IGF-I Receptor Research Articles

Hepatic transcriptome profiling unveils candidate genes in cattle with liver abscesses under the influence of beef genetics in dairy cattle.

Liver abscesses are a significant concern in cattle feeding, linked to visceral condemnation and carcass trimming; however, the molecular mechanism of development and progression of liver abscesses is unknown. This study aimed to evaluate the hepatic transcriptomic profile, immunohistochemistry, and IGF-I circulation in beef × dairy (Angus × Holstein) steers with and without liver abscesses. Samples were collected from twelve steers (final body weight of 719 ± 5.8 kg) originating from the same feedlot and were selected based on liver scores at harvest. The animals were divided into abscessed (n = 6) and healthy livers (n = 6). Blood samples were used to measure circulating insulin-like growth factor I (IGF-I) levels using an ELISA kit. Liver samples were divided into two portions; one portion was used for immunohistochemistry (IHC) to identify IGF-I receptor (IGF-IR) abundance, while the second portion was used for RNA extraction, library preparation, and sequencing (Illumina NovaSeq 6000 platform). Differentially expressed genes (DEGs) were identified with the DESeq2 R package, using an adjusted p-value ≤ 0.05 and fold change > 1.5. Sera IGF-I was not affected by liver condition; however, IGF-IR abundance was up-regulated in abscessed livers. A total of 568 DEGs were identified, with 372 up-regulated and 196 down-regulated in abscessed livers. Notably, the most highly up-regulated genes were FGF23, NXPH4, and CYP7A1, while EPHA6, CD70, and INHBA showed the most significant downregulation. Protein-protein interaction (PPI) network analysis identified THBS1 and COL1A2 as significant hub genes. The DEGs showed enrichment in biological processes related to angiogenesis, cell migration, adhesion, and extracellular matrix organization. Pathway analysis indicated activation in signaling pathways, including hepatic fibrosis, interleukin, and IGF-I signaling. These findings reveal candidate genes and pathways linked to inflammatory responses and tissue remodeling, offering valuable evidence that enhances our understanding of the progression of liver abscesses in cattle.

Hepatic transcriptome profiling unveils candidate genes in cattle with liver abscesses under the influence of beef genetics in dairy cattle

Liver abscesses are a significant concern in cattle feeding, linked to visceral condemnation and carcass trimming; however, the molecular mechanism of development and progression of liver abscesses is unknown. This study aimed to evaluate the hepatic transcriptomic profile, immunohistochemistry, and IGF-I circulation in beef × dairy (Angus × Holstein) steers with and without liver abscesses. Samples were collected from twelve steers (final body weight of 719 ± 5.8 kg) originating from the same feedlot and were selected based on liver scores at harvest. The animals were divided into abscessed (n = 6) and healthy livers (n = 6). Blood samples were used to measure circulating insulin-like growth factor I (IGF-I) levels using an ELISA kit. Liver samples were divided into two portions; one portion was used for immunohistochemistry (IHC) to identify IGF-I receptor (IGF-IR) abundance, while the second portion was used for RNA extraction, library preparation, and sequencing (Illumina NovaSeq 6000 platform). Differentially expressed genes (DEGs) were identified with the DESeq2 R package, using an adjusted p-value ≤ 0.05 and fold change > 1.5. Sera IGF-I was not affected by liver condition; however, IGF-IR abundance was up-regulated in abscessed livers. A total of 568 DEGs were identified, with 372 up-regulated and 196 down-regulated in abscessed livers. Notably, the most highly up-regulated genes were FGF23, NXPH4, and CYP7A1, while EPHA6, CD70, and INHBA showed the most significant downregulation. Protein-protein interaction (PPI) network analysis identified THBS1 and COL1A2 as significant hub genes. The DEGs showed enrichment in biological processes related to angiogenesis, cell migration, adhesion, and extracellular matrix organization. Pathway analysis indicated activation in signaling pathways, including hepatic fibrosis, interleukin, and IGF-I signaling. These findings reveal candidate genes and pathways linked to inflammatory responses and tissue remodeling, offering valuable evidence that enhances our understanding of the progression of liver abscesses in cattle.

P-439 Role of Growth hormone in increasing the endometrial receptivity in aged women with thin endometrium undergoing Frozen embryo transfer cycle

Abstract Study question Is there a role for Growth hormone in increasing the clinical pregnancy rate by increasing the endometrial receptivity in aged women with thin endometrium ? Summary answer Growth hormone significantly increases the clinical pregnancy rate by increasing the endometrial receptivity in aged women with thin endometrium What is known already Growth hormone is a peptide hormone secreted by anterior Pituitary gland. There is an age related decline in the production of growth hormone. In aged women, Growth hormone supplementation increases the oocyte development and oocyte competence, thereby increasing the number of mature oocytes retrieved and increasing the fertilization potential augmenting IVF success rate. Growth hormone promotes granulosa cell proliferation and cumulus cell functions Beneficial effects of growth hormone are exerted via IGF1 and Growth Hormone receptors (GHR). Similar Growth Hormone Receptors are identified in endometrium as well which can promote the endometrial proliferation and endometrial vascularity . Study design, size, duration This is a Case Control study involving 90 patients , aged > 40 years with thin endometrium. 45 participants in Treatment group received Growth hormone 4 IU SC every alternative days along with Hormone Replacement Therapy from day 2 till embryo transfer . 45 participants in Control group received only HRT. Women with Uterine anomalies , previously scarred uterus and Ashermann Syndrome were excluded . Study period extended from January 2023 to December 2024 . Participants/materials, setting, methods Patients with thin endometrium were included in this study - Endometrial thickness less than 7 mm after 15 days of Estradiol valerate therapy in a frozen embryo transfer cycle. Patients were allotted in Treatment and Control group based on personal choice after informed consent . Clinical pregnancy rate was the primary outcome analyzed . Endometrial thickness and endometrial vascularity were the secondary outcomes analyzed. Main results and the role of chance There were no significant differences in socio demographic characteristics between groups. Age , BMI , sperm factor and number of cancelled Frozen embryo transfer cycles were matched. All patients enrolled in this study had at least 1 cancelled Frozen Embryo Transfer cycle due to thin endometrium .Treatment group who received Growth hormone therapy had a clinical pregnancy rate of 66.6 % (30/45) documented by the presence of a gestational sac in uterine cavity in TVS, 20 days after embryo transfer whereas Control group had a clinical pregnancy rate of 46.6%(21/45) . Endometrial thickness on the day of start of progesterone and Endometrial vascularity on the day of embryo transfer were comparable between both groups and not significantly different . 12 patients in Treatment group and 9 patients in Control group underwent Oocyte donation cycles . Further follow up of pregnancy till delivery was not done - so miscarriage rate and live birth rate were not analyzed in this study . Limitations, reasons for caution Results need to be interpreted with caution because of limited sample size. Pre Implantation Genetic Diagnosis for Aneuploidy (PGD A ) was not done on all embryos that were transferred . Total dosage of Growth hormone used in treatment group differed slightly between patients . Wider implications of the findings Growth hormone being a mitogen positively can up regulate the mRNA coding genes for implantation promoting cytokines, which can benefit women with Recurrent Implantation Failure . Dosage , duration , Frequency and route of administration of growth hormone has to be standardized . Trial registration number Yes

Systemic IGF-1 administration prevents traumatic brain injury induced gut permeability, dysmorphia, dysbiosis, and the increased number of immature dentate granule cells

Traumatic brain injury (TBI) occurs in 2–3 million Americans each year and is a leading cause of death and disability. Among the many physiological consequences of TBI, the hypothalamic pituitary axis (HPA) is particularly vulnerable, including a reduction in growth hormone (GH) and insulin-like growth factor (IGF-1). Clinical and preclinical supplementation of IGF-1 after TBI has exhibited beneficial effects. IGF-1 receptors are prominently observed in many tissues, including in the brain and in the gastrointestinal (GI) system. In addition to causing damage in the brain, TBI also induces GI system damage, including inflammation and alterations to intestinal permeability and the gut microbiome. The goal of this study was to assess the effects of systemic IGF-1 treatment in a rat model of TBI on GI outcomes. Because GI dysfunction has been linked to hippocampal dysfunction, we also examined proliferation and immature granule cells in the hippocampal dentate gyrus. 10-week-old male rats were treated with an intraperitoneal (i.p.) dose of IGF-1 at 4 and 24 h after lateral fluid percussion injury (FPI). At 3- and 35-days post-injury (DPI), gut permeability, gut dysmorphia, the fecal microbiome, and the hippocampus were assessed. FPI-induced permeability of the blood-gut-barrier, as measured by elevated gut metabolites in the blood, and this was prevented by the IGF-1 treatment. Gut dysmorphia and alterations to the microbiome were also observed after FPI and these effects were ameliorated by IGF-1, as was the increase in immature granule cells in the hippocampus. These findings suggest that IGF-1 can target gut dysfunction and damage after TBI, in addition to its role in influencing adult hippocampal neurogenesis.

Squalane as a Promising Agent Protecting UV-Induced Inhibition of Collagen Biosynthesis and Wound Healing in Human Dermal Fibroblast.

Squalane, a highly stable derivative of squalene, has received attention for its potential application in dermatology and cosmetics due to its biocompatibility, moisturizing properties, and antioxidant activity. This study investigates the effects of squalane on UVA-induced oxidative stress, inflammation, deregulation of collagen metabolism, and some growth signaling pathways in human dermal fibroblasts (HDFs). It has been found that squalane at concentrations of 0.005-0.015% counteracted the UVA-induced inhibition of oxidative stress, collagen biosynthesis, prolidase activity, expression of the β1-integrin receptor, insulin-like growth factor-I receptor (IGFR), transforming growth factor-β (TGF-β), phosphorylated kinases ERK1/2, and increase in the expression of p38 kinase in HDFs. Moreover, squalane at the studied concentrations counteracted UVA-induced increase in the expression of NF-κB and COX-2 in HDFs, suggesting its anti-inflammatory activity. Interestingly, squalane augmented the UVA-induced expression of nuclear factor erythroid 2-related factor 2 (Nrf2). The functional significance of squalane activities was found in a model of wound healing in HDFs. Squalane at the studied concentrations stimulated fibroblast migration, facilitating the repair process following exposure of the cells to UVA radiation. These results demonstrate the ability of squalane to counteract UVA-induced cell damage and suggest its potential to support skin regeneration, highlighting its application in anti-aging, post-sun repair, and regenerative care formulations.

Increased Risk of Cancer-An Integral Component of the Cardio-Renal-Metabolic Disease Cluster and Its Management.

Cancer risk increases by 25 to 250% not only in dysmetabolic obese or overweight people with overt type 2 diabetes but also in individuals with intermediate hyperglycemia (pre-diabetes), with especially pronounced risk of pancreatic or hepatocellular cancer and obesity-related cancers, e.g., colorectal and kidney cancers, bladder cancer in men, and endometrial and breast cancers in women. Cancer may often be present before or upon the diagnosis of diabetes, as there is a common pathogenetic dysmetabolic-inflammatory background with insulin resistance for developing diabetes, cardiorenal disease, and cancer in parallel. The mechanisms involved relate to hyperinsulinemia as a potential carcinogenic priming event with ectopic visceral, hepatic, pancreatic, or renal fat accumulation that subsequently fuel inflammation and lipo-oncogenic signals, causing mitochondrial oxidative stress and deregulation. Moreover, hyperinsulinemia may foster mitogenic MAP kinase-related signaling, which can also occur via IGF1 receptors due to increased free IGF1 levels in obesity. Weight reduction of 10% or more in obese people with diabetes or pre-diabetes, e.g., through intensive lifestyle intervention or bariatric (=metabolic) surgery or through treatment with GLP-1 receptor agonists or metformin, is associated with significantly lower incidence of "diabesity"-associated cancers. In conclusion, there seems to be huge utility in adopting the new "Cardio-Renal-Metabolic-Cancer Syndrome" approach, also looking for cancer at the time of diabetes diagnosis in addition to proactively screening for undiagnosed dysglycemia.

Genetic determinants and clinical significance of circulating and tumor-specific levels of insulin-like growth factor binding protein 7 (IGFBP7) in a Swedish breast cancer cohort

Previous research indicates that insulin-like growth factor binding protein 7 (IGFBP7) protein levels in breast cancer tissue and blood are prognostic. However, genetic determinants of IGFBP7 in breast cancer remain largely unexplored. We examined IGFBP7 in a cohort of 1701 patients with first breast cancer from Sweden, enrolled prior to surgery 2002–16 and followed for up to 15 years. Genotyping was performed on blood samples using OncoArray. Tumor-specific protein levels of IGFBP7, insulin receptor (InsR), and IGF-I receptor (IGFIR) were assessed on tumor tissue microarrays in 964 patients. Furthermore, 275 patients had plasma IGFBP7 levels measured. A genetic proxy marker for circulating IGFBP7 levels was constructed from five candidate single-nucleotide polymorphisms (SNPs) (rs6852762, rs1714014, rs9992658, rs10004910, and rs4865180) based on number of recessive genotypes. Age-adjusted linear regression was used to evaluate SNPs and tumor-specific IGFBP7 levels in relation to circulating IGFBP7 levels. Cox regression adjusted for age, tumor characteristics, and adjuvant treatments was used to assess associations with clinical outcomes. Circulating and tumor-specific IGFBP7 levels were significantly positively correlated. High circulating and genetically predicted IGFBP7 levels were associated with increased risk for distant metastasis and all-cause mortality. A significant interaction between high tumor-specific IGFBP7 levels and membrane-bound InsR resulted in a four-fold increased risk of breast cancer events and distant metastases. Both measured and genetically predicted IGFBP7 levels were independent prognostic biomarkers in breast cancer.

Transforming Myofibroblasts Into Lipid-Filled Cells to Treat Dupuytren Disease.

Transforming Myofibroblasts Into Lipid-Filled Cells to Treat Dupuytren Disease.

Impact of Prenatal Dietary Soy on Cerebellar Neurodevelopment and Function in Experimental Fetal Alcohol Spectrum Disorder.

Background: Prenatal alcohol exposure (PAE) models can cause neurodevelopmental abnormalities like those observed in fetal alcohol spectrum disorder (FASD). Previous studies link experimental PAE effects in the brain to impaired signaling through insulin/IGF and Notch pathways that mediate neuronal survival, growth, migration, energy metabolism, and plasticity. Importantly, concurrent administration of peroxisome proliferator-activated receptor agonists or dietary soy prevented many aspects of FASD due to their insulin-sensitizing, anti-inflammatory, and antioxidant properties. Objective: To determine if dietary soy interventions during pregnancy would be sufficient to normalize central nervous system structure and function, we examined the effects of maternal gestation-limited dietary soy on cerebellar postnatal development, motor function, and critical signaling pathways. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% caloric ethanol with casein or soy isolate as the protein source. The ethanol and soy feedings were discontinued upon delivery. The offspring were subjected to rotarod motor function tests, and on postnatal day 35, they were sacrificed to harvest cerebella for histological and molecular studies. Results: Despite the postnatal cessation of alcohol exposure, chronic gestational exposure reduced brain weight, caused cerebellar hypoplasia, and impaired motor performance. Gestational dietary soy prevented the ethanol-associated reduction in brain weight and largely restored the histological integrity of the cerebellum but failed to normalize motor performance. Ethanol withdrawal abolished the impairments in insulin/IGF signaling that were previously associated with ongoing ethanol exposures, but ethanol's inhibitory effects on Notch and Wnt signaling persisted. Soy significantly increased cerebellar expression of the insulin and IGF-1 receptors and abrogated several ethanol-associated impairments in Notch and Wnt signaling. Conclusions: Although gestation-restricted dietary soy has significant positive effects on neurodevelopment, optimum prevention of FASD's long-term effects will likely require dietary soy intervention during the critical periods of postnatal development, even after alcohol exposures have ceased.

Controversies Surrounding IGF-I Receptor Involvement in Thyroid-Associated Ophthalmopathy.

Background: Thyroid-associated ophthalmopathy (TAO, aka thyroid eye disease [TED], Graves' orbitopathy) remains poorly understood and inadequately treated since its initial description. It is disfiguring, can threaten vision, and represents an autoimmune process closely associated with thyroid disease. Unambiguous connections linking TAO to the glandular maladies of Graves' disease (GD) remain incompletely clarified. Detecting the thyrotropin receptor (TSHR) in periocular tissues suggests that this cell-surface protein represents a shared autoantigen with the thyroid gland, but we now know that its expression is ubiquitous. Most patients with TAO have relatively high circulating levels of activating anti-TSHR autoantibodies. Emerging more recently is the importance of insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of TAO. The TSHR/IGF-IR signaling complex apparently drives circulating fibrocytes and the unique phenotypes of fibroblasts inhabiting the TAO orbit (GD-OF). Methods: The PubMed database was scanned for articles dating back to the earliest time periods covered. Keywords used for primary searches included thyroid-associated ophthalmopathy, Graves' orbitopathy, TED, orbit, TSH receptor, IGF-I receptor, and autoimmune thyroid disease. Secondary searches used numerous other search terms. Results: GD-OF have been characterized extensively as being particularly responsive to the immunological factors and key effectors in TAO pathogenesis. Both TSHR and IGF-IR are overexpressed by GD-OF and CD34+ fibrocytes and form a signaling complex. They are activated through this TSHR/IGF-IR complex to produce large amounts of hyaluronan and express multiple cytokines. This complex mediates cellular responses to pathogenic IgGs in TAO. CD34+ fibrocytes and CD34+ OF also express relatively high levels of multiple thyroid autoantigens. Identifying IGF-IR as a key component of a receptor complex and its intertwining signaling activities with those of TSHR has led to a targeted medical therapy for TAO. This therapy involves the selective systemic inhibition of IGF-IR. Conclusions: Much has been learned over the preceding decades about the pathogenesis of TAO. Among these is the identification of IGF-IR as a pivotal component underpinning the disease. This has led directly to development of an effective targeted therapy. Important gaps in our understanding persist, and current therapies have limitations. Thus, despite these advancements, considerably more remains to be achieved.

Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood–brain barrier

Anxiety disorder, a prevalent mental health issue, is one of the leading causes of disability worldwide. Damage to the blood–brain barrier (BBB) is implicated in anxiety, but its regulatory mechanisms remain unclear. Herein, we show that adrenomedullin 2 (ADM2), a novel angiogenic growth factor, alleviates autistic and anxiety-like behaviors in mice. Based on transcriptome analysis and biochemical analyses, we found that ADM2 facilitates the expression of insulin-like growth factor 2 (IGF-II), which then triggers the activation of the AKT-GSK3β-mTOR signaling pathway via the IGF-II receptor (IGF-IIR), rather than the IGF-I receptor (IGF-IR). Furthermore, as evidenced by increased Evans blue staining and decreased VE-cadherin levels, the BBB exhibited dysfunction in ADM2 knockout mice with anxiety-like behaviors. In in vitro studies, ADM2 administration promoted the expression of VE-cadherin and decreased IGF-II leakage through the endothelial barrier in a BBB model. Taken together, ADM2 may alleviate anxiety-like behavior and social deficits by enhancing BBB integrity and increasing IGF-II levels in the brain. These findings highlight the potential of ADM2 as a therapeutic target for anxiety and related mental disorders.

Engineering of a lysosomal-targeted GAA enzyme.

Pompe disease is a tissue glycogen disorder caused by genetic insufficiency of the GAA enzyme. GAA enzyme replacement therapies for Pompe disease have been limited by poor lysosomal trafficking of the recombinant GAA molecule through the native mannose-6-phosphate-mediated pathway. Here, we describe the successful rational engineering of a chimeric GAA enzyme that utilizes the binding affinity of a modified IGF-II moiety to its native receptor to bypass the mannose-6-phosphate-mediated lysosomal trafficking pathway, conferring a significant increase in cellular uptake of the GAA enzyme. We also demonstrate the ablation of binding between our modified IGF-II tag and two off-target receptors: IGF-I receptor and insulin receptor, as well as preserved enzymatic activity of the chimeric GAA molecule.

Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats

Insulin receptor substrate (IRS)-1 and IRS-2 are major molecules that transduce signals from insulin and insulin-like growth factor-I receptors. The physiological functions of these proteins have been intensively investigated in mice, while little is known in other animals. Our previous study showed that the disruption of IRS-2 impairs body growth but not glucose tolerance or insulin sensitivity in rats, which led us to hypothesize that IRS-1 plays more pivotal roles in insulin functions than IRS-2. Here, we created IRS-1 knockout (KO) rats to elucidate the physiological roles of IRS-1 in rats. The body weight of IRS-1 KO rats at birth was lower than that of wild-type (WT) littermates, and postnatal growth of IRS-1 KO rats was severely impaired. Compared with WT rats, IRS-1 KO rats displayed insulin resistance but maintained euglycemia because of compensatory hyperinsulinemia. In addition, despite the increased activity of insulin-stimulated IRS-2-associated phosphatidylinositol-3 kinase (PI3K), insulin-induced phosphorylation of the kinases downstream of PI3K was suppressed in the liver and skeletal muscle of IRS-1 KO rats. Taken together, these results indicate that in rats, IRS-1 is essential for normal growth and the glucose-lowering effects of insulin. IRS-1 appears to be more important than IRS-2 for insulin functions in rats.

Impact of initial postweaning feed intake on weanling piglet metabolism, gut health, and immunity.

Low feed intake (FI) in weanling pigs can be hypothesized as both a cause and consequence of intestinal disturbances and metabolic stress. We explored the associations between individual daily FI patterns, metabolic status, and intestinal physiology. Female pigs (n = 24) were selected based on high or low cumulative FI between d1 and d3 relative to weaning (d0) from 12 pens equipped with electronic feeding stations at 1-wk after weaning for dissection and sampling. Four classes of pigs were created with pigs that started with a high or low FI (d1 to d3) and continued with a high or low FI (d4 to d6) (HH, HL, LH, and LL, respectively; n = 6) for data analysis. In plasma, HL pigs showed higher plasma glutamate dehydrogenase than LL pigs (P < 0.05). A low FI d1 to d3 increased plasma creatinine and lactate dehydrogenase, and reduced insulin-like growth factor (IGF-I), gastrointestinal organ weights, and jejunal villus surface area at 1wk after weaning (P < 0.05). However, low FI d4 to d6 increased plasma haptoglobin, PigMAP, bile acids, and bilirubin levels and reduced jejunal villus length (P < 0.05). In jejunum tissue, HH pigs had the highest jejunal upregulated IGF-I receptor and a reduced local inflammatory gene expression when compared to HL pigs (MyD88), and similarly, when compared to all classes (FAXDC2). For the main effects, pigs classified as high FI d1 to d3 had upregulated immune systems including IL-6, TGFB1, TLR2, and TLR4 genes compared to low FI d1 to d3 pigs (P < 0.05). In a multivariate model, variance in average daily gain (R2 = 0.82) was mostly explained by positive correlations with FI d1 to d3, jejunal morphometrics, and plasma IGF-I, while negatively explained by histamine in digesta, and creatinine, PigMAP, triglycerides, and haptoglobin in plasma. In conclusion, pigs transitioning from high to a low FI showed distinct metabolic alterations and a subtle local inflammation masked by the vigorous local immune response in pigs with initial (d1 to d3) high FI. Pigs with an initial low FI had a fasting-like metabolic state, indicated by hepatic alterations pointing at shifting protein metabolism into energy production. Altogether, FI during the initial days postweaning significantly impacts pig growth, immunity, and metabolism, with a sustained low intake (i.e., up to 6 d) triggering a systemic inflammatory response.

Editor’s Note to: “Inhibition of Death-Receptor Mediated Apoptosis in Human Adipocytes by the Insulin-Like Growth Factor I (IGF-I)/IGF-I Receptor Autocrine Circuit”

Editor’s Note to: “Inhibition of Death-Receptor Mediated Apoptosis in Human Adipocytes by the Insulin-Like Growth Factor I (IGF-I)/IGF-I Receptor Autocrine Circuit”

Advances of IGF-1R inhibitors in Graves' ophthalmopathy.

Graves' ophthalmopathy is the most common extra-thyroidal organ manifestation of Graves' disease. The mainstay of clinical treatment is glucocorticoids; however, side effects and relapse are common problems, and current treatment options cannot alter the disease progression. IGF-1R is an important component of the signaling pathway in Graves' ophthalmopathy, and downstream signaling of IGF-1 and IGF-1R plays a role in many immune-related diseases, possibly leading to disease occurrence through changes in immune phenotype and protein synthesis. Teprotumumab is a human monoclonal antibody targeting the insulin-like growth factor-I receptor (IGF-1R). Clinical trials have shown that teprotumumab reduces proptosis better than placebo, and may be beneficial for patients with worsening disease after steroid cessation. In this review, we discuss the role and prospects of IGF-1R inhibitors in thyroid-associated ophthalmopathy.

Paraptosis-A Distinct Pathway to Cell Death.

Cell death is a critical biological process necessary for development, tissue maintenance, and defense against diseases. To date, more than 20 forms of cell death have been identified, each defined by unique molecular pathways. Understanding these different forms of cell death is essential for investigating the pathogenesis of diseases such as cancer, neurodegenerative disorders, and autoimmune conditions and developing appropriate therapies. Paraptosis is a distinct form of regulated cell death characterized by cytoplasmic vacuolation and dilatation of cellular organelles like the mitochondria and endoplasmic reticulum (ER). It is regulated by several signaling pathways, for instance, those associated with ER stress, calcium overload, oxidative stress, and specific cascades such as insulin-like growth factor I receptor (IGF-IR) and its downstream signaling pathways comprising mitogen-activated protein kinases (MAPKs) and Jun N-terminal kinase (JNK). Paraptosis has been observed in diverse biological contexts, including development and cellular stress responses in neuronal, retinal, endothelial, and muscle cells. The induction of paraptosis is increasingly important in anticancer therapy, as it targets non-apoptotic stress responses in tumor cells, which can be utilized to induce cell death. This approach enhances treatment efficacy and addresses drug resistance, particularly in cases where cancer cells are resistant to apoptosis. Combining paraptosis-inducing agents with traditional therapies holds promise for enhancing treatment efficacy and overcoming drug resistance, suggesting a valuable strategy in anticancer therapy.

Apelin/APJ signaling in IGF-1-induced acute mitochondrial and antioxidant effects in spontaneously hypertensive rat myocardium.

IGF-1 and apelin are released in response to exercise training with beneficial effects. Previously we demonstrated that a swimming routine is effective to convert pathological into physiological cardiac hypertrophy, and that IGF-1 improves contractility and the redox state, in spontaneously hypertensive rats (SHR). Now, we hypothesize that the apelinergic pathway is involved in the cardioprotective effects of IGF-1 in the SHR. We assessed the redox state and mitochondrial effects of IGF-1 or apelin in the presence/absence of AG1024 or ML221 [pharmacological antagonists of IGF1 (IGF1R) and apelin (APJ) receptors, respectively] in SHR isolated cardiomyocytes or perfused hearts. Acute IGF-1 (10 nmol/L) significantly: -reduced H2O2 production (IGF-1:62 ± 6; control:100 ± 8.1, %), -increased the activity of superoxide dismutase (IGF-1:193 ± 17, control: 100 ± 13,%), -prevented H2O2-induced ΔΨm loss (TMREF10min/F0 min: IGF-1:0.93 ± 0.017, control: 0.72 ± 0.029), -reduced mitochondrial permeability transition pore (mPTP) opening estimated by the calcium retention capacity (nmol/mg protein, IGF-1:251 ± 34, control:112 ± 5), and -increased P-AMPK (IGF-1:129 ± 0.9, control: 100 ± 2%) and P-AKT (IGF-1:143 ± 17 control:100 ± 6, %). These effects were suppressed not only by the antagonism of IGF1R but also of APJ. Moreover, IGF-1 significantly increased APJ (IGF-1:198 ± 29 control:100 ± 15,%) and apelin mRNAs (IGF-1:251 ± 48, control:100 ± 6,%). On the other hand, an equipotent dose of exogenous apelin (50 nmol/L) emulated IGF-1 effects being cancelled by the antagonism of APJ however not by AG1024. IGF-1/IGF1R stimulates the apelinergic pathway, improving the redox balance and mitochondria status in the pathologically hypertrophied myocardium of the SHR.

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

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.