IGF-I Research Articles

Associations of body composition measures with circulating insulin-like growth factor-I, testosterone, and sex hormone-binding globulin concentrations in 16,000 men.

Adiposity is positively associated with risk of some cancer sites and other health conditions in men; however, it is unclear if endogenous hormones play a role in these associations. We examined how body composition, measured from magnetic resonance imaging (MRI) and common measures of adiposity (e.g., body mass index (BMI)), are related to hormone concentrations in men from the UK Biobank study. Up to 16,237 men with available body composition data (including visceral, subcutaneous, and liver fat, muscle fat infiltration (MFI), lean tissue, and common adiposity measures) and serum hormone measurements (insulin-like growth factor-I (IGF-I), total testosterone, sex hormone-binding globulin (SHBG), and calculated free testosterone) were included. Multivariable-adjusted linear regression models were used to determine the geometric mean hormone and SHBG concentrations across categories of each exposure. Common measurements of adiposity were highly correlated with MRI measures of central and total adiposity (r = 0.76-0.91), although correlations with ectopic fat (liver fat and MFI) were lower (r = 0.43-0.54). Most adiposity measurements showed an inverse U- or J-shaped association with circulating IGF-I and free testosterone; however, MFI was linearly inversely associated, and lean tissue volume was positively associated with both IGF-I and free testosterone concentrations. All body composition measures were inversely associated with total testosterone and SHBG concentrations (relative geometric mean difference between Q5 vs. Q1: 20-30%). Our results show that common adiposity and most MRI measures of adiposity relate similarly to serum hormone concentrations; however, associations with ectopic fat (particularly MFI) and lean tissue were different.

Growth hormone-releasing hormone and cancer.

The hypothalamic hormone growth hormone-releasing hormone (GHRH), in addition to promoting the synthesis and release of growth hormone (GH), stimulates the proliferation of human normal and malignant cells by binding to GHRH-receptor (GHRH-R) and its main splice variant, SV1. Both GHRH and GHRH-Rs are expressed in various cancers, forming a stimulatory pathway for cancer cell growth; additionally, SV1 possesses ligand independent proliferative effects. Therefore, targeting GHRH-Rs pharmacologically has been proposed for the treatment of cancer. Various classes of synthetic GHRH antagonists have been developed, endowed with strong anticancer activity in vitro and in vivo, in addition to displaying anti-inflammatory, antioxidant and immune-modulatory functions. GHRH antagonists exert indirect effects by blocking the pituitary GH/hepatic insulin-like growth factor I (IGF-I) axis, or directly inhibiting the binding of GHRH on tumor GHRH-Rs. Additionally, GHRH antagonists block the mitogenic functions of SV1 in tumor cells. This review illustrates the main findings on the antitumor effects of GHRH antagonists in experimental human cancers, along with their underlying mechanisms. The development of GHRH antagonists, with reduced toxicity and high stability, could lead to novel therapeutic agents for the treatment of cancer and inflammatory diseases.

Evolutionary Sequences and Structural Information-driven Reconstruction of New Insulin-like Growth Factor-I Peptide Variants.

Insulin-like growth factor-I (IGF-I) is crucial in controlling cell growth, proliferation, and apoptosis. Its strong link to the development of cancers such as breast, prostate, lung, thyroid, and colorectal has positioned the IGF-1 signalling pathway as a promising target for novel cancer therapies. When activated, the IGF-1 receptor (IGF-1R) binds to IGF-I, playing a central role in promoting tumour cell growth and survival. In this study, we combined evolutionary sequences with structural and functional data of IGF-1 to reconstruct ancestral sequences and design novel IGF-1 peptide variants. The insulin-like growth factor system exhibits a vast sequence diversity, yet it shares a similar structural topology with conserved three pairs of disulfide linkages. Our study reveals that IGF-1 is associated with the IGF system of cell surface receptors through protein-protein interactions. Reconstructed IGF-1 variants show similar structure fold to reported viral IGF-1 competitive antagonists. This new insight guides the design of novel natural IGF-1 mimic peptides. It enhances our understanding of IGF-1's functionality and opens new avenues for the development of therapeutic peptides and small molecules as anticancer agents.

6667 IGF1 Induces The Expression of CYR61 In Metastatic Prostate Cancer

Abstract Disclosure: G.L. Ortiz Hernández: None. M. Walker: None. L. Woods-Burnham: None. R.A. Kittles: None. C.A. Casiano: None. S.L. Neuhausen: None. The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF1). High serum levels of IGF1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. The correlation between PCa aggressiveness and circulating levels of CYR61 and IGF1 is poorly studied. Our goal was to assess the contribution of the interaction of CYR61-IGF1 to PCa cell proliferation. Their combined role may explain a proportion of aggressive PCa. This study was designed to characterize the role of IGF1-induced expression of CYR61 in metastatic PCa cellular models and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, migration, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. In addition, we found that IGF1 induces protein expression of CYR61 in a time-dependent manner, validated by both immunoblotting and confocal microscopy. PC3 cell lines are androgen receptor negative (AR-) and glucocorticoid receptor positive (GR+), which is characteristic of aggressive, advanced metastatic castration-resistant prostate cancer (mCRPC). Currently, we are conducting the same experiments in LNCaP cells, which are AR+/GR-, to determine if the CYR61-IGF1 interplay also occurs in PCa cells capable of AR signaling. In conclusion, we found that CYR61 expression is induced by IGF1 and its inhibition decreased the capacity of metastatic PCa cells to proliferate. Our results suggest that CYR61 inhibition may have the potential for treating metastatic PCa. Presentation: 6/1/2024

6667 IGF1 Induces the Expression of CYR61 in Metastatic Prostate Cancer

Abstract Disclosure: G.L. Ortiz Hernández: None. M. Walker: None. L. Woods-Burnham: None. R.A. Kittles: None. C.A. Casiano: None. S.L. Neuhausen: None. The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF1). High serum levels of IGF1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. The correlation between PCa aggressiveness and circulating levels of CYR61 and IGF1 is poorly studied. Our goal was to assess the contribution of the interaction of CYR61-IGF1 to PCa cell proliferation. Their combined role may explain a proportion of aggressive PCa. This study was designed to characterize the role of IGF1-induced expression of CYR61 in metastatic PCa cellular models and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, migration, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. In addition, we found that IGF1 induces protein expression of CYR61 in a time-dependent manner, validated by both immunoblotting and confocal microscopy. PC3 cell lines are androgen receptor negative (AR-) and glucocorticoid receptor positive (GR+), which is characteristic of aggressive, advanced metastatic castration-resistant prostate cancer (mCRPC). Currently, we are conducting the same experiments in LNCaP cells, which are AR+/GR-, to determine if the CYR61-IGF1 interplay also occurs in PCa cells capable of AR signaling. In conclusion, we found that CYR61 expression is induced by IGF1 and its inhibition decreased the capacity of metastatic PCa cells to proliferate. Our results suggest that CYR61 inhibition may have the potential for treating metastatic PCa. Presentation: 6/1/2024

8518 Prevalence of Hearing Dysfunction in Patients with Autoimmune Thyroid Disorders, Thyroid Eye Disease and the General US population: A Claims Database Analysis

Abstract Disclosure: T.J. Smith: Consulting Fee; Self; Amgen Inc, Viridian, Minghui, Lassen, Lundbeck. Other; Self; US patents covering the use of IGF-1 receptor inhibitors in TED which are held by UCLA and the Lundquist Institute. A. Meyers: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. Q. Fu: Stock Owner; Self; Amgen Inc. Other; Self; Amgen Inc, former employee. R.J. Holt: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. K. Zhu: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. Background: Autoimmune thyroid conditions including Graves’ disease (GD) have been associated with hearing impairment.([1]-3) Approximately 90% of patients (pts) with thyroid eye disease (TED) have hyperthyroidism/GD. Teprotumumab, an insulin-like growth factor-I receptor inhibitor, significantly improves TED signs/symptoms and became the first FDA-approved treatment for TED in 2020. Hearing-related adverse events were identified in pivotal trials of teprotumumab in TED.4 This epidemiology study aims to describe the prevalence of hearing loss/ototoxicity via claims data in commercially insured pts with autoimmune thyroid conditions, TED, and those receiving teprotumumab, as well as the general population (gen pop). Methods: Five mutually exclusive cohorts were created using deidentified claims data (Merative MarketScan®): GD pts (index is first GD diagnosis [dx] code), TED pts (index is later of both GD dx or eye symptom codes within 1 yr), teprotumumab pts (index is first claim for teprotumumab), other Thyroid Disorders (TD) pts (index is TD dx), and gen pop pts. Pts with teprotumumab claim were excluded from other cohorts. Eligible pts were ≥18 years (yrs) of age, continuously enrolled for ≥6 months pre and post index, between 1/1/2020-12/21/2021. Demographics (age, sex) were described between the cohorts and the gen pop. Proportions of pts with inpatient and outpatient claims for hearing loss/ototoxicity claims and proportions with hearing loss/ototoxicity claims in the 3 yrs preceding index were calculated. Age-standardized prevalence was presented using gen pop as the reference. Results: Of 21,256,714 eligible pts, 82,629 GD, 4,455 TED, 2,758 teprotumumab, 1,261,250 TD and 4,857,408 gen pop pts were identified. 47% pts in the gen pop cohort were female vs 72.1-75.7% in the other cohorts. Gen pop cohort was younger (mean [SD] age: 53 [15.1] yrs) vs 58.0-61.5 [15.1-15.6] yrs in other cohorts. Age-standardized prevalence of hearing loss/ototoxicity claims on/after index date was 3.3% for GD, 5.2% for TED, 4.3% for teprotumumab, 3.9% for TD, and 3.9% for gen pop pts. Hearing loss/ototoxicity claims were prevalent in the 3 years prior to index among these patients: 30.8% GD, 36.6% TED, 35.4% teprotumumab, 31.5% TD, and 27.3%) gen pop pts had a hearing loss/ototoxicity claim. Conclusions: In this descriptive unadjusted analysis, we observed similar prevalence of hearing loss/ototoxicity claims across thyroid disorders, TED pts, teprotumumab pts, and the gen pop group. Between 27%-37% had claims prior to thyroid diagnosis or receiving teprotumumab. It is expected that future analyses could adjust the rates for potential confounders across cohorts.

12231 PAPP-A As A Potential Target In Thyroid Eye Disease

Abstract Disclosure: C.A. Conover: None. L.K. Bale: None. D. Hamadi: None. M. Stan: ; Tourmaline, Genentech, Third Rock Ventures, ArgenX, Septerna, OrthoDi. ; Horizon, Immunovant, Lassen, Sling. Background: Proptosis in Thyroid Eye Disease (TED) can result in facial disfigurement and visual dysfunction. Studies revealed an interaction between thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor-I receptor (IGF-IR) that is essential in promoting TED pathogenesis. Treatment with Insulin-like growth factor I receptor (IGF-IR) inhibitors has been shown to be effective in reducing proptosis but with side effects. PAPP-A is metalloprotease that can increase pericellular IGF bioavailability through specific cleavage of inhibitory IGF binding proteins, in particular IGFBP-4. We propose that inhibition of IGF-IR indirectly and more selectively with PAPP-A inhibitory antibodies attenuates IGF-IR signaling in TED with fewer side effects. Methods: Informed consent was obtained from TED patients undergoing surgery in Mayo Clinic operating suites in Rochester, MN. Retro-orbital tissue was collected from 19 TED patients and 2 control subjects for fibroblast isolation and culture and was performed in a sterile tissue culture facility. TED and control fibroblasts were treated with pro-inflammatory cytokines, and flow separation of CD34- and CD34+ orbital fibroblasts was done, the latter representing infiltrating fibrocytes into the orbit in TED. Main outcome measured were PAPP-A expression and proteolytic activity, IGF-I stimulation of phosphatidylinositol 3 kinase/Akt pathway and inhibition by immuno-neutralizing antibodies against PAPP-A, CD34+ status and associated PAPP-A and IGF-IR expression. Results: Primary cultured cells showed that PAPP-A is expressed in orbital fibroblasts from TED patients but not in control subject fibroblasts and were markedly increased by pro-inflammatory cytokines stimulation. IGF-IR expression was not affected by cytokine treatment. Inhibition of PAPP-A’s proteolytic activity suppressed IGF-IR activation in orbital fibroblasts from TED patients. CD34+ orbital fibroblasts represent 80% of cells in culture from TED patients, and approximately 70% of these cells were accountable for PAPP-A and IGF-IR expression. Conclusion: These results support a role for PAPP-A in TED pathogenesis and indicate the potential for novel therapeutic targeting of the IGF axis. Presentation: 6/2/2024

Higher peak height velocity in early maturing girls depends on insulin rather than fat mass or IGF-I

Abstract Objective Age at pubertal onset has decreased over the recent decades. Early maturing girls have longer puberty duration, and higher peak height velocity (PHV) than late maturing girls. To what extent this is generated by increased insulin-like growth factor-I (IGF-I), fat mass, or fasting insulin levels is currently unknown. Design, setting, participants A population-based study—part of the COPENHAGEN puberty study—longitudinal part. Eighty-one girls evaluated biannually for a median of 10 (2-15) visits for a total of 815 evaluations. Methods Pubertal staging, anthropometric measures, PHV, skin fold thickness (SFT), and IGF-I and fasting insulin levels were measured. Results Early maturing girls achieved similar final height compared to late maturing girls (166.1 vs 167.1 cm, P = .36). Early pubertal onset was associated with significantly greater PHV (8.7 vs 7.4 cm/year, P < .001) and a longer puberty duration (age at onset of breast development to age at PHV [1.8 vs 1.1 years, P < .001]) compared with late maturation. After correcting for age at pubertal onset, neither body mass index, SFT, nor IGF-I levels differed between early vs late maturing girls. By contrast, fasting insulin levels were significantly higher in early compared with late maturing girls 1.5, 2.0, and 3.0 years after pubertal onset (all P = .039). Conclusion Growth velocity was higher and more prolonged in early compared with late maturing girls and associated with higher insulin levels. Thus, the higher insulin levels may compensate for the shorter total growth period by intensifying the pubertal growth period. Clinical trial registration number NCT01411527.

Somapacitan in Children Born SGA: 52-week Efficacy, Safety, and IGF-I Response Results from the Phase 2 REAL5 Study.

Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in short children born small for gestational age (SGA). Evaluate efficacy, safety, tolerability as well as total and bioactive insulin-like growth factor-I (IGF-I) response of once-weekly somapacitan compared to daily GH in children born SGA. REAL5 is a randomized, multi-center, open-label, controlled phase 2 study comprising a 26-week main phase, 26-week extension, and an ongoing 4-year safety extension (NCT03878446). Thirty-eight sites across 12 countries. Sixty-two GH-treatment-naïve, prepubertal short children born SGA were randomized; 61 completed 52-weeks of treatment. Patients randomized (1:1:1:1:1) to somapacitan (0.16, 0.20 or 0.24 mg/kg/week) or daily GH (0.035 or 0.067 mg/kg/day), all administered subcutaneously. Estimated mean height velocity (HV; cm/year) at week 52 was 8.5, 10.4 and 10.7 cm/year for somapacitan 0.16, 0.20 and 0.24 mg/kg/week, respectively, and 9.3 and 11.2 cm/year for daily GH 0.035 and 0.067 mg/kg/day, respectively. Dose-dependent increases in total IGF-I as well as peak IGF-I bioactivity were observed for both treatments and were similar between comparator groups. For somapacitan, exposure-response modelling indicated highest efficacy with 0.24 mg/kg/week after 52 weeks of treatment. Similar safety and tolerability were demonstrated across all groups. A sustained dose-dependent growth response was demonstrated for somapacitan after 52 weeks of treatment. Overall, somapacitan 0.24 mg/kg/week provides similar efficacy, safety, and tolerability, as well as comparable bioactive and total IGF-I response, as daily GH (0.067 mg/kg/day) in children born SGA.

Hormonal and inflammatory responses in prepubertal vs. pubertal male children following an acute free-weight resistance training session.

Examine the acute hormonal and cytokine responses to free-weight resistance training in trained prepubertal and pubertal male children. Prepubertal (n = 21; age 11.4 ± 1.1years; Tanner I-II) and pubertal male children (n = 20; age 15.8 ± 0.7years; Tanner III-V) conducted a moderate-intensity free-weight resistance training program to failure with venous blood sampling before (pre), immediately after (post) and during the recovery phase of the program (post-15,-30min). Growth hormone (GH), insulin-like growth factor-I (IGF-I), cortisol, testosterone, IL-6, and TNF-α were analyzed in serum samples. Biological maturation was assessed according to the stages of the Tanner scale. There was a significant time-by-group interaction in IGF-I response (p = 0.044; η2 = 0.209) and testosterone (p < 0.001; η2 = 0.508), indicating a greater change in the pubertal group compared to the prepubertal group. Both groups significantly increased post-exercise GH levels (p < 0.05). Only the prepuberal group significantly increased levels of IL-6 at all post-exercise time points (p < 0.05). Both groups showed a significant (p < 0.05) increase in TNF-α levels compared to resting levels. These data suggest that acute testosterone and IGF-I response following resistance training differ between trained prepubertal and pubertal male children. Moderate-intensity resistance training performed to failure may thus have different effects in trained prepubertal and pubertal male children, which should be considered when giving training advice. Clinical trials number: NCT05022992.

Association of Whole Blood Amino Acid and Acylcarnitine Metabolome with Anthropometry and IGF-I Serum Levels in Healthy Children and Adolescents in Germany.

Physiological changes of blood amino acids and acylcarnitines during healthy child development are poorly studied. The LIFE (Leipziger Forschungszentrum für Zivilisationserkrankungen) Child study offers a platform with a large cohort of healthy children to investigate these dynamics. We aimed to assess the intra-person variability of 28 blood metabolites and their associations with anthropometric parameters related to growth and excess body fat. Concentrations of 22 amino acids (AA), 5 acylcarnitines (AC) and free carnitine of 2213 children aged between 3 months and 19 years were analyzed using liquid chromatography/tandem mass spectrometry. Values were transformed into standard deviation scores (SDS) to account for sex- and age-related variations. The stability of metabolites was assessed through the coefficient of determination. Associations with parameters for body composition and insulin-like growth factor-I (IGF-I) SDS were determined by the Pearson correlation and linear regression. Our research revealed substantial within-person variation in metabolite concentrations during childhood and adolescence. Most metabolites showed a positive correlation with body composition parameters, with a notable influence of sex, pubertal status and weight group. Glycine exhibited negative associations with parameters of body fat distribution, especially in normal weight girls, overweight/obese boys and during puberty. Blood AA and AC measurements may contribute to elucidating pathogenesis pathways of adiposity-related comorbidities, but the specific timings and conditions of development during childhood and adolescence need to be taken into consideration.

Upregulation of Insulin-like Growth Factor-I in Response to Chemotherapy in Children with Acute Lymphoblastic Leukemia.

The treatment of childhood cancer is challenged by toxic side effects mainly due to chemotherapy-induced organ damage and infections, which are accompanied by severe systemic inflammation. Insulin-like growth factor I (IGF-I) is a key regulating factor in tissue repair. This study investigated associations between the circulating IGF-I levels and chemotherapy-related toxicity in pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we included 114 patients (age: 1-17 years) with newly diagnosed ALL treated according to The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2013 and 2018. The patients' plasma levels of IGF-I, and the primary binding protein, IGFBP-3, were measured weekly during the first six weeks of treatment, including the induction therapy. The patients' systemic inflammation was monitored by their C-reactive protein (CRP) and interleukin (IL)-6 levels and their intestinal epithelial damage by their plasma citrulline levels. IGF-I and IGFBP-3 were converted into sex-and age-adjusted standard deviation scores (SDS) using 1621 healthy children as reference. At ALL diagnosis, IGF-I levels were decreased (median (quartiles): -1.2 SDS (-1.9 to -0.5), p = 0.001), but increased significantly following the initiation of chemotherapy, peaking on day 8 (0.0 SDS (from -0.8 to 0.7), p < 0.001). This increase correlated with the levels of CRP (rho = 0.37, p < 0.001) and IL-6 (rho = 0.39, p = 0.03) on day 15, when these markers reached maximum levels. A larger IGF-I increase from day 1 to 15 correlated with a slower recovery rate of the intestinal damage marker citrulline from day 15 to 29 (rho = -0.28, p = 0.01). Likewise, IGFBP-3 was reduced at diagnosis, followed by an increase after treatment initiation, and was highly correlated with same-day IGF-I levels. This study demonstrates a chemotherapy-induced increase in IGF-I, with a response that appears to reflect the severity of tissue damage and systemic inflammation, preceding CRP and IL-6 increases. IGF-I may have potential as an early reactive biomarker for acute toxicity in patients with ALL.

Effect of birth type and sex on growth performance, wither height, humerus-radius bone dimensions, humerus-ulna growth plate width and selected hormone profile in growing Gurcu goat kids.

In this study, the effects of sex and birth type on growth performance, withers height (WH), radiographic measurements and selected hormone profiles in Gurcu goat kids were investigated. Twenty kids (single female=5, single male=5, twin female=5, twin male=5) were included in the study. Body weight (BW), WH, radiographic measurements (humerus length [HL], radius length [RL], proximal humerus epiphyseal plate width [HEP] and distal ulna epiphyseal plate width [UEP]) and biochemical analysis (for serum calcitonin, free triiodothyronine [FT3], free thyroxine [FT4], growth hormone [GH] and insulin-like growth factor-I [IGF-I]) were performed at 1, 3, 5, 7, 9 and 12 months of age. BW was significantly higher in males starting from the seventh month compared to females (p<0.05). HL was higher in males at seventh (p=0.009) and ninth (p=0.033) months, whereas RL was lower in twins at the third month (p=0.021). UEP was wider in males at seventh (p=0.008) and ninth (p=0.036) months. Closure of HEP was observed in 65% of kids by the 12th month. Calcitonin was lower in twins at third (p=0.045) and fifth (p=0.006) months, with changes observed due to group and time effects (p<0.05), whereas other hormones only changed with time (p<0.05). Positive correlations were observed between BW, WH, HL, RL and IGF-I. There was a negative correlation between BW, WH, HL, RL, IGF-I and HEP, UEP, calcitonin, FT3, FT4, GH. Sex and birth type in Gurcu goat kids may have an impact on growth performance, radiographic measurements and certain hormonal profiles.

Does insulin-like growth factor-I level associate with pregnancy outcomes in primary and secondary infertile women undergoing in vitro fertilization? A prospective cohort study.

Infertility, which affects 8%-12% of couples worldwide and 21.9% of couples in Pakistan in particular, is a major reproductive health issue. In vitro fertilization (IVF) has emerged as a prevalent therapeutic intervention. Recent studies have identified insulin-like growth factor-I (IGF-I) as a promising biomarker for assessing embryo viability and predicting implantation outcomes in IVF procedures.

Correlation of tri-ponderal mass index with insulin-like growth factor-I and insulin-like growth factor binding protein-3 in children and adolescents.

We aimed to investigate the relationship between the tri-ponderal mass index (TMI), a new indirect measure of fat mass, and insulin-like growth factor (IGF)-I/IGF binding protein (IGFBP)-3. The study included 1,630 children and adolescents who visited Jeonbuk National University Children's Hospital. Each patient's medical record was retrospectively reviewed for age, sex, height, weight, body mass index (BMI), TMI, and IGF-1 and IGFBP-3 levels. Study participants were divided by sex and then categorized by age, BMI, and TMI. Finally, the correlations of TMI with IGF-1 level, IGF-1 standard deviation score (SDS), IGFBP-3 level, IGFBP-3 SDS, and IGF-1/IGFBP-3 ratio were investigated. All participants were <19 years of age. BMI correlated with IGF-1 and IGFBP-3 levels in both sexes; however, the relationship with TMI differed by sex. TMI correlated with IGF-1 and IGFBP-3 SDS in boys and with IGF-1, IGFBP-3, and IGFBP-3 SDS in girls across all ages. In boys, BMI and TMI significantly correlated with IGF-1, IGF-1 SDS, IGFBP-3, IGFBP-3 SDS, and the IGF-1/IGFBP-3 ratio in the normal-weight group. TMI also correlated with IGF-1, IGFBP-3, and IGFBP-3 SDS in the overweight group. In girls, BMI significantly correlated with IGF-1, IGF-1 SDS, IGFBP-3, IGFBP-3 SDS, and the IGF-1/IGFBP-3 ratio in the normal-weight group and with IGFBP-3 and IGFBP-3 SDS in the overweight group, while TMI correlated with IGF-1, IGF-1 SDS, and the IGF-1/IGFBP-3 ratio in the normal-weight group; with IGF-1, IGFBP-3, and IGFBP-3 SDS in the overweight group; and with IGFBP-3 SDS in the obese group. TMI may more strongly correlate with IGFBP-3 level than BMI in overweight boys and with IGFBP-3 SDS in overweight and obese girls. The correlation of IGFBP-3 SDS with TMI may be helpful for evaluating weight status in adolescent girls.

Distinct In Vitro Differentiation Protocols Differentially Affect Cytotoxicity Induced by Heavy Metals in Human Neuroblastoma SH-SY5Y Cells.

The SH-SY5Y cell line is widely used in neurotoxicity studies. However, the effects of inducing cell differentiation on the cytotoxic effects of heavy metals are unclear. Therefore, we investigated the effects of mercuric chloride (HgCl2), cadmium chloride (CdCl2), arsenic trioxide (As2O3), and methylmercury (MeHg) on SH-SY5Y cells differentiated in the presence of insulin-like growth factor-I (IGF-I) or all-trans retinoic acid (ATRA). Neurite outgrowth with distinct changes in neuronal marker expression, phenotype, and cell cycle was induced in SH-SY5Y cells by IGF-I treatment for 1day or ATRA treatment for up to 7days. The cytotoxic effects of HgCl2 decreased at lower concentrations and increased at higher concentrations in both IGF-I- and ATRA-differentiated cells compared with those in undifferentiated cells. Differentiation with IGF-I, but not with ATRA, increased the cytotoxic effects of CdCl2. Decreased cytotoxic effects of As2O3 and MeHg were observed at lower concentrations in IGF-I-differentiated cells, whereas increased cytotoxic effects of As2O3 and MeHg were observed at higher concentrations in ATRA-differentiated cells. Changes in the cytotoxic effects of heavy metals were observed even after 1day of ATRA exposure in SH-SY5Y cells. Our results demonstrate that the differentiation of SH-SY5Y cells by IGF-I and ATRA induces different cellular characteristics, resulting in diverse changes in sensitivity to heavy metals, which depend not only on the differentiation agents and treatment time but also on the heavy metal species and concentration.

Differences in Bone Metabolism between Children with Prader-Willi Syndrome during Growth Hormone Treatment and Healthy Subjects: A Pilot Study.

Despite therapy with growth hormone (GH) in children with Prader-Willi syndrome (PWS), low bone mineral density and various orthopedic deformities have been observed often. Therefore, this study aimed to analyze bone markers, with an emphasis on vitamin K-dependent proteins (VKDPs), in normal-weight children with PWS undergoing GH therapy and a low-energy dietary intervention. Twenty-four children with PWS and 30 healthy children of the same age were included. Serum concentrations of bone alkaline phosphatase (BALP), osteocalcin (OC), carboxylated-OC (Gla-OC), undercarboxylated-OC (Glu-OC), periostin, osteopontin, osteoprotegerin (OPG), sclerostin, C-terminal telopeptide of type I collagen (CTX-I), and insulin-like growth factor-I (IGF-I) were determined using immunoenzymatic methods. OC levels and the OC/CTX-I ratios were lower in children with PWS than in healthy children (p = 0.011, p = 0.006, respectively). Glu-OC concentrations were lower (p = 0.002), but Gla-OC and periostin concentrations were higher in patients with PWS compared with the controls (p = 0.005, p < 0.001, respectively). The relationships between IGF-I and OC (p = 0.013), Gla-OC (p = 0.042), and the OC/CTX-I ratio (p = 0.017) were significant after adjusting for age in children with PWS. Bone turnover disorders in children with PWS may result from impaired bone formation due to the lower concentrations of OC and the OC/CTX-I ratio. The altered profile of OC forms with elevated periostin concentrations may indicate more intensive carboxylation processes of VKDPs in these patients. The detailed relationships between the GH/IGF-I axis and bone metabolism markers, particularly VKDPs, in children with PWS requires further research.

TSHR-IGF-IR complex drives orbital fibroblast misbehavior in thyroid eye disease.

Evolving understanding of thyroid eye disease (TED) has led to rapidly advancing therapeutic options. Most new treatments under development or recently available to patients are predicated on insights into disease mechanism. TED, a disfiguring process, involves inflammation and remodeling of the connective tissues around the eye. TED most frequently presents as a component of Graves' disease. Advances in our understanding of cells involved in TED and their molecular interactions have led to novel therapeutic targets. Among these cell types are orbital fibroblasts and a subset comprising monocyte progenitor cells, known as CD34 + CXCR4 + fibrocytes. Among the attributes of fibrocytes is their expression of several autoantigens associated with Graves' disease, including TSHR, thyroglobulin and thyroperoxidase. Fibrocytes also express high levels of the insulin-like growth factor-I (IGF-I) receptor, thought to mediate fibroblast activation. Therapeutically targeting the TSHR/IGF-IR receptor complex using an IGF-I receptor antagonist, teprotumumab, has resulted in substantial clinical benefit for patients with TED. The neural axon repellent, Slit2, and its cognate receptor, ROBO1, appear to modulate the inflammatory phenotype of these orbit-infiltrating fibrocytes. More detailed understanding of orbital fibroblasts and the distinctions between cell subsets comprising them should lead to more effective therapies with fewer side effects.

Impairment of synaptic plasticity in the primary somatosensory cortex in a model of diabetic mice.

Type 1 and type 2 diabetic patients experience alterations in the Central Nervous System, leading to cognitive deficits. Cognitive deficits have been also observed in animal models of diabetes such as impaired sensory perception, as well as deficits in working and spatial memory functions. It has been suggested that a reduction of insulin-like growth factor-I (IGF-I) and/or insulin levels may induce these neurological disorders. We have studied synaptic plasticity in the primary somatosensory cortex of young streptozotocin (STZ)-diabetic mice. We focused on the influence of reduced IGF-I brain levels on cortical synaptic plasticity. Unit recordings were conducted in layer 2/3 neurons of the primary somatosensory (S1) cortex in both control and STZ-diabetic mice under isoflurane anesthesia. Synaptic plasticity was induced by repetitive whisker stimulation. Results showed that repetitive stimulation of whiskers (8 Hz induction train) elicited a long-term potentiation (LTP) in layer 2/3 neurons of the S1 cortex of control mice. In contrast, the same induction train elicited a long-term depression (LTD) in STZ-diabetic mice that was dependent on NMDA and metabotropic glutamatergic receptors. The reduction of IGF-I brain levels in diabetes could be responsible of synaptic plasticity impairment, as evidenced by improved response facilitation in STZ-diabetic mice following the application of IGF-I. This hypothesis was further supported by immunochemical techniques, which revealed a reduction in IGF-I receptors in the layer 2/3 of the S1 cortex in STZ-diabetic animals. The observed synaptic plasticity impairments in STZ-diabetic animals were accompanied by decreased performance in a whisker discrimination task, along with reductions in IGF-I, GluR1, and NMDA receptors observed in immunochemical studies. In conclusion, impaired synaptic plasticity in the S1 cortex may stem from reduced IGF-I signaling, leading to decreased intracellular signal pathways and thus, glutamatergic receptor numbers in the cellular membrane.

Cord Blood Fetuin-B, Fetal Growth Factors and Lipids in Gestational Diabetes Mellitus.

Fetuin-B is a hepatokine/adipokine implicated in glucose homeostasis and lipid metabolism. We sought to assess whether cord blood fetuin-B levels are altered in gestational diabetes mellitus (GDM) and the association with fetal growth factors and lipids. In a nested case-control study of 153 pairs of neonates of mothers with GDM and euglycemic pregnancies in the Shanghai Birth Cohort, we assessed cord blood fetuin-B in relation to fetal growth factors and lipids [high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterols (TC) and triglycerides (TG)]. Cord blood fetuin-B concentrations were higher in the newborns of GDM vs. euglycemic mothers (mean ± SD: 2.35±0.96 vs 2.05±0.73 mg/L, P=0.012), and were positively correlated with LDL (r=0.239, P<0.0001), TC (r=0.230, P=0.0001), insulin-like growth factor-Ⅰ [IGF-Ⅰ (r=0.137, P=0.023)] and IGF-Ⅱ (r=0.148, P=0.014) concentrations. Similar associations were observed adjusting for maternal and neonatal characteristics. The study is the first to demonstrate that fetuin-B levels are elevated in fetal life in GDM, and that fetuin-B affects lipid metabolic health during fetal life in humans. The secretion of fetuin-B appears to be related to the secretion of insulin-like growth factors (IGF-Ⅰ and IGF-Ⅱ).