Low Serum Insulin-like Growth Factor-1 Research Articles

The Association of Insulin-Like Growth Factor-1 With Bone Mineral Density in Survivors of Childhood Acute Leukemia

Abstract Background: The purpose of the current study is to investigate bone mineral deficit of children in survivors of childhood acute leukemia and examine the association of insulin-like growth factor-1 (IGF-1) with bone mineral density (BMD) status and the presence of osteoporosis. Methods: In a cross-sectional study of children diagnosed with different types of acute leukemia at age between 6 months and 18 years, serum IGF-1 and IGFBP-3, were assessed in relation to lumbar spine BMD (LSBMD) by using dual-energy x-ray absorptiometry and non-traumatic vertebral fracture by lateral thoracolumbar spine radiographs. Standard deviation scores (SDS) were calculated based on the age- and gender-adjusted population mean. Results: Among 189 children after completion of acute leukemia treatment, 22 (11.6%) children had LSBMD SDS less than -2.0 while 80 (42.3 %) children were diagnosed with osteoporosis. Mean areal BMD and LSBMD SDS of the subjects were 0.862±0.197 g/cm2 and -0.6±1.6, respectively. IGF-1 and IGFBP-3 were lower in children with LSBMD lower than -2.0 (P<0.05) and those with osteoporosis (P<0.05). LSBMD SDS showed linear correlation with serum IGF-1 (P=0.041). Low serum IGF-1 level (OR=0.724, P=0.042) and elder age of leukemia diagnosis (OR=1.089, P=0.023) were suggested risk factor of the occurrence of osteoporosis. Conclusions: Substantial number of survivors from childhood acute leukemia undergo bone mineral deficits, and serum IGF-1 status could be a prognostic factor associated with bone mass acquisition and future occurrence of osteoporosis.

Expression of IGF-1, IGF-1 Receptor and Growth Hormone Receptor in Hepatic Tissue in Adults Across the Spectrum of Nonalcoholic Fatty Liver Disease (NAFLD)

Background: Obesity is a state of relative growth hormone (GH) and insulin-like growth factor-1 (IGF-1) deficiency, and the GH/IGF-1 axis has been implicated in the pathophysiology of nonalcoholic fatty liver disease (NAFLD) and the progression to steatohepatitis (NASH) in preclinical models and human studies. GH has both lipolytic and anti-inflammatory properties while IGF-1 has been implicated in reducing hepatic fibrosis and promoting hepatic regeneration. The GH/IGF-1 axis may be a therapeutic target in NAFLD/NASH, however, IGF-1, IGF-1 receptor (IGF-1R) and GH receptor (GHR) expression in adult human hepatic tissue has not been studied across the spectrum of disease severity. Methods: We quantified IGF-1, IGF-1R, and GHR gene expression in hepatic tissue from 318 adults with obesity using the Nanostring nCounter assay. Subjects were classified into four categories of disease severity based on histopathology: normal liver histology (NLH) (n=76, 24%), steatosis only (Steatosis) (n=88, 28%), NASH without fibrosis (NASH F0) (n=72, 23%), and NASH with fibrosis (NASH F1-F4) (n=82, 26%). Gene expression analysis is presented as normalized gene counts by group with p-value of the generalized linear model controlled for age, sex and BMI. Results: Mean (±SD) age (whole cohort 44.0±12 years) and BMI (whole cohort 46.8±7.2 kg/m2) did not differ across groups (p=0.2 for both). ALT was higher with increasing disease severity (NLH 30.1±26.7, Steatosis 31.9±15.7, NASH F0 35.7±16.5, NASH F1-4 48.4±34.9, p<0.001). IGF-1 gene expression was lower in all NAFLD/NASH groups compared to the NLH reference group (NLH 485.4±292.7; Steatosis 396.3±238.0, p=0.04; NASH F0 349.8±220.1, p=0.01 and NASH F1-4 341.2±268.6, p=0.03, all p-values vs NLH). There was no difference in IGF-1R or GHR gene expression across disease severity groups (IGF-1R NLH 43.3±10.2, Steatosis 41.4±11.6, NASH F0 38.8±8.8 and NASH F1-4 39.1±8.1, p>0.05 between any disease state; GHR NLH 6382±2366, Steatosis 6544±2699, NASH F0 7220±2542 and NASH F1-4 5997±2352, p>0.05 between any disease state). Conclusion: We demonstrated that IGF-1 gene expression was lower in liver tissue from patients with NAFLD and NASH than healthy controls. This is consistent with our prior finding that histologic NASH and fibrosis are associated with lower serum IGF-1 levels. Moreover, we demonstrated that hepatic IGF-1R and GHR gene expression is not lower in liver tissue from patients with NAFLD and does not decline across disease severity. This reinforces our prior finding that GHR staining intensity and zonality by immunohistochemistry does not change with increasing disease severity in NAFLD/NASH. These data demonstrate that the GH axis is relatively suppressed but that expression of GHR and IGF-1R receptors is stable with worsening disease severity in NAFLD/NASH, suggesting that GH augmentation may be a viable therapeutic target in NAFLD.

Growth hormone receptor knockout to reduce the size of donor pigs for preclinical xenotransplantation studies.

Many genetically multi-modified donor lines for xenotransplantation have a background of domestic pigs with rapid body and organ growth. The intrinsic growth potential of porcine xeno-organs may impair their long-term function after orthotopic transplantation in non-human primate models. Since growth hormone is a major stimulator of postnatal growth, we deleted its receptor (GHR-KO) to reduce the size of donor pigs in one step. Heart weight and proteome profile of myocardium were investigated in GHR-KO and control pigs. GHR-KO mutations were introduced using CRISPR/Cas9 in an α1,3-galactosyltransferase (GGTA1)-deficient background expressing the human cluster of differentiation (hCD46) and human thrombomodulin (hTHBD) to generate quadruple-modified (4GM) pigs. At age 6months, GHR-KO pigs had a 61% reduced body weight and a 63% reduced heart weight compared with controls. The mean minimal diameter of cardiomyocytes was 28% reduced. A holistic proteome study of myocardium samples from the two groups did not reveal prominent differences. Two 4GM founder sows had low serum insulin-like growth factor 1 (IGF1) levels (24±1ng/mL) and reached body weights of 70.3 and 73.4kg at 9months. Control pigs with IGF1 levels of 228±24ng/mL reached this weight range three months earlier. The 4GM sows showed normal sexual development and were mated with genetically multi-modified boars. Offspring revealed the expected Mendelian transmission of the genetic modifications and consistent expression of the transgenes. GHR-KO donor pigs can be used at an age beyond the steepest phase of their growth curve, potentially reducing the problem of xeno-organ overgrowth in preclinical studies.

Low Serum Branched-Chain Amino Acid and Insulin-Like Growth Factor-1 Levels Are Associated with Sarcopenia and Slow Gait Speed in Patients with Liver Cirrhosis.

Branched-chain amino acid (BCAA) and insulin-like growth factor 1 (IGF-1) are essential for muscle protein synthesis. We investigated the association of serum BCAA and IGF-1 levels with sarcopenia and gait speed in 192 patients with liver cirrhosis (LC). Sarcopenia was diagnosed according to the Japan Society of Hepatology criteria. Slow gait speed was defined as <1.0 m/s. Subjects were divided into three groups based on baseline BCAA or IGF-1 levels: low (L), intermediate (I), and high (H) groups. The L-BCAA group had the highest prevalence of sarcopenia (60.4%, p < 0.001) and slow gait speed (56.3%, p = 0.008), whereas the H-BCAA group had the lowest prevalence of sarcopenia (8.5%, p < 0.001). The L-IGF-1 group showed the highest prevalence of sarcopenia (46.9%, p < 0.001), whereas the H-IGF-1 group had the lowest prevalence of sarcopenia (10.0%, p < 0.001) and slow gait speed (18.0%, p = 0.003). Using the optimal BCAA and IGF-1 cutoff values for predicting sarcopenia (372 μmol/L and 48.5 ng/mL, respectively), the sensitivity and specificity were 0.709 and 0.759 for BCAA and 0.636 and 0.715 for IGF-1, respectively. Low serum BCAA and IGF-1 levels were associated with sarcopenia and slow gait speed in patients with LC.

Low serum insulin-like growth factor-1 level is a predictor of low total weight loss percentage after sleeve gastrectomy

Obesity is a leading cause of metabolic disorders and mortality. Laparoscopic sleeve gastrectomy (LSG) confers beneficial effects not only on weight but also on metabolic disorder development. However, some patients show insufficient weight loss after LSG. A total weight loss percentage (%TWL) <20% after LSG is defined as insufficient. The prediction of patients with insufficient weight loss after LSG before the procedure is performed may prove helpful. To determine predictors of %TWL after LSG. Longitudinal study in a university hospital. We retrospectively reviewed 90 obese patients who underwent LSG and were followed up for 12 months thereafter. We analyzed the relationship between %TWL and preoperative clinical parameters, such as age, sex, body mass index, lipid and glucose metabolism, and some hormones. Patients were divided into 2 groups, %TWL <20% and 20% ≤ %TWL. Multiple regression model and logistic regression models were performed. LSG led to significant improvements in weight, liver, and kidney function, and lipid and glucose metabolism. The serum insulin-like growth factor-1 (IGF-1) level was significantly lower in patients with %TWL <20%. Sex, diabetes presence, body mass index, and IGF-1 were independent predictors of %TWL. Receiver operating characteristic curve analysis showed that the cutoff value of IGF-1 for %TWL <20% was 100.0ng/mL. Male sex, diabetes presence, lower preoperative BMI, and IGF-1 values were independently associated with lower %TWL (%TWL <20%). Serum IGF-1 can be used to screen for patients at risk of low %TWL after LSG.

Bone geometry and microarchitecture deficits in children with Alagille syndrome.

Alagille syndrome (ALGS) is an autosomal dominant disorder attributed to mutations in the Notch signaling pathway. Children with ALGS are at increased risk for fragility fracture of unknown etiology. Our objective was to characterize bone mass, geometry, and microarchitecture in children with ALGS. This was a cross-sectional study of 10 children (9 females), ages 8-18years, with a clinical diagnosis of ALGS. Bone density was assessed via DXA (Hologic Discovery A) at several skeletal regions. Tibia trabecular and cortical bone was assessed via pQCT (Stratec XCT 2000) at the distal 3% and 38% sites, respectively. Tibia bone microarchitecture was assessed via HR-pQCT (Scanco XtremeCT II) at an ultradistal site located at 4% of tibia length and a cortical site at 30% of tibia length. Z-scores were calculated for DXA and pQCT measures. In the absence of XtremeCT II HR-pQCT reference data, these outcome measures were descriptively compared to a sample of healthy children ages 5-20years (n=247). Anthropometrics and labs were also collected. Based on one-sample t-tests, mean Z-scores for height and weight (both p<.05), were significantly less than zero. DXA bone Z-scores were not significantly different from zero, but were highly variable. For pQCT bone measures, Z-scores for total bone mineral content at the distal 3% site and cortical bone mineral content, cortical area, and cortical thickness at the distal 38% site were significantly less than zero (all p<.05). There was good correspondence between pQCT measures of cortical thickness Z-scores and DXA Z-scores for aBMD at the whole body less head, 1/3 radius, and femoral neck (all p<.05). Compared to healthy children, those with ALGS generally had lower trabecular number and greater trabecular separation despite having greater trabecular thickness (measured via HR-pQCT). Bilirubin and bile acids, markers of hepatic cholestasis, were associated with poorer bone measures. For example, greater bilirubin was associated with lower trabecular number (Spearman's rho [ρ]=-0.82, p=.023) and greater trabecular separation (ρ=0.82, p=.023) measured via HR-pQCT, and greater bile acids were associated with lower cortical area measured via pQCT (ρ=-0.78, p=.041) and lower serum insulin-like growth factor-1 (ρ=-0.86, p=.002). In summary, deficits in cortical bone size and trabecular bone microarchitecture were evident in children with ALGS. Further investigation is needed to understand the factors contributing to these skeletal inadequacies, and the manner in which these deficits contribute to increased fracture risk.

Parity and dietary energy allowance during gestation influence piglet energy status and serum insulin-like growth factor 1 at birth

Over- or under-supplying energy by 15% to gestating sows had minimum consequences for piglet chemical body composition or energy storage (liver and muscle glycogen) at birth, when estimated amino acid requirements were met. Providing gestating sows with energy 15% below versus 15% above requirements increased piglet serum insulin-like growth factor 1 (IGF-1) concentrations at birth (P &lt; 0.05). Piglets from first versus second parity sows had lower serum IGF-1 but greater liver glycogen and body fat. Precisely matching the estimated energy and nutrient requirements throughout gestation and across parities likely improves piglet quality; over-supplying energy appears most detrimental for piglet IGF-1 serum concentrations at birth.

Low Serum Insulinlike Growth FactorII Levels Correlate with High BMI in American Indian Adults.

Insulinlike growth factorII (IGF-II) regulates metabolism and growth. In humans, both positive and negative relationships have been reported between serum IGF-II levels and obesity. This study assessed the relationship between serum IGF-II levels and BMI and determined whether IGF-II levels predict weight gain. Serum samples were available from 911 American Indians with a recorded BMI. IGF-II was measured using enzyme-linked immunosorbent assay. Serum IGF-II levels were negatively correlated with BMI (r = -0.17, P = 4.4 × 10-7 , adjusted for age, sex, and storage time). The strongest correlation was in participantsaged≥ 30 years (r = -0.28, P = 3.4 × 10-8 , N = 349), a modest correlation was in participants aged20 to 29 years (r = -0.15, P = 7.6 × 10-3 , N = 322), and participants aged15 to 19 years had no correlation (r = 0.05, P = 0.48, N = 240). IGF-II levels did not predict weight gain. However, among individuals who had genotypes for 64 established obesity variants (age ≥ 20 years, N = 671), a genetic risk score for high BMI was associated with lower IGF-II (β = -0.08 SDof IGF-II per SDof the genetic risk score, P = 0.025). There is a negative relationship between IGF-II levels and BMI, in which the correlation is stronger at older ages. The association between genetic risk for BMI and IGF-II levels suggests that this correlation may be due to an effect of obesity on IGF-II.

Gonadotropin versus Follicle-Stimulating Hormone for Ovarian Response in Patients Undergoing in vitro Fertilization: A Retrospective Cohort Comparison

Poor ovarian responders generally refer to patients who respond poorly to ovarian stimulation for assisted reproductive techniques (ART) such as in-vitro fertilization (IVF) and hence experience low live birth rate. Various controlled ovarian stimulation (COS) protocols have been developed during the past 3 decades for IVF/ICSI to improve oocyte quality and ultimately live birth rate, to increase ovarian response in POR patients, and to reduce the risk of ovarian hyperstimulation syndrome. Both highly puri?ed human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) have been widely used for COS during IVF/ICSI. Their in?uence on treatment outcome in women undergoing IVF/ICSI hasbeen actively debated. To compare highly purified human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. This retrospective cohort study included 60 patients with poor ovarian response (30 received hp-hMG and 30 received rFSH) undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. Pregnancy-related outcomes, ovarian response, oocyte, and embryo parameters were compared between the 2 groups. Additionally, serum insulin-like growth factor-1 and insulin-like growth factor binding protein-1 levels on the day of oocyte retrieval were compared between the 2 groups. The 2 treatments resulted in comparable numbers of oocytes retrieved and embryos, comparable oocyte retrieval rate, mature oocyte rate, and fertilization rate, and also comparable clinical pregnancy rates, implantation rates, and miscarriage rate. However, hp-hMG led to statistically insignificant higher viable embryo rate (54.0% vs 44.8%; P = 0.174) and live birth rate per pregnancy (16.7% vs 10%) versus rFSH. Finally, statistically significantly higher serum insulin-like growth factor-1 level (178.53 [13.70] ng/mL vs 164.93 [12.17] ng/mL; P = 0.01) and statistically insignificantly lower serum insulin-like growth factor binding protein-1 level (19.53 [3.56] ng/mL vs the lower insulin-like growth factor binding protein-1 level SD is (2.76 [20.83] ng/mL; P > 0.05) on the day of oocyte retrieval were associated with hp-hMG versus rFSH. hp-HMG and rFSH did not lead to significantly different treatment outcomes in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol, although significantly higher serum insulin-like growth factor-1 level and insignificantly lower serum insulin-like growth factor binding protein-1 level on the day of oocyte retrieval associated with hp-HMG might suggest a beneficial endocrine environment. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Elevated levels of IL-6 and IGFBP-1 predict low serum IGF-1 levels during continuous infusion of rhIGF-1/rhIGFBP-3 in extremely preterm infants

ObjectiveSteady state insulin-like growth factor-1 (IGF-1) levels vary significantly during continuous intravenous infusion of recombinant human insulin-like growth factor-1/recombinant human insulin-like growth factor binding protein-3 (rhIGF-1/rhIGFBP-3) in the first weeks of life in extremely preterm infants. We evaluated interleukin-6 (IL-6) and insulin-like growth factor binding protein-1 (IGFBP-1) levels as predictors of low IGF-1 levels. MethodsNineteen extremely preterm infants were enrolled in a trial, 9 received rhIGF-1/rhIGFBP-3 and 10 received standard neonatal care. Blood samples were analyzed daily for IGF-1, IL-6 and IGFBP-1 during intervention with rhIGF-1/rhIGFBP-3. ResultsThirty seven percent of IGF-1 values during active treatment were <20 μg/L. Among treated infants, higher levels of IL-6, one and two days before sampled IGF-1, were associated with IGF-1 < 20 μg/L, gestational age adjusted OR 1.30 (95% CI 1.03–1.63), p = .026, and 1.57 (95% CI 1.26–1.97), p < .001 respectively. Higher levels of IGFBP-1 one day before sampled IGF-1 was also associated with IGF-1 < 20 μg/L, gestational age adjusted OR 1.74 (95% CI 1.19–2.53), p = .004. ConclusionIn preterm infants receiving continuous infusion of rhIGF-1/rhIGFBP-3, higher levels of IL-6 and IGFBP-1 preceded lower levels of circulating IGF-1. These findings demonstrate a need to further evaluate if inflammation and/or infection suppress serum IGF-1 levels.The trial is registered at ClinicalTrials.gov (NCT01096784).

Clinical relevance of insulin-like growth factor-1 to cardiovascular risk markers

Objective Insulin-like growth factor-1 (IGF-1) is an anabolic hormone, the levels of which decline with age. The present study aimed to determine the impact of age-related declines in serum IGF-1 levels on various physiological processes. Design We retrospectively reviewed the medical records of patients whose serum IGF-1 levels were estimated in our department, and assessed the relationships between serum IGF-1 levels and various physiological parameters. Results A total of 427 patients with a mean (± standard deviation) age of 52.8 (± 17.1) years were included in the analysis. The levels of serum IGF-1 showed significant positive correlation with those of hemoglobin and hematocrit, and negative correlation with the presence of inflammatory and fibrin-related markers including C-reactive protein (CRP) and procalcitonin (PCT), and D-dimer and fibrin degradation products (FDP). These tendencies persisted after exclusion of patients with pituitary disease. Conclusions In this study population of diverse diseases and backgrounds, a decline in serum IGF-1 levels with age was associated with an increase in inflammatory and fibrin-related markers. This may explain the correlation between low serum IGF-1 levels and an increased risk of cardiovascular events. Our findings suggest that serum IGF-1 is a clinically relevant marker of cardiovascular risk, particularly in males.

Decreased Levels of Serum IGF-1 and Vitamin D Are Associated With Cognitive Impairment in Patients With Type 2 Diabetes.

To determine the association of serum insulin-like growth factor 1 (IGF-1) and vitamin D levels with cognition status in patients with type 2 diabetes mellitus (T2DM). A total of 173 patients with T2DM were recruited and divided into mild cognitive impairment (MCI) group (n = 94) and normal cognition (NC) group (n = 79). Levels of IGF-1 and 25(OH)D were measured and compared, and the correlations among IGF-1, 25(OH)D, and cognitive function were analyzed. Insulin-like growth factor 1 and 25(OH)D levels significantly decreased in MCI group than those in the NC group (both P < .001). Multiple stepwise regression analysis revealed that IGF-1 (β = .146, P < .001) and 25(OH)D (β = .199, P < .001) independently predicted Montreal Cognitive Assessment (MoCA) scores. Partial least square regression showed that contributions of both 25(OH)D (P < .001) and IGF-1 (P < .001) to MoCA scores were significant, while no cross-effect was observed between them (P = .714). Low serum IGF-1 and 25(OH)D levels may separately predict poor cognitive performance in patients with diabetes.

290-LB: Repeated Neonatal Oral Sucrose Treatment Affects Growth and Insulin-Like Growth Factor-1 in Mice

Premature infants (&amp;lt;;37 weeks of gestation) often require hospitalization in the neonatal intensive care unit, where they may experience painful procedures due to medical care. Oral sucrose is the non-pharmacological standard of care for minor procedural pain relief; 0.5-2mL of a 24% sucrose solution is administered orally prior to each painful procedure. Throughout hospitalization infants can be exposed to high and cumulative volumes of sucrose; however, little is known about the long-term effects of oral sucrose on growth and development. The objective of this study was to determine the long-term effects of repeated neonatal oral sucrose treatment on growth, adiposity, and glucose homeostasis. Neonatal female and male mice (C57BL/6J) were randomly assigned to one of five treatment groups (n=6-10 mice/group/sex): sham (only handled), sterile water, sucrose, fructose, or glucose. Pups were treated 10 times/day for the first six days of life with 0.2g/kg weight of respective treatments (1-4 μl/dose; 24% solutions) orally to mimic what is given to preterm babies. At 3 weeks (weeks), mice were weaned onto a control diet and fed until euthanasia, at 16 weeks. There were no effects of neonatal oral sucrose treatment on glucose and insulin tolerance, and glucose stimulated insulin secretion at weaning or during adulthood. Female sucrose-treated compared to water-treated mice gained less weight (15.4±1.60 vs. 17.4±1.90g), had smaller tibias (15.9± 0.35 vs. 16.67±0.24mm), and lower serum insulin-like growth factor 1 (IGF-1) (378± 98.0 vs. 661±196ng/ml) at 16 weeks. No differences in growth were found in males. However, IGF-1 levels were lower in sucrose-treated vs. sham male mice (401± 143 vs. 641±165ng/ml). Our findings suggest that repetitive neonatal sucrose treatment may affect growth in females through an IGF-1-dependent pathway. Disclosure C.Y. Ramirez Contreras: None. E. Mussai: None. A.M. Wiedeman: None. A. Mehran: None. M. Salehzadeh: None. N. Boonpattrawong: None. M. Ranger: None. K.K. Soma: None. L. Holsti: Other Relationship; Self; Provincial Health Services Association. A.M. Devlin: None. Funding British Columbia Children's Hospital Research Institute

Growth Hormone (GH) Therapy During the Transition Period: Should We Think About Early Retesting in Patients with Idiopathic and Isolated GH Deficiency?

To investigate growth hormone (GH) secretion at the transition age, retesting of all subjects who have undergone GH replacement therapy is recommended when linear growth and pubertal development are complete to distinguish between transitional and persistent GH deficiency (GHD). Early retesting of children with idiopathic and isolated GHD (i.e., before the achievement of final height and/or the adult pubertal stage) can avoid possible over-treatment. Here, we report data from our population with idiopathic and isolated GHD to encourage changes in the management and timing of retesting. We recruited 31 patients (19 males) with idiopathic GHD who received recombinant GH (rGH) for at least 2 years. All of the patients were retested at the transition age at least 3 months after rGH discontinuation. Permanent GHD was defined as a GH peak of <19 ng/mL after administration of growth hormone–releasing hormone (GHRH) + arginine as a provocative test. Permanent GHD was confirmed in only five of 31 patients (16.13%). None of these patients presented low serum insulin-like growth factor (IGF)-1 levels (<−2 standard deviation score (SDS)). Only one male patient with an IGF-1 serum level lower than −2 SDS showed a normal GH stimulation response, with a GH peak of 44.99 ng/mL. Few patients with idiopathic and isolated GHD demonstrated persistence of the deficit when retested at the transition age, suggesting that the timing of retesting should be anticipated to avoid overtreatment.

Low Serum IGF-1 in Boys with Recent Onset of Juvenile Idiopathic Arthritis.

Background Liver-derived insulin-like growth factor-1 (IGF-1) contributes bone formation. Decreased IGF-1 levels are common in juvenile idiopathic arthritis (JIA), but whether IGF-1 is related to sex and differ during the pathogenic progress of JIA is unknown. Objective The aim of this study was to examine IGF-1 levels in boys and girls with newly diagnosed JIA, with established JIA and in controls. Methods The study group included 131 patients from the Estonian population-based prevalence JIA study. Blood samples were obtained from 27 boys and 38 girls with early JIA (≤1 month from the diagnosis), 29 boys and 36 girls with established JIA (mean disease duration 18 months), and from 47 age- and sex-matched controls. Results IGF-1 levels in boys were significantly decreased in early JIA compared to male controls, while IGF-1 levels in girls were comparable between JIA and controls. In early JIA, IGF-1 levels were 12-fold lower in boys relative to girls. In controls, IGF-1 levels correlated with both age and height, while these correlations were lost in boys with early JIA. Conclusion We report a sex-dependent deficiency in serum IGF-1 in boys with early JIA, which argues for sex-related differences in biological mechanisms involved in the disease pathogenesis.

The Association of IGF-1 with Clinical Symptoms in Female Patients With Fibromyalgia Syndrome

Introduction: Fibromyalgia syndrome (FMS) is a disease of unknown etiology, which is characterised by chronic pain. Disturbed growth hormone response, low serum insulin-like growth factor-1 (IGF-1) may play a role in etiopathogenesis of fibromyalgia and may be related to the severity of some symptom. The aim of this study is to investigate serum IGF-1 levels and relationship of clinical symptoms in female patients with fibromyalgia syndrome. Materials and Methods: Thirty-seven patients with FMS and thirty healthy subjects were included in this study. All individuals were assessed for clinical findings, widespread pain (Visual Analogue Scale), functional disability and health state (health assesment questionnarie and fibromyalgia impact questionnarie), anxiety (anxiety State and Trait Anxiety Inventory) and depression (Beck depression inventory). Likert scale was used for evaluate morning stiffness, level of fatigue, pain, muscle spasm and tenderness. Results: In this study, serum IGF-1 levels of patients with fibromyalgia were significantly lower compared to the control group (p=0.004). The IGF-1 levels were significantly correlated with age (r=-0.496; p<0.01), muscle spasm (r=-0.333; p<0.05), tender points (r=-456; p<0.01) and morning stiffness (r=-0.463; p<0.01). Conclusion: Low levels of serum IGF-1 in female patients with fibromyalgia syndrome were associated with number of tender points, muscle spasm and stiffness. We have concluded that low levels of serum IGF-1 might play role in the pathogenesis of fibromyalgia and might be related to severity of symptoms.

C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome.

Cardio-facio-cutaneous (CFC) syndrome, a genetic disorder caused by germline mutations in BRAF, KRAS, MAP2K1 and MAP2K2, is characterized by growth retardation, heart defects, dysmorphic facial appearance and dermatologic abnormalities. We have previously reported that knock-in mice expressing the CFC syndrome-associated mutation, Braf Q241R, showed growth retardation because of gastrointestinal dysfunction. However, other factors associated with growth retardation, including chondrogenesis and endocrinological profile, have not been examined. Here, we show that 3- and 4-week-old BrafQ241R/+ mice have decreased body weight and length, as well as reduced growth plate width in the proximal tibiae. Furthermore, proliferative and hypertrophic chondrocyte zones of the growth plate were reduced in BrafQ241R/+ mice compared with Braf+/+ mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in BrafQ241R/+ mice. In accordance with growth retardation and reduced growth plate width, decreased serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) were observed in BrafQ241R/+ mice at 3 and 4 weeks of age. Treatment with C-type natriuretic peptide (CNP), a stimulator of endochondral bone growth and a potent inhibitor of the FGFR3-RAF1-MEK/ERK signaling, increased body and tail lengths in Braf+/+ and BrafQ241R/+ mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1/IGFBP-3 levels could be associated with the growth retardation observed in BrafQ241R/+ mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome.

Association between Insulin-Like Growth Factor-1 and Frailty among Older Adults.

Frailty is a course experienced in advanced aging. Identification of a biological factor associated with frailty is required. Although serum insulin-like growth factor-1 (IGF-1) is a potential factor related with frailty, consensus has not been reached regarding this relationship. This study aimed to investigate the association between IGF-1 and frailty in older adults. Cross-sectional study. Cohort study that was part of the "National Center for Geriatrics and Gerontology - Study of Geriatric Syndromes." The study participants were 4133 older adults (mean age, 71.8 ± 5.4 years). We assessed serum IGF-1 levels and frailty status and collected demographic variables, including cognitive function, as covariates. Frailty and pre-frailty were present in 274 subjects (7%) and 1930 subjects (47%), respectively. Subjects were divided into four groups based on quartiles of IGF-1 levels. Multinomial logistic analysis showed that the lowest group had significant odds of pre-frailty (crude model: odds ratio [OR] 1.58, 95% confidence interval [CI] 1.30-1.90, p < .001; adjusted model: OR 1.38, 95% CI 1.13-1.68, p = .002) and frailty (crude model: OR 3.42, 95% CI 2.38-4.92, p < .001; adjusted model: OR 1.54, 95% CI 1.02-2.32, p = .039), compared with the highest group. Lower serum IGF-1 levels were independently related with frailty in older adults.

Growth hormone insensitivity: Mexican case report.

Herein, we present a 14-year-old patient with short stature (134 cm) referred from Paediatrics to our department for complementary evaluation since growth hormone (GH) treatment failed to show any improvement. He was born premature and small for gestational age. Genital examination classified the patient as Tanner I–II with small penis and testicular size for his age. Biochemical analyses revealed normal GH levels with low serum insulin-like growth factor-1 (IGF-1). Molecular diagnosis confirmed several mutations in IGF1R and IGFALS, and so he was diagnosed with Laron Syndrome or GH insensibility and treated with IGF-1 substitutive therapy.Learning points:Evaluation of the GH/IGF-1 axis when short stature does not respond to conservative treatment must be included in the ordinary practice.Laron Syndrome real incidence should be calculated once undiagnosed cases arise, as treatment, due to lack of market, is unaffordable.Even when adulthood is reached, and no longitudinal growth can be achieved, still IGF-1 treatment in Laron Syndrome patients should be pursued as metabolic and protective derangements could arise.

Serum IGF-1 is associated with cognitive functions in early, drug-naïve Parkinson’s disease

ObjectiveCognitive deficits are common in Parkinson’s disease (PD) since the early stages and many patients eventually develop dementia. Yet, occurrence of dementia in PD is unpredictable. Evidence supports the hypothesis that insulin-like growth factor-1 (IGF-1) is involved in cognitive deficits. Our aim was to evaluate the relationship between serum IGF-1 levels and neuropsychological scores in a large cohort of drug-naïve PD patients during the earliest stages of the disease.MethodsSerum IGF-1 levels were determined in 405 early, drug-naïve PD patients and 191 healthy controls (HC) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). The association between serum IGF-1 levels and neuropsychological scores was evaluated with linear regression analysis.ResultsIGF-1 levels were similar in PD and HC. In PD patients the lowest IGF-1 quartile was a predictor of lower performances at the Semantic Fluency task (β = -3.46, 95%CI: -5.87 to -1.01, p = 0.005), the Symbol Digit Modalities Score (β = -2.09, 95%CI: -4.02 to -0.15, p = 0.034), and Hopkins Verbal Learning Test Retention (β = -0.05, 95%CI: -0.09 to -0.009, p = 0.019).ConclusionsLower serum IGF-1 levels are associated to poor performances in cognitive tasks assessing executive function, attention and verbal memory in a large cohort of early PD patients. Follow-up studies are warranted to assess if IGF-1 is related to the development of dementia in PD.