IGF-I Research Articles

Insulin and insulin-like growth factor-I receptors in astrocytes exert different effects on behavior and Alzheimer´s-like pathology

Background: Pleiotropic actions of insulin and insulin-like growth factor I (IGF-I) in the brain are context- and cell-dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF-I receptor (IGF-IR), respectively), is less clear. Methods: We compared mice lacking IR or IGF-IR in glial fibrillary astrocytic protein (GFAP)-expressing astrocytes in a tamoxifen-regulated manner, to clarify their role in this type of glial cells, as the majority of data of their actions in brain have been obtained in neurons. Results: We observed that mice lacking IR in GFAP astrocytes (GFAP IR KO mice) develop mood disturbances and maintained intact cognition, while at the same time show greater pathology when cross-bred with APP/PS1 mice, a model of familial Alzheimer´s disease (AD). Conversely, mice lacking IGF-IR in GFAP astrocytes (GFAP-IGF-IR KO mice) show cognitive disturbances, maintained mood tone, and show control-dependent changes in AD-like pathology. Conclusions: These observations confirm that the role of IR and IGF-IR in the brain is cell-specific and context-dependent.

Reliability of salivary biomarkers as skeletal maturity indicators: A systematic review

To assess the reliability of different salivary biomarkers as skeletal maturity indicators when compared with other methods of skeletal maturity assessment. A comprehensive search was conducted on three electronic databases: PUBMED, Google scholar and Cochrane library for the articles published from 2000 to July 2021. Assessment of skeletal age on the basis of levels of different salivary biomarkers at different pubertal stages was considered as the primary outcome. Electronic search, data collection and risk of bias assessment were performed by two authors with conflict resolution by the third author. Total 158 articles were retrieved after screening of titles, abstracts and full texts of all articles, of which 15 articles were selected for qualitative synthesis. All these studies were cross-sectional in design. These studies compared the levels of different salivary biomarkers as Alkaline Phosphatase (ALP), Insulin-like Growth Factor - I (IGF-I), Insulin-like Growth Factor Binding Protein-3 (IGFBP-3), Cortisol, Indian Hedgehog (IHH) protein and Dehydroepiandrosterone sulphate (DHEAS) with other methods of skeletal age estimation. Out of these six biomarkers salivary IGF-1 is a reliable indicator for skeletal maturity assessment. The current evidence suggests that salivary biomarkers can be used as an adjunct for growth prediction during orthodontic treatment planning along with other methods of skeletal maturation assessment. Still there is need for further research with longitudinal studies in this field.

Quercetin can affect porcine ovarian cell functions and to mitigate some of the effects of the environmental contaminant toluene

The present in vitro experiments aimed to examine the effects of the plant polyphenol quercetin and the environmental contaminant toluene on basic ovarian cell functions, including the ability of quercetin to be a natural protector against the adverse effects of toluene. The influence of toluene, quercetin, and their combination on proliferation (accumulation of PCNA), apoptosis (accumulation of bax) and release of progesterone, testosterone and insulin-like growth factor I (IGFI) by cultured porcine ovarian granulosa cells was investigated. Toluene stimulated cell proliferation and inhibited progesterone, IGF-I and testosterone release but did not affect apoptosis. Quercetin, when administered alone, inhibited cell proliferation, apoptosis, IGF-I and testosterone release and stimulated progesterone output. When administered in combination with toluene, quercetin mitigated toluene's effects on proliferation and on progesterone release and induced toluene to exhibit a pro-apoptotic effect. These observations demonstrate the direct effects of both quercetin and toluene on basic ovarian functions and a protective effect of quercetin against the effects of toluene. Therefore, quercetin-containing plants could be regulators of porcine reproduction and natural protectors against the adverse effects of the environmental contaminant toluene.

Expression and localization of apelin and apelin receptor (APJ) in buffalo ovarian follicles and corpus luteum and the in-vitro effect of apelin on steroidogenesis and survival of granulosa cells

Apelin is an adipose tissue-derived hormone with many physiological functions, including the regulation of female reproduction. It acts through an orphan G protein-coupled receptor APJ/APLNR. The present study aimed to investigate the expression of apelin and its receptor APJ in the ovarian follicles and corpus luteum (CL) and the role of apelin on steroidogenesis and cell survival. Ovarian follicles were classified into four groups based on size and estradiol (E2) level in the follicular fluid as follows: (i) F1 (4–6 mm; <0.5 ng/mL) (ii) F2 (7–9 mm; 0.5–5 ng/mL) (iii) F3 (10–13 mm; 5–40 ng/mL) and (iv) F4 (dominant/pre-ovulatory follicle) (>13 mm; >180 ng/mL). The corpora lutea (CL) were categorized into early (CL1), mid (CL2), late luteal (CL3), and regressing (CL4) CL stages. Expression of apelin increased with follicle size, with significantly greatest in the dominant or pre-ovulatory follicle (P < 0.05). Expression of APJ was greater in large and dominant follicles than in small and medium follicles (P < 0.05). In CL, the mRNA and protein abundance of apelin and apelin receptor was greater during mid (CL2) and late luteal (CL3) stages as compared to early (CL1) and regressing (CL4) stages (P < 0.05). Both the factors were localized in granulosa and theca cells of follicles and small and large luteal cells of CL. The pattern of the intensity of immunofluorescence was similar to mRNA and protein expression. Granulosa cells were cultured in vitro and treated at 1, 10, and 10 ng/mL apelin-13 either alone or in the presence of the follicle-stimulating hormone (FSH) (30 ng/mL) or insulin-like growth factor-I (IGF-I) (10 ng/mL) for 48 h. The luteal cells were treated with apelin-13 at 1, 10, and 100 ng/mL doses for 48 h. Apelin treatment at 10 and 100 ng/ml significantly (P < 0.05) increased E2 secretion, cytochrome P450 aromatase or CYP19A1 expression in GC. In luteal cells, apelin at 10 ng/mL and 100 ng/mL significantly (P < 0.05) increased progesterone (P4) secretion and HSD3B1 expression. In GCs, apelin, either alone or in combination, increased PCNA expression and inhibited CASPASE3 expression suggesting its role in cell survival. In conclusion, this study provides novel evidence for the presence of apelin and receptor APJ in ovarian follicles and corpora lutea and the stimulatory effect on E2 and P4 production and promotes GC survival in buffalo, suggesting the role of apelin in follicular and luteal functions in buffalo.

Evaluation of Insulin-Like Growth Factor-I (IGF-I) as a Predictor of Preeclampsia

Introduction: Preeclampsia (PE) is a serious pregnancy-induced disease characterized by hypertension, proteinuria and other systemic disorders after 20 weeks of gestation and is a leading cause of maternal and fetal morbidity and mortality. The main pathological characteristics of preeclampsia are poor trophoblast cell invasion and uterine spiral artery remodeling dysfunction caused by placenta ischemia and oxidative stress. Nowadays, preeclampsia is considered to be the results of the interactions of genetic and environmental factors. However, its accurate pathogenesis remains unknown. It was considered IGF-1 might be involved in the pathogenesis of preeclampsia. As is known, the behaviors of cells, the formation of placenta and the growth of fetus are widely regulated by insulin-like growth factor 1 (IGF-1). Several studies have shown that IGF-1 was significantly reduced in preeclampsia. Objectives: To assess the role of Insulin like Growth Factor-I (IGF-I) as a Predictor of Preeclampsia. Materials and Methods: It was a prospective cohort study conducted in General Obstetrics and Gynaecology Unit OPD, Dhaka Medical College Hospital from January, 2020 to December, 2020. Pregnant women between 8 weeks to 15 weeks were enrolled for study after fulfilling selection criteria. Serum concentration of Insulin like growth factor-I (IGF-I) was assessed with cut off value of IGF-I 175.9 ng/ml. The value above 175.9 ng/ml was categorized as normal IGF-I and value below 175.9 ng/ml was categorized as low IGF-I. The patients who had value above 175.9 ng/ml were grouped as A. The value below 175.9 ng/ml was grouped as B. Then they were followed up monthly upto 28 weeks, two weekly upto 36 weeks, weekly upto delivery and puerperium for development of preeclampsia or not. All information was recorded in data collection sheet. Data were analyzed by SPSS-23. Data were compared and correlated among groups and presented by tables and figures. Result: Maternal serum concentration .....

Insulin and insulin-like growth factor-I receptors in astrocytes exert different effects on behavior and Alzheimer´s-like pathology.

Background: Pleiotropic actions of insulin and insulin-like growth factor I (IGF-I) in the brain are context- and cell-dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF-I receptor (IGF-IR), respectively), is less clear. Methods: We compared mice lacking IR or IGF-IR in glial fibrillary astrocytic protein (GFAP)-expressing astrocytes in a tamoxifen-regulated manner, to clarify their role in this type of glial cells, as the majority of data of their actions in brain have been obtained in neurons. Results: We observed that mice lacking IR in GFAP astrocytes (GFAP IR KO mice) develop mood disturbances and maintained intact cognition, while at the same time show greater pathology when cross-bred with APP/PS1 mice, a model of familial Alzheimer´s disease (AD). Conversely, mice lacking IGF-IR in GFAP astrocytes (GFAP-IGF-IR KO mice) show cognitive disturbances, maintained mood tone, and show control-dependent changes in AD-like pathology. Conclusions: These observations confirm that the role of IR and IGF-IR in the brain is cell-specific and context-dependent.

A systematic literature review to evaluate extended dosing intervals in the pharmacological management of acromegaly

PurposeThis systematic literature review investigated whether extended dosing intervals (EDIs) of pharmacological acromegaly treatments reduce patient burden and costs compared with standard dosing, while maintaining effectiveness.MethodsMEDLINE/Embase/the Cochrane Library (2001–June 2021) and key congresses (2018–2021) were searched and identified systematic literature review bibliographies reviewed. Included publications reported on efficacy/effectiveness, safety and tolerability, health-related quality of life (HRQoL), and patient-reported and economic outcomes in longitudinal/cross-sectional studies in adults with acromegaly. Interventions included EDIs of pegvisomant, cabergoline, and somatostatin receptor ligands (SRLs): lanreotide autogel/depot (LAN), octreotide long-acting release (OCT), pasireotide long-acting release (PAS), and oral octreotide; no comparator was required.ResultsIn total, 35 publications reported on 27 studies: 3 pegvisomant monotherapy, 11 pegvisomant combination therapy with SRLs, 9 LAN, and 4 OCT; no studies reported on cabergoline, PAS, or oral octreotide at EDIs. Maintenance of normal insulin-like growth factor I (IGF-I) was observed in ≥ 70% of patients with LAN (1 study), OCT (1 study), and pegvisomant monotherapy (1 study). Achievement of normal IGF-I was observed in ≥ 70% of patients with LAN (3 studies) and pegvisomant in combination with SRLs (4 studies). Safety profiles were similar across EDI and standard regimens. Patients preferred and were satisfied with EDIs. HRQoL was maintained and cost savings were provided with EDIs versus standard regimens.ConclusionsClinical efficacy/effectiveness, safety, and HRQoL outcomes in adults with acromegaly were similar and costs lower with EDIs versus standard regimens. Physicians may consider acromegaly treatment at EDIs, especially for patients with good disease control.

Feeding after spawning and energy balance at spawning are associated with repeat spawning interval in steelhead trout

Consecutive and skip repeat spawning (1- or ≥2-year spawning interval) life histories commonly occur in seasonally breeding iteroparous fishes. Spawning interval variation is driven by energetic status and impacts fisheries management. In salmonids, energetic status (either absolute level of energy reserves or the rate of change of energy reserves, i.e., energy balance) is thought to determine reproductive trajectory during a critical period ∼1 year prior to initial spawning. However, information on repeat spawners is lacking. To examine the timing and the aspects of energetic status that regulate repeat spawning interval, female steelhead trout (Oncorhynchus mykiss) were fasted for 10 weeks after spawning and then fed ad libitum and compared to ad libitum fed controls. Plasma growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels were measured to assess long-term energy balance. Plasma estradiol levels showed that some fish in both groups initiated a consecutive spawning cycle. In fasted fish, GH was lower at spawning in consecutive versus skip spawners. In consecutive spawners, GH was higher at spawning in fed versus fasted fish. These results suggest that fish with a less negative energy balance at spawning initiated reproductive development in the absence of feeding, but that feeding during the post-spawning period enabled initiation of reproduction in some fish with a more negative energy balance at spawning. Thus, both energy balance at spawning and feeding after spawning regulated reproductive schedules. These results show that the critical period model of salmonid maturation applies to regulation of repeat spawning, and that the reproductive decision window extends into the first 10 weeks after spawning.

Nano Zinc Oxide Improves Performance, IGF-I mRNA Expression, Meat Quality, and Humeral Immune Response and Alleviates Oxidative Stress and NF-κB Immunohistochemistry of Broiler Chickens

A 35-day trial was set to explore the effects of different dietary zinc sources on growth, insulin-like growth factor I (IGF-I) mRNA expression, meat quality, immune response, antioxidant activity, and immunohistochemistry of nuclear factor kappa B (NF-κ7B) of broiler chickens. Ross 308 broiler chicks (n = 156) were randomly assigned into four experimental groups. The G1 received the basal control diet without zinc supplementation; the G2, G3, and G4 were supplemented with zinc oxide, zinc lysine, and nano zinc oxide, respectively, at a level of 40 mg Zn/kg diet. The data revealed that nano zinc oxide linearly improved the overall growth performance parameters. Nano zinc oxide linearly elevated (P < 0.001) mRNA expression of IGF-I followed by G3. The pH value of breast muscle in G4 shows a linearly decreasing value (P < 0.001). Also, the linearly highest expressible release volume percentage and lightness (L*) value with the lowest redness (a*) value (P < 0.05) were recorded in G4 and G3. A numerical increase in the total antibody titer was recorded on the 35th day in the G3 and G4. A numerical elevation in the superoxide dismutase (SOD) and a numerical reduction in the serum malondialdehyde (MDA) were recorded in the G4. The section of the liver from G4 revealed significantly very low expression of NF-κB staining. It is concluded that nano zinc oxide is considered the more trending zinc source. It had no negative effects on the health status and can be used in broiler diet premix.

Quantification of insulin-like growth factor-I by liquid chromatography-mass spectrometry.

We describe three methods of sample preparation for the liquid chromatography coupled with mass spectrometric measurement of insulin-like growth factor-I concentration in blood. One method involves trypsin digestion, the second involves intact protein quantification and the third method is a combination of the first two. Step-by-step directions are provided for sample collection and handling including transport, storage conditions as well as detailed instructions for preparation for analysis, which can be modified for larger or smaller sample volumes as needed. A fully 15 N-labelled internal standard is used and the merits of a single-point calibrator are discussed. Example instrumental conditions are presented for both intact and digest methods.

Effect of Dietary Pomelo Peel Powder on Growth Performance, Diarrhea, Immune Function, Antioxidant Function, Ileum Morphology, and Colonic Microflora of Weaned Piglets.

This trial evaluated how dietary-accommodated pomelo peel powder (PPP) affected average daily feed intake (ADFI) and average daily gain (ADG), diarrhea, antioxidation, and colonic microbial in weaned piglets. Thirty piglets weaned at 28 d were divided into three groups: a basal diet (CON); a CON containing 75 mg/kg chlortetracycline (CTC); and a CON containing 8 g/kg (PPP). This trial had a period of 28 days. Piglets supplemented with PPP had higher ADFI and ADG than piglets in CTC and CON (p &lt; 0.05). The diarrhea rate in PPP and CTC was lower than in CON in the 3rd and 4th weeks (p &lt; 0.05). Serum superoxide dismutase and glutathione peroxidase enzyme activities, and total antioxidant capacity in PPP were higher than those in CON (p &lt; 0.05). Serum interleukin (IL)-4, insulin-like growth factor-I, immunoglobulin (Ig)A, and IgG concentrations in the PPP and CTC groups were higher than those in the CON group (p &lt; 0.05). Serum IL-1β, IL-8, IL-17, and interferon (IFN)-γ concentrations and the cecal pH in PPP were lower than those in CON (p &lt; 0.05). Serum IL-1β, IFN-γ, and IgA concentrations of piglets in PPP were lower than in CTC (p &lt; 0.05). The villus height and villus height/crypt depth of the ileum of piglets in PPP and CTC were higher than those in CON (p &lt; 0.05), but there was no difference between PPP and CTC (p &gt; 0.05). The Firmicutes and Cyanobacteria relative abundances in PPP and CTC (p &lt; 0.05) were lower than those in CON, whereas the Bacteroidetes relative abundances in PPP and CTC were higher than those in CON. The Prevotellaceae relative abundance in CTC was higher than in CON (p &lt; 0.05), whereas the Lactobacillaceae relative abundance in CTC was lower than in CON (p &lt; 0.05). The Ruminococcaceae relative abundance in PPP was higher than in CON (p &lt; 0.05), whereas the Veillonellaceae relative abundance in PPP was lower than in CON (p &lt; 0.05). PPP can improve ADFI and ADG, relieve diarrhea, and enhance the colonic microflora of weaned piglets. Therefore, PPP is expected to replace CTC as a feed additive to alleviate weaning stress and ensure normal growth and development of piglets.

Corrigendum to: Direct action of leptin, obestatin and ginkgo on hormone release by luteinised human ovarian granulosa cells.

The role of metabolic hormones, medicinal plants and their interrelationships in the control of human reproductive processes are poorly understood. To examine how leptin, obestatin and ginkgo (Ginkgo biloba L.) affect human ovarian hormone release. We analysed the influence of leptin and obestatin alone and in combination with ginkgo extract on cultured human ovarian granulosa cells. The release of progesterone (P), insulin-like growth factor I (IGF-I), oxytocin (OT) and prostaglandin F (PGF) were analysed by enzyme immunoassay and enzyme-linked immunosorbent assay. Leptin addition promoted the release of all the measured hormones. Obestatin stimulated the release of P, IGF-I and OT and inhibited PGF output. Ginkgo suppressed P, IGF-I and OT and promoted PGF release. Furthermore, ginkgo changed the stimulatory action of leptin on PGF to an inhibitory one. Leptin and obestatin are involved in the control of human ovarian hormone release and ginkgo influences their function. Leptin and obestatin could be useful as stimulators of human ovarian cell functions. The suppressive influence of ginkgo on ovarian function should lead to the development of ginkgo-containing drugs.

Mechano-growth factor E-domain modulates cardiac contractile function through 14-3-3 protein interactomes.

In the heart, alternative splicing of the igf-I gene produces two isoforms: IGF-IEa and IGF-IEc, (Mechano-growth factor, MGF). The sequence divergence between their E-domain regions suggests differential isoform function. To define the biological actions of MGF's E-domain, we performed in silico analysis of the unique C-terminal sequence and identified a phosphorylation consensus site residing within a putative 14-3-3 binding motif. To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E18) and phospho-null (S/A18) peptides were delivered to mice at different doses for 2 weeks. Cardiovascular function was measured using echocardiography and a pressure-volume catheter. At the lowest (2.25mg/kg/day) and highest (9mg/kg/day) doses, the peptides produced a depression in systolic and diastolic parameters. However, at 4.5mg/kg/day the peptides produced opposing effects on cardiac function. Fractional shortening analysis also showed a similar trend, but with no significant change in cardiac geometry. Microarray analysis discovered 21 genes (FDR p < 0.01), that were expressed accordant with the opposing effects on contractile function at 4.5mg/kg/day, with the nuclear receptor subfamily 4 group A member 2 (Nr4a2) identified as a potential target of peptide regulation. Testing the regulation of the Nr4a family, showed the E-domain peptides modulate Nr4a gene expression following membrane depolarization with KCl in vitro. To determine the potential role of 14-3-3 proteins, we examined 14-3-3 isoform expression and distribution. 14-3-3γ localized to the myofilaments in neonatal cardiac myocytes, the cardiac myocytes and myofilament extracts from the adult heart. Thermal shift analysis of recombinant 14-3-3γ protein showed the S/A18 peptide destabilized 14-3-3γ folding. Also, the S/A18 peptide significantly inhibited 14-3-3γ's ability to interact with myosin binding protein C (MYPC3) and phospholamban (PLN) in heart lysates from dobutamine injected mice. Conversely, the S/E18 peptide showed no effect on 14-3-3γ stability, did not inhibit 14-3-3γ's interaction with PLN but did inhibit the interaction with MYPC3. Replacing the glutamic acid with a phosphate group on Ser 18 (pSer18), significantly increased 14-3-3γ protein stability. We conclude that the state of Ser 18 phosphorylation within the 14-3-3 binding motif of MGF's E-domain, modulates protein-protein interactions within the 14-3-3γ interactome, which includes proteins involved in the regulation of contractile function.

Effect of Dietary Administration of Green Macroalgae (Ulva intestinalis) on Mucosal and Systemic Immune Parameters, Antioxidant Defence, and Related Gene Expression in Zebrafish (Danio rerio).

This study investigated the effects of adding green macroalgae gutweed (Ulva intestinalis) powder to zebrafish (Danio rerio) feed at different levels on innate immune responses, antioxidant defence, and gene expression. A total of 600 zebrafish (0.3 ± 0.08 g) were randomly allocated to 12 aquariums in four treatments with three replicates (50 fish per aquarium). Zebrafish were fed with different levels of U. intestinalis powder 0, 0.25, 0.5, and 1% for eight weeks. Whole-body extract (WBE) immune parameters including total protein level, globulin level, and lysozyme activity were evaluated and revealed statistically significant increased in all U. intestinalis supplemented groups compared to the control (P < 0.05). However, mucus immune parameters (total protein, globulin, and lysozyme) were statistically different in only 1% gutweed supplemented groups from other groups. While glutathione peroxidase (GPx) and superoxide dismutase (SOD) increased with the addition of gutweed (P < 0.05), catalase (CAT) did not change (P > 0.05). The study results showed that dietary gutweed remarkably upregulated immune-related genes such as lysozyme (Lyz) and Interleukin 1 beta (IL-1β). Antioxidant-related genes (SOD and CAT) and growth-related genes, including growth hormone (GH) and insulin-like growth factor-I (IGF-1), were remarkably upregulated with gutweed treatment (P < 0.05). In conclusion, dietary U. intestinalis showed beneficial effects on immunity, and same effects were observed in case of antioxidant and growth related genes expression in zebrafish.

PMON166 Safety Comparison of 40- vs 60-mg/day Doses of Oral Octreotide Capsules for Treatment of Acromegaly in the CHIASMA OPTIMAL Trial

Abstract Background Oral octreotide capsules (OOC) are a treatment option for patients with acromegaly in the United States who have previously responded to injectable somatostatin receptor ligands (iSRLs, octreotide or lanreotide). In previous phase 3 studies, the safety of OOC was shown to be consistent with iSRLs, without dose-dependent adverse reactions. In the double-blind, placebo-controlled period (DPC) of the CHIASMA OPTIMAL trial (NCT03252353), patients were randomized to twice-daily OOC at 40-mg/day, with the option for up-titration to 80-mg/day. In contrast, patients entered the open-label extension (OLE) at a 60-mg/day dose. Objective Examine the safety of 40-mg/day versus 60-mg/day OOC doses. Methods Eligible patients had the option to enroll in the OLE following the core trial. All patients received OOC 60-mg/day upon entering the OLE regardless of prior treatment in the DPC, including patients who received placebo in the DPC. OOC doses were up- or down-titrated based on insulin-like growth factor I (IGF-I) level and/or acromegaly signs or symptoms. The current analysis compared the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAE-related study drug discontinuation, and acromegaly-related TEAEs (defined as new or worsening signs or symptoms of acromegaly). Results Twenty-eight patients randomized to OOC in the DPC (40-mg/day dose) and 19 who were originally randomized to placebo and continued into the OLE (60-mg/day dose) were included in the analysis. Biochemical control was similar in both groups as demonstrated by mean IGF-I levels over the respective periods. Ninety-six percent of patients on 40-mg/day and 57.9% on 60-mg/day experienced ≥1 TEAEs. Two patients on 60-mg/day reported a total of 2 SAEs, both deemed unrelated to study drug. Two patients on 40-mg/day experienced TEAEs leading to study drug discontinuation (headache and gastrointestinal symptoms). The incidence of acromegaly-related TEAEs was generally lower in those on 60-mg/day versus 40-mg/day. Conclusions This is the first analysis exploring differences in OOC doses. The nature and incidence of TEAEs occurring with an OOC dose of 60-mg/day versus 40-mg/day were similar, though this analysis was limited by differences in TEAE reporting across sequential phases of a lengthy trial. A trend was observed for decreased incidence of acromegaly-related TEAEs with the 60-mg/day dose. This finding is in line with previous analyses showing no dose-related TEAEs with OOC. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Label-free biosensor for trace insulin-like growth factor-I assay based on rGO-SnS2 heterostructure nanocomposite

Insulin-like growth factor-I (AgIGF-I) is a key biomarker in tumor progression. In this work, a novel label-free electrochemical impedance biosensing platform for detection of AgIGF-I was developed on the basis of a nanocomposite of reduced graphene oxidetin sulfide (rGO-SnS2) loaded with gold nanoparticles (AuNPs). The rGO-SnS2 surface serves as an interfacial matrix, exhibiting outstanding electrochemical activity because of its large surface area; meanwhile, the abundant active sites in rGO-SnS2 promote AuNP deposition and improve antibody (Ab) immobilization. The specific recognition between IGF-I antibody (AbIGF-I) and antigen (AgIGF-I) at the interface induces changes in electrochemical impedance, which can distinguish AgIGF-I from a complex biological media to ensure the selectivity. Electron transfer resistance (Rct) corresponds to the number of analytes on the interface, which serves as the basis for the design of an electrochemical impedance biosensor. Under optimized conditions, the designed biosensor exhibits a linear response range of 0.25–750.0 pg/mL and an ultralow detection limit of 0.12 pg/mL (S/N = 3), and the results based on an electrochemical method are consistent with those of enzyme-linked immunosorbent assay (ELISA). Such an electrochemical biosensor is highly effective for IGF-I sensing in human plasma samples, which broadens the application of the heterostructure [email protected]2 nanocomposite in bioanalysis and clinical diagnosis.

RF26 | PMON335 Once-Weekly Somapacitan Versus Daily Growth Hormone in Children Born Small for Gestational Age: Results From a Randomized Phase 2 Trial

Abstract Treatment of persistent short stature in children born small for gestational age (SGA) requires daily growth hormone (GH) injections that can be burdensome for patients and caregivers. Once-weekly somapacitan is a long-acting GH currently in phase 3 development for replacement therapy in children with GH deficiency. We report the 26-week results of the first phase 2, multinational, randomized, open-label, controlled, dose-finding trial (NCT03878446) investigating the efficacy and safety of somapacitan as treatment for short stature in children born SGA compared with daily GH (Norditropin®, Novo Nordisk A/S). A total of 62 (35.5% female) GH-treatment-naïve, prepubertal children received 0.16, 0.20 or 0.24 mg/kg/week subcutaneous (s.c.) somapacitan, or 0.035 or 0.067 mg/kg/day s.c. daily GH for 26 weeks (main phase). All children are subsequently included in an extension to this trial. The primary outcome was annualized height velocity (HV). At week 26, the estimated mean HV was: 8.9, 11.0 and 11.3 cm/year for 0.16 mg/kg/week (n=12), 0.20 mg/kg/week (n=13) and 0.24 mg/kg/week (n=12) somapacitan, respectively, versus 10.3 and 11.9 cm/year for 0.035 mg/kg/day (n=12) and 0.067 mg/kg/day (n=13) daily GH, respectively. A dose-dependent response in the estimated mean HV was observed with both somapacitan and daily GH. The effect of somapacitan on HV was not statistically significantly different compared with daily GH. A similar pattern was observed for change from baseline in height standard deviation score (SDS) and change from baseline in HV SDS. Consistent dose-dependent increases were observed in insulin-like growth factor-I (IGF-I) SDS with both somapacitan and daily GH. Exposure-response modeling of somapacitan exposure versus HV and IGF-I SDS vs. HV indicated an exposure-dependent increase in HV for both these parameters. Somapacitan was well tolerated at all doses investigated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to glucose metabolism, and no detection of anti-drug antibodies in any of the dose groups. In conclusion, all investigated doses of weekly somapacitan were efficacious and well tolerated throughout the study period. Based on the totality of data on improvements in height-based parameters combined with exposure-response analyses, a somapacitan dose of 0.24 mg/kg/week appears as the most efficacious dose, providing similar efficacy, safety and tolerability to daily GH 0.067 mg/kg/day after 26 weeks of treatment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:51 p.m. - 12:56 p.m.

PMON60 Growth Hormone (GH) Replacement Therapy (GHRT) in Patients with Adult GH Deficiency (AGHD) Aged ≥60 Years: Data from NordiNet® IOS and the ANSWER Program

Abstract There are limited data on the effectiveness and safety of GHRT in older patients with AGHD. We compared real-world GHRT outcomes in older (aged ≥60 years) versus middle-aged (35–&amp;lt;60 years) adults. NordiNet® IOS (NCT00960128) and ANSWER (NCT01009905) were non-interventional studies investigating long-term effectiveness and safety of GHRT with Norditropin® (somatropin, Novo Nordisk). Safety was assessed in the Full Analysis Set (FAS) from both studies (non-GH-naïve patients included). The Effectiveness Analysis Set (EAS) was from NordiNet® IOS only (GH-naïve patients; ANSWER-EAS included patients previously treated for ≤6 months). Serious adverse reactions (SARs) and non-serious ARs (NSARs) with a suspected causal relationship to GHRT, and serious adverse events (SAEs) not considered related to GHRT are presented as incidence rates per 1000 patient-years and as incidence rate ratios (IRRs) for older versus middle-aged adults. Of the 759 patients in the EAS, 545 were middle-aged and 214 older adults, mean (standard deviation) age 48.5 (7.0) and 67.2 (4.9) years, with 45.9% and 39.3% females, respectively. At baseline, GH dose was 0.24 (0.16) and 0.20 (0.10) mg/day, insulin-like growth factor-I standard deviation score (IGF-I SDS) was -0.94 (1.40) and -0.82 (1.36) and BMI was 29.29 (6.09) and 28.95 (4.58) kg/m2, respectively. Mean follow-up was 5.4 (4.3) and 5.3 (3.9) years, respectively. Of the 2348 patients in the FAS, 1696 were middle-aged and 652 older adults, aged 48.4 (7.1) and 67.1 (5.1) years, of which 52.4% and 43.3% were female, respectively. Baseline GH dose was 0.32 (0.24) and 0.26 (0.18) mg/day, IGF-I SDS was -0.58 (1.53) and -0.27 (1.54) and BMI was 30.50 (7.26) and 29.42 (5.39) kg/m2, respectively. Mean follow-up was 5.2 (4.5) and 4.7 (3.9) years, respectively. Mean GH exposure was greater in women than men, and in middle-aged than older women (FAS); it increased slightly over time in all groups. Baseline IGF-I SDS was slightly higher in older versus middle-aged women, but not men (EAS). Mean IGF-I SDS increased from below 0 to values ≤1.24 with GHRT. Mean changes in BMI (EAS) and HbA1c (EAS and FAS) were small and similar between age groups in both sexes. No statistically significant differences were observed between older and middle-aged adults regarding incidence rates for NSARs (5.66 vs 5.38; IRR [mean; 95%CI] 1.051 [0.604;1.831]) and SARs (1.00 vs 2.52; IRR 0.396 [0.119;1.324]). As expected, SAE incidence rate (considered unrelated to GHRT) was higher in the older group (16.64 vs 9.04, IRR 1.840 [1.291;2.622]). Similarly, the IRRs of patients ≥75 (n=59) years versus the middle-aged group were only significant for SAEs (23.09 vs 9.04; IRR 2.553 [1.113;5.855]). These data suggest similar clinical outcomes with GHRT in patients with AGHD aged ≥60 compared with 35–&amp;lt;60 years without additional risk of adverse drug reactions in older patients. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

RF14 | LBMON195 Once-weekly Somapacitan Is Effective And Well Tolerated In Children With GH Deficiency: A Randomized Phase 3 Trial

Abstract Growth hormone (GH) replacement therapy usually requires daily subcutaneous (s.c.) injections that can be burdensome for patients and their caregivers. Somapacitan, a long-acting reversible albumin-binding GH derivative, is in development for once-weekly s.c. administration in children with GH deficiency (GHD). REAL4 is a randomised, multi-national, open labelled, and active-controlled parallel group phase 3 trial, comprising a 52-week main phase and three-year extension period (NCT03811535). Two-hundred GH-treatment-naïve, prepubertal children with GHD (74.5% male) were randomly assigned in a 2: 1 ratio to receive 0.16 mg/kg/week s.c. somapacitan (n=132) or daily s.c. GH (0.034 mg/kg/day Norditropin®; n=68). The 52-week main trial results are presented here. The primary endpoint was annualized height velocity (HV) after 52 weeks of treatment. At week 52, the estimated mean HV was 11.2 cm/year for somapacitan compared to 11.7 cm/year for daily GH. The estimated treatment difference was -0.5 [95% CI -1.1 to 0.2] cm/year, confirming non-inferiority (non-inferiority threshold: -1.8 cm/year). Secondary height-related endpoints supported the primary endpoint. Insulin-like growth factor-I standard deviation score (IGF-I SDS) showed consistent increases for both somapacitan and daily GH over the 52 weeks, with change differences from baseline not statistically significant between treatment groups. At week 52, mean IGF-I SDS levels were similar between somapacitan (+0.28) and daily GH (+0.10) and within normal range (-2 to +2). Somapacitan was well tolerated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to changes in glucose metabolism, no neutralizing anti-somapacitan or anti-GH antibodies were detected, and a low number of patients reported injection-site reactions, with similar proportions for somapacitan (5.3%) and daily GH (5.9%). In both treatment groups, 1.5% of patients reported injection site pain. Adherence was high for both treatments. The mean and median adherence for somapacitan treatment were 95.8% and 100%, respectively. The mean and median adherence for the daily GH group were 88.3% and 96.9%, respectively. In conclusion, once-weekly somapacitan has a similar efficacy and safety profile as daily GH with similar mean IGF-I levels in treatment-naïve children with GHD. Presentation: Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

RF35 | PSAT263 Efficacy of Teprotumumab for Thyroid Eye Disease in Hypothyroid Patients

Abstract Background Thyroid eye disease (TED) is an autoimmune inflammatory process that can lead to eye-bulging (proptosis) and double-vision (diplopia). Teprotumumab, an insulin-like growth factor-I receptor inhibitory antibody, has demonstrated improvements in proptosis and diplopia. Thyroid dysregulation has been linked to increased TED severity1 and may trigger TED flares,2 thus, treatment efficacy of hypo- or hyperthyroid patients with teprotumumab is of interest. This post-hoc analysis of pooled phase 2 and 3 trial data3 examined teprotumumab efficacy in patients with low baseline FT4 levels. Methods Patients from Phase 2 and 3 teprotumumab trials with low baseline FT4 (≤11.5 pmol/L) were included. Patients received teprotumumab or placebo for 24 weeks (8 infusions). Proportions of proptosis (≥2 mm reduction), clinical activity score (CAS, 7-point scale, CAS 0 or 1), and diplopia (≥1 Gorman diplopia scale grade improvement) responders were determined at Week 24. Additionally, the Graves’ ophthalmopathy- quality of life (GO-QOL) questionnaire measured quality of life. Results Nine teprotumumab-treated patients (6 female [67%], 54.6±10.7 years old) and 8 (6 female [75%], 50.0±14.9 years old) patients made up the teprotumumab and placebo groups, respectively. Mean baseline proptosis in the study eye was 25.1±3.9 mm in teprotumumab patients and 21.9±3.8 mm in placebo patients. At Week 24, 78% (7/9) teprotumumab-treated vs. 38% (3/8) placebo-treated patients were proptosis responders. Further, mean proptosis reduction was 2.9±0.6 mm with teprotumumab vs. 1.2±0.7 mm with placebo. 67% (6/9) vs. 13% (1/8) of teprotumumab vs. placebo patients were CAS responders at Week 24. Of those with baseline diplopia, 86% (6/7) vs. 40% (2/5) were diplopia responders, respectively. In the teprotumumab group, the least square mean change from baseline in overall GO-QOL score improved by 23.4±6.4, which was a large clinical change. In contrast, the placebo group improved by 6.9±7.4. Conclusions After 24 weeks, responses to teprotumumab were greater versus placebo in patients with low baseline FT4 in two clinical trials. Responses in these mildly hypothyroid patients in this study were consistent with those in the overall pooled population as follows: Proptosis response: 78% and 77%, respectively; mean proptosis reduction: 2.9 mm and 3.14 mm; diplopia response 86% and 70%; CAS response 67% and 62%, respectively. Thus, pretreatment hypothyroid status does not affect clinical responses to teprotumumab in TED. References Bartalena L. Best Pract Res Clin Endocrinol Metab 2012; 26: 371-379. Patel P, et al. Ophthalmic Plast Reconstr Surg 2015; 31(6): 445-448. Kahaly et al. Lancet Diabetes and Endocrinol 2021; 9(6): 360-372 Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:26 p.m. - 12:41 p.m.