlier live ICU discharge, risk of new infection, and muscle weakness. RESULTS Late PN attenuated a rise in serum GH and IGF-I (P < 0.0001), did not affect IGFBP3, and attenuated a decrease in IGFBP1 concentrations from admission to d4/LD (P < 0.0001) as compared with early PN. Late PN decreased nonpulsatile (P = 0.005), but not pulsatile, GH secretion. Adjusting the multivariable models for the observed GH axis alterations increased the independent benefit of late PN for all outcomes. GH axis alterations induced by late PN were independently associated with adverse outcomes (P ≤ 0.03). CONCLUSION Accepting macronutrient deficits early during critical illness further suppressed the GH axis, which statistically attenuated its clinical outcome benefits.
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rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial.
Ley, D, Hallberg, B, Hansen-Pupp, I, Dani, C, Ramenghi, LA, Marlow, N, Beardsall, K, Bhatti, F, Dunger, D, Higginson, JD, et al
The Journal of pediatrics. 2019;:56-65.e8
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Abstract
OBJECTIVE To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants. STUDY DESIGN This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 230/7 weeks to 276/7 weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 µg/kg/ 24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 296/7 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 404/7 weeks. Target exposure was ≥70% IGF-1 measurements within 28-109 µg/L and ≥70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures. RESULTS Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3-4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures. CONCLUSIONS rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3-4 intraventricular hemorrhage. TRIAL REGISTRATION ClinicalTrials.gov: NCT01096784.
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ACROSTART: A retrospective study of the time to achieve hormonal control with lanreotide Autogel treatment in Spanish patients with acromegaly.
Álvarez-Escolá, C, Venegas-Moreno, EM, García-Arnés, JA, Blanco-Carrera, C, Marazuela-Azpiroz, M, Gálvez-Moreno, MÁ, Menéndez-Torre, E, Aller-Pardo, J, Salinas-Vert, I, Resmini, E, et al
Endocrinologia, diabetes y nutricion. 2019;(5):320-329
Abstract
OBJECTIVES The ACROSTART study was intended to determine the time to achieve normalization of GH and IGF-I levels in responding patients with acromegaly administered different dosage regimens of lanreotide Autogel (Somatuline® Autogel®). METHODS From March 2013 to October 2013, clinical data from 57 patients from 17 Spanish hospitals with active acromegaly treated with lanreotide for ≥4 months who achieved hormonal control (GH levels <2.5ng/ml and/or normalized IGF-I levels in ≥2 measurements) were analyzed. The primary objective was to determine the time from start of lanreotide treatment to hormonal normalization. RESULTS Median patient age was 64 years, 21 patients were male, 39 patients had undergone surgery, and 14 patients had received radiotherapy. Median hormonal values at start of lanreotide treatment were: GH, 2.6ng/ml; IGF-I, 1.6×ULN. The most common starting dose of lanreotide was 120mg (29 patients). The main initial regimens were 60mg/4 weeks (n=13), 90mg/4 weeks (n=6), 120mg/4 weeks (n=13), 120mg/6 weeks (n=6), and 120mg/8 weeks (n=9). An initial treatment regimen with a long interval (≥6 weeks) was administered in 25 patients. Mean duration of lanreotide treatment was 68 months (7-205). Median time to achieve hormonal control was 4.9 months. Injections were managed without healthcare assistance in 13 patients. Median number of visits to endocrinologists until hormonal control was achieved was 3. Fifty-one patients were "satisfied"/"very satisfied" with treatment and 49 patients did not miss any dose. CONCLUSIONS Real-life treatment with lanreotide Autogel resulted in early hormonal control in responding patients, with high treatment adherence and satisfaction despite disparity in starting doses and dosing intervals.
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The Influence of Maternal Obesity and Breastfeeding on Infant Appetite- and Growth-Related Hormone Concentrations: The SKOT Cohort Studies.
Larnkjær, A, Ong, KK, Carlsen, EM, Ejlerskov, KT, Mølgaard, C, Michaelsen, KF
Hormone research in paediatrics. 2018;(1):28-38
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BACKGROUND/AIMS: Exposure to obesity during pregnancy may lead to adverse changes in the offspring's metabolic profile. We compared appetite- and growth-related hormones in a cohort of infants born to obese mothers (SKOT-II) with infants born mainly to nonobese mothers (SKOT-I). METHODS Infants from SKOT-I (n = 273) and SKOT-II (n = 132) were examined including anthropometric measurements and blood samples analyzed for glucose, insulin, insulin-like growth factor-I (IGF-I), adiponectin, and leptin. Information on breastfeeding and parental characteristics were also collected. RESULTS At 9 months of age, SKOT-II infants were 3.6% heavier and 1.2% longer than SKOT-I infants even though their mothers were shorter. There was no difference in body mass index (BMI). SKOT-II infants had higher levels of insulin, adiponectin, and leptin but lower levels of IGF-I compared to SKOT-I infants (all p ≤ 0.015). These differences remained, except for leptin, when adjusted for current weight. Breastfeeding versus nonbreastfeeding at 9 months was associated with lower concentrations of all hormones (all p ≤ 0.003). In adjusted models, maternal BMI at 9 months was positively associated with insulin and adiponectin and negatively with IGF-I. CONCLUSIONS Pre-pregnancy obesity confers symmetrically larger infant body size and higher levels of most growth- and appetite-related hormones but surprisingly lower levels of IGF-I, suggesting other possible infant growth-promoting effects through insulin.
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Safety and metabolic effects of tesamorelin, a growth hormone-releasing factor analogue, in patients with type 2 diabetes: A randomized, placebo-controlled trial.
Clemmons, DR, Miller, S, Mamputu, JC
PloS one. 2017;(6):e0179538
Abstract
OBJECTIVE Use of growth hormone is associated with side effects, including insulin resistance. The objective of this study was to determine whether tesamorelin, a stabilized growth hormone-releasing hormone analogue, would alter insulin sensitivity or control of diabetes. DESIGN A 12-week randomized, placebo-controlled study of 53 patients with type 2 diabetes. Three treatment groups: placebo, 1 and 2 mg tesamorelin. MEASUREMENTS Fasting glucose, glucose and insulin from oral glucose tolerance test, glycosylated hemoglobin (HbA1c), home blood glucose, insulin-like growth factor-1, and lipids. MAIN OUTCOME MEASURE Relative insulin response following oral ingestion of glucose. RESULTS No significant differences were observed between groups in relative insulin response over the 12-week treatment period. At Week 12, fasting glucose, HbA1c and overall diabetes control were not significantly different between groups. In addition, relevant modifications in diabetes medications were similar between groups. Total cholesterol (-0.3±0.6 mmol/L) and non-HDL cholesterol (-0.3±0.5 mmol/L) significantly decreased from baseline to Week 12 in the tesamorelin 2 mg group (p<0.05 vs. placebo). No patient discontinued the study due to loss of diabetes control. CONCLUSIONS Treatment of type 2 diabetic patients with tesamorelin for 12 weeks did not alter insulin response or glycemic control. TRIAL REGISTRATION ClinicalTrials.gov NCT01264497.
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Insulin Resistance and the IGF-I-Cortical Bone Relationship in Children Ages 9 to 13 Years.
Kindler, JM, Pollock, NK, Laing, EM, Oshri, A, Jenkins, NT, Isales, CM, Hamrick, MW, Ding, KH, Hausman, DB, McCabe, GP, et al
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2017;(7):1537-1545
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IGF-I is a pivotal hormone in pediatric musculoskeletal development. Although recent data suggest that the role of IGF-I in total body lean mass and total body bone mass accrual may be compromised in children with insulin resistance, cortical bone geometric outcomes have not been studied in this context. Therefore, we explored the influence of insulin resistance on the relationship between IGF-I and cortical bone in children. A secondary aim was to examine the influence of insulin resistance on the lean mass-dependent relationship between IGF-I and cortical bone. Children were otherwise healthy, early adolescent black and white boys and girls (ages 9 to 13 years) and were classified as having high (n = 147) or normal (n = 168) insulin resistance based on the homeostasis model assessment of insulin resistance (HOMA-IR). Cortical bone at the tibia diaphysis (66% site) and total body fat-free soft tissue mass (FFST) were measured by peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA), respectively. IGF-I, insulin, and glucose were measured in fasting sera and HOMA-IR was calculated. Children with high HOMA-IR had greater unadjusted IGF-I (p < 0.001). HOMA-IR was a negative predictor of cortical bone mineral content, cortical bone area (Ct.Ar), and polar strength strain index (pSSI; all p ≤ 0.01) after adjusting for race, sex, age, maturation, fat mass, and FFST. IGF-I was a positive predictor of most musculoskeletal endpoints (all p < 0.05) after adjusting for race, sex, age, and maturation. However, these relationships were moderated by HOMA-IR (pInteraction < 0.05). FFST positively correlated with most cortical bone outcomes (all p < 0.05). Path analyses demonstrated a positive relationship between IGF-I and Ct.Ar via FFST in the total cohort (βIndirect Effect = 0.321, p < 0.001). However, this relationship was moderated in the children with high (βIndirect Effect = 0.200, p < 0.001) versus normal (βIndirect Effect = 0.408, p < 0.001) HOMA-IR. These data implicate insulin resistance as a potential suppressor of IGF-I-dependent cortical bone development, though prospective studies are needed. © 2017 American Society for Bone and Mineral Research.
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Benefits of resistance exercise in lean women with fibromyalgia: involvement of IGF-1 and leptin.
Bjersing, JL, Larsson, A, Palstam, A, Ernberg, M, Bileviciute-Ljungar, I, Löfgren, M, Gerdle, B, Kosek, E, Mannerkorpi, K
BMC musculoskeletal disorders. 2017;(1):106
Abstract
BACKGROUND Chronic pain and fatigue improves by exercise in fibromyalgia (FM) but underlying mechanisms are not known. Obesity is increased among FM patients and associates with higher levels of pain. Symptom improvement after aerobic exercise is affected by body mass index (BMI) in FM. Metabolic factors such as insulin-like growth factor 1 (IGF-1) and leptin may be involved. In this study, the aim was to evaluate the role of metabolic factors in lean, overweight and obese women during resistance exercise, in relation to symptom severity and muscle strength in women with FM. METHODS Forty-three women participated in supervised progressive resistance exercise, twice weekly for 15-weeks. Serum free and total IGF-1, IGF-binding protein 3 (IGFBP3), adiponectin, leptin and resistin were determined at baseline and after 15-weeks. Level of current pain was rated on a visual analogue scale (0-100 mm). Level of fatigue was rated by multidimensional fatigue inventory (MFI-20) subscale general fatigue (MFIGF). Knee extension force, elbow flexion force and handgrip force were assessed by dynamometers. RESULTS Free IGF-1 (p = 0.047), IGFBP3 (p = 0.025) and leptin (p = 0.008) were significantly decreased in lean women (n = 18), but not in the overweight (n = 17) and the obese (n = 8). Lean women with FM benefited from resistance exercise with improvements in current pain (p= 0.039, n = 18), general fatigue (MFIGF, p = 0.022, n = 18) and improved elbow-flexion force (p = 0.017, n = 18). In overweight and obese women with FM there was no significant improvement in pain or fatigue but an improvement in elbow flexion (p = 0.049; p = 0.012) after 15 weeks of resistance exercise. CONCLUSION The clearest clinical response to resistance exercise was found in lean patients with FM. In these individuals, individualized resistance exercise was followed by changes in IGF-1 and leptin, reduced pain, fatigue and improved muscular strength. In overweight and obese women FM markers of metabolic signaling and clinical symptoms were unchanged, but strength was improved in the upper limb. Resistance exercise combined with dietary interventions might benefit patients with FM and overweight. TRIAL REGISTRATION The trial was registered 21 of October 2010 with ClinicalTrials.gov identification number: NCT01226784 .
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Bioavailable IGF-1 and its Relation to the Metabolic Syndrome in a Bi-Ethnic Population of Men and Women.
Koegelenberg, AS, Schutte, R, Smith, W, Schutte, AE
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2016;(2):130-6
Abstract
Insulin-like growth factor 1 (IGF-1), an insulin sensitivity and vasculoprotective factor, associates negatively with the metabolic syndrome. However, IGF-1 is reduced by factors such as inflammation, oxidative stress and liver dysfunction. We investigated the relationship between bioavailable IGF-1 and the number of metabolic syndrome components and determined whether this relationship is independent of inflammation, oxidative stress and gamma glutamyl transferase (γ-GT; a marker of liver dysfunction). This study included 907 black and white participants stratified by sex (aged 43.0±11.8 years). Among them 63 participants had fasting glucose levels of ≥+7.0+mmol/l and/or used diabetes medication. Via standard methods we determined waist circumference, fasting glucose, triglycerides, high-density lipoprotein cholesterol and blood pressure. We also determined high-sensitivity C-reactive protein (CRP), reactive oxygen species (ROS), γ-GT, IGF-1 and insulin-like growth factor binding protein 3 (IGFBP-3). IGF-1/IGFBP-3 was used as an estimate of bioavailable IGF-1. Total IGF-1 was similar between men and women (p=0.10), however, bioavailable IGF-1 was lower in women (p<0.001). In multivariate-adjusted analyses, IGF-1/IGFBP-3 was inversely associated with the number of metabolic syndrome components in both sexes (men: β=- 0.11; p=0.013 and women: β=- 0.17; p=0.003). Upon inclusion of ROS, γ-GT and CRP, significance was lost. In patients without diabetes, the results for men changed marginally, but were consistent for women. We found an inverse association between bioavailable IGF-1 and the number of metabolic syndrome components. But the relationship was dependent on oxidative stress, liver dysfunction and inflammation, suggesting underlying processes by which the metabolic syndrome attenuates IGF-1.
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Influence of a fermented protein-fortified dairy product on serum insulin-like growth factor-I in women with anorexia nervosa: A randomized controlled trial.
Trombetti, A, Carrier, E, Perroud, A, Lang, F, Herrmann, FR, Rizzoli, R
Clinical nutrition (Edinburgh, Scotland). 2016;(5):1032-8
Abstract
BACKGROUND & AIMS Patients with anorexia nervosa (AN) have low serum IGF-I levels that may contribute to a lower bone mineral mass. We investigated the effects of a fermented, protein-fortified, dairy product on serum IGF-I levels in patients with AN during an in-hospital refeeding program. METHODS In this multicenter, randomized, double-blind, placebo-controlled, clinical trial conducted at 3 university hospitals and 3 private clinics in France and Switzerland, 62 women recently admitted with confirmed AN and with a baseline low serum IGF-I level were randomized to 2 daily isocaloric fresh cheese pots containing either 15 g/150 g or 3 g/150 g (controls) of protein for 4 weeks. The primary outcome was the change in IGF-I levels. RESULTS In the primary intention-to-treat analysis, mean serum IGF-I levels increased during the intervention phase from 22.9 ± 1.5 to 28.6 ± 1.3 nmol/L (means ± SEM) (+20.2%) in the intervention group and from 20.2 ± 1.2 to 25.7 ± 1.5 nmol/L (+16.8%) in controls. In a preplanned analysis of covariance with repeated measures, the between-group difference was close to statistical significance (P = 0.071). In a post-hoc mixed-regression model analysis, the difference was statistically significant (4.9 nmol/l increase; P = 0.003), as was the change of the ratio IGF-I/IGF-BP3 (P=0.004). There was no between-group difference in biochemical markers of bone turnover (osteocalcin, P1NP, CTX) or in serum parathyroid hormone level. Serum calcium levels slightly increased during the intervention phase in the higher protein group (P = 0.02). IGF-BP2 decreased significantly more in the intervention group during the follow up period at week 4 after supplements cessation (P = 0.019). CONCLUSIONS Intake of a fermented, protein-fortified, isocaloric dairy product during 4 weeks may slightly increase serum IGF-I levels in women with AN, without significant changes in bone turnover markers. CLINICAL TRIAL REGISTRATION NUMBER NCT01823822 (www.clinicaltrials.gov).