IGF-binding Protein Research Articles

Redox Biology and Insulin-like Growth Factor-Binding Protein-6: A Potential Relationship

Insulin-like growth factor-binding protein 6 (IGFBP-6) is primarily recognized for its inhibitory effects on insulin-like growth factor 2 (IGF-2), regulating processes such as cell proliferation, differentiation, and survival. However, recent studies have revealed that IGFBP-6 also participates in a range of IGF-independent activities, notably in redox biology, immune regulation, and fibrosis. These IGF-independent actions involve interactions with redox-sensitive signaling pathways that influence mitochondrial metabolism, neutrophil function, and fibroblast activity, all of which are central to redox-dependent processes in inflammation and fibrosis. Despite these insights, the precise mechanisms by which IGFBP-6 modulates redox signaling remain largely unexplored. This review examines the growing understanding of IGFBP-6 beyond its classical role as an IGF-binding protein, with a focus on its involvement in redox homeostasis. By exploring these emerging roles, we aim to elucidate how IGFBP-6 contributes to redox homeostasis and to assess its potential as a therapeutic target in oxidative stress-related diseases, including fibrosis, cancer, and immune dysfunction.

Humans with obesity exhibit impaired circulating total, but not free, IGF-1 response to acute endurance exercise.

We investigated how obesity impacts the response of circulating insulin-like growth factor-1 (IGF-1) to a single bout of endurance exercise in humans with and without obesity. Blood samples were collected before exercise, at 15 and 40 min during a 45-min cycling session at 65% of heart rate reserve, and 15 min post-exercise. Serum levels of total IGF-1, free IGF-1, IGF binding proteins 1 (IGFBP-1) and 3 (IGFBP-3), growth hormone, and insulin were measured. Both total IGF-1 and IGFBP-3 serum concentrations increased significantly (p < 0.05) during exercise in the study participants without obesity but not in those with obesity, returning to basal levels immediately after exercise. There was a statistically significant main effect on the growth hormone response, with circulating levels being higher in participants without obesity (p < 0.05). No significant effects were observed for either free IGF-1 or IGFBP-1 serum concentrations in response to exercise in either group (p > 0.05). We conclude that humans with obesity have blunted serum total IGF-1 response during exercise. However, a concurrent attenuation in serum IGFBP-3 response, which regulates free (i.e., biologically active) IGF-1 in circulation, results in no change in circulating free IGF-1 levels during endurance exercise in individuals with obesity.

The role of IGF-2 and its variants in enhancing endothelial migration and angiogenesis

IntroductionAngiogenesis, the formation of new blood vessels, is essential for physiological processes such as tissue repair as well as pathological conditions including cancer. While insulin-like growth factor 2 (IGF-2) is identified as a key regulator of angiogenesis, the contributions of its variants remain less explored.MethodsWe compared the effects of wildtype IGF-2 with that of Des(1-6)IGF-2, which has lower affinity to IGF-binding proteins (IGFBPs), and Leu27IGF2, which interacts selectively with the IGF-Receptor 2. We analyzed their effect on endothelial cell migration and tube formation as well as on the secretome of endothelial cells using an antibody array. In addition, the regulatory influence of IGF-binding protein 6 (IGFBP-6) in modulating these effects was investigated. Finally, the ability of the three different variants of IGF-2 to induce blood vessel formation was studied using the chicken ‘chorioallantoic membrane’ (CAM) assay.ResultsIGF-2 and Des(1-6)IGF-2 significantly promoted endothelial cell migration and tube formation in vitro, while also increasing blood vessel formation in ovo. An angiogenesis antibody array revealed that these effects were mediated through the upregulation of several angiogenic proteins, including IL-6, uPAR, and MCP-1. Interestingly, Leu27IGF-2 exhibited a weaker effect, suggesting that IGF receptor 1 and/or insulin receptor activation plays a major role in these processes. IGFBP-6 effectively inhibits IGF-2-induced effects but has no impact on Des(1-6)IGF-2, highlighting the latter’s ability to evade IGFBP-mediated inhibition due to structural modifications.ConclusionThese results suggest that Des(1-6)IGF-2 may serve as a potent pro-angiogenic agent with therapeutic potential, while IGFBP-6 could offer a strategy for suppressing pathological angiogenesis.

Predictive Effect of IGFBP-3 on Low-Dose Tamoxifen Efficacy in Noninvasive Breast Cancer in the Phase III Tam-01 Trial.

Low-dose tamoxifen 5 mg/day (babytam) for 3 years can decrease the incidence of new breast cancer events in women with breast intraepithelial neoplasia by 42% with limited toxicity, which provides a new treatment option for these disorders. However, predictive biomarkers of babytam efficacy are lacking. We studied whether baseline levels of insulin-like growth factor-1 (IGF-I), IGF-binding protein-3 (IGFBP-3), estradiol, and sex hormone-binding globulin (SHBG) and their ratios predict babytam efficacy on breast cancer events in a preplanned secondary analysis. Within a 1:1 placebo-controlled, multicenter randomized trial of babytam or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ, 406 of 500 participants consented to blood sampling at baseline and at 1 and 3 years. Serum IGF-I, IGFBP-3, estradiol, and SHBG levels and their ratios were measured using chemiluminescent immunoassays. Biomarker changes were estimated using mixed-effects models, and incidence rate ratios were calculated after 10 years of follow-up with Poisson regression. Subgroup analyses were performed using an interaction test and subpopulation treatment effect pattern plot. Baseline levels of IGFBP-3 in the three top quartiles (≥3.44 µg/mL), but not in the lower quartile, predicted greater babytam efficacy compared with placebo (Pinteraction = 0.006). Baseline IGF-I, estradiol, or SHBG levels were not predictive of babytam efficacy, whereas the IGF-I/IGFBP-3 ratio was borderline significant (Pinteraction = 0.067). High baseline levels of IGFBP-3 (≥3.44 µg/mL) predicted babytam efficacy and may help differentiate which women benefit most from this treatment.

IGF-Binding Protein 7 and Cadmium-Induced Hepatorenal Fibrosis.

Chronic cadmium exposure can induce the onset and progression of hepatorenal fibrosis; however, its molecular basis is unclear. Insulin-like growth factor-binding protein 7 (IGFBP7) is not only a biomarker of acute kidney injury (AKI), but also plays a functional role in promoting kidney injury and inflammation. Abnormal repair of AKI causes kidney fibrosis and chronic kidney disease. IGFBP7 has also been reported as a more sensitive biomarker for liver fibrosis. However, its role in hepatorenal fibrosis requires further investigation. IGFBP7 global and conditional knockout mice were used to determine the role of IGFBP7 in cadmium-induced hepatorenal fibrosis. Then, liquid chromatography-mass spectrometry, truncated mutants, co-immunoprecipitation, and microscale thermophoresis were employed to unravel the downstream mechanisms. IGFBP7 expression was significantly elevated in kidney and liver tissues of mice subjected to chronic cadmium exposure. IGFBP7 deficiency attenuated cadmium-induced hepatorenal dysfunction and fibrosis, whereas restoration of IGFBP7 expression in IGFBP7-deficient mice reproduced hepatorenal fibrosis. Mechanistically, IGFBP7 interacted with alpha-enolase (ENO1) and inhibited its ubiquitination and degradation. Upregulated ENO1 further promoted glucose metabolic reprogramming and lactate accumulation. Conversely, lactate accumulation enhanced IGFBP7 transcription and expression through histone H3K18 lactylation. Importantly, therapy targeting IGFBP7 significantly ameliorated cadmium-induced hepatorenal fibrosis. IGFBP7 promoted cadmium-induced hepatorenal fibrosis by enhancing ENO1-driven abnormal glycolysis and lactate accumulation.

Associations of circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 with the expression of stem cell markers in benign breast tissue

Abstract Background The insulin-like growth factor (IGF) pathway is implicated in a naturally occurring process of tissue remodeling during which cells acquire stem cell-like characteristics. We examined associations of circulating IGF-1 and IGF binding protein-3 (IGFBP-3) with expression of CD44, CD24, and ALDH1A1 stem cell markers in benign breast biopsies. Methods This study included 151 cancer-free women with incident biopsy-confirmed benign breast disease and blood samples within the Nurses’ Health Study II. The data on reproductive and other BCa risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was done on tissue microarrays. For each core, the IHC expression was assessed using QuPath, and expressed as % of cells that stain positively for a specific marker out of the total cell count. Generalized linear regression was used to examine the associations of plasma IGF-I and IGFBP-3 (continuous log-transformed and quartiles) with log-transformed expression of each marker (in epithelium and stroma), adjusted for BCa risk factors. Results In multivariate analysis, continuous circulating IGF-1 and IGFBP-3 measures were not associated with the continuous expression of any of the markers in the epithelium or stroma. Women whose IGFBP-3 levels were in the top quartile appeared to have lower expression of stromal CD24 compared to those in the lowest quartile (β = − 0.38, 95% CI − 0.69, − 0.08, p-trend = 0.06). Conclusions Higher circulating IGFBP-3 levels were associated with lower stromal CD24 expression in benign breast tissue. Our findings provide indirect evidence of the inducing effect of IGF pathway on epithelial-to-mesenchymal transitions and stem cell activity in the breast.

Associations between Serum Insulin-Like Growth Factor-Related Molecules and Colorectal Cancer Risk by Tumor Location: A Nested Case-Control Study

Introduction: The activity of the mitogen insulin-like growth factor (IGF) is controlled by IGF-binding protein (IGFBP). Colorectal cancers (CRCs) are heterogeneous, with left- and right-sided CRCs, showing different clinical and molecular characteristics. This case-control study, nested in the Japan Collaborative Cohort study, assessed associations between serum levels of IGF-related molecules and incidences of CRC by location. Methods: A baseline survey obtained serum samples from 39,242 participants. Subjects diagnosed with CRC during follow-up were regarded as cases. Conditional logistic regression modeling was used to calculate odds ratios (ORs) for cancer incidence associated with IGF-related molecules. Results: This analysis included 176 cases and 524 controls. No IGF-related molecules appeared associated with risks of overall or left-sided CRC. Both total IGFBP3 and free IGFBP3 (estimated as IGFBP3 – [IGF1 + IGF2]) were associated with incidence of right-sided CRC (p for trends = 0.027 and 0.003, respectively), with the third tertile of total and free IGFBP3 showing the highest risk (OR = 6.25 and 7.96, respectively). Free IGF, estimated as (IGF1 + IGF2)/IGFBP3, was inversely associated with incidence of right-sided CRC (p for trends = 0.014), with the third tertile showing the lowest risk (OR = 0.18). Among subjects followed for over 3 years, the association of IGF-related molecules with overall CRC was similar. Free IGFBP3 was associated with the incidence of right-sided CRC (p for trends = 0.004). Free IGF was inversely associated with the incidence of right-sided CRC (p for trends = 0.002). However, free IGFs were associated with a risk of left-sided CRC (p for trends = 0.041), with the third tertile showing the highest risk (OR = 3.10). Conclusions: Serum IGF-related molecules are associated with the risk of CRC. These associations might differ by tumor location.

Targeted proteomics of serum IGF-I, -II, IGFBP-2, -3, -4, -5, -6 and ALS.

The insulin-like growth factors (IGFs) regulate growth in humans. IGF-I and IGF binding protein (IGFBP)-3 are biomarkers in children with growth disorders. We investigate a targeted proteomics method for absolute quantitation of eight IGF protein family members in human serum, including the peptide hormones IGF-I and -II, and the six binding proteins IGFBP-2, -3, -4, -5, -6 and acid labile subunit (ALS). Serum preparation was optimized for targeted proteomics of IGF related proteins on a clinical LC-MS/MS platform (UHPLC coupled with Triple-Q MS). We created quality controls, standards and internal standards and 289 serum samples from healthy children and adolescents were measured in ten batches over two months. The method was compared to WHO reference standards, clinical and research immunoassays, and relative proteomics profiling. The sensitivity and reproducibility were sufficient for most but not all IGF protein family members. Targeted proteomics correlated well with clinical immunoassays forIGF-I (R2=0.88) and for IGFBP-3 (R2=0.46), (p<0.001). The correlation between targeted proteomics and non-clinical immunoassays for IGF-II, IGFBP-2, -4, -5, -6 and ALS varied between proteins. We present a method for parallel quantification of IGF-I, IGFBP-3, 5 and ALS for clinical verification studies, whereas targeted proteomics of the five remaining IGF related proteins (IGF-II, IGFBP-2, -4, and -6) require further examination. The sensitivity of our new IGF-I method suggests a possible diagnostic role for targeted proteomics of IGF-I in the management of children with extremely low levels of circulating IGF-I.

Expanded Hemodialysis with Theranova Dialyzer and Residual Kidney Function in Patients Starting Long-Term Hemodialysis: A Randomized Controlled Trial.

Expanded hemodialysis using a medium cutoff dialyzer improves the clearance of middle-molecular toxins compared with conventional hemodialysis. This study evaluated the effect of expanded hemodialysis on preserving residual kidney function in patients starting treatment with long-term hemodialysis. Patients who initiated long-term hemodialysis were randomized to receive dialysis with either a Theranova 400 (Baxter) or a high-flux dialyzer with a similar surface area over 12 months. The primary outcome was a change in GFR over 12 months, as determined by the mean of urea and creatinine clearance. The secondary outcome was a change in 24-hour urine volume, middle molecules, and kidney injury markers. A total of 80 patients on hemodialysis (mean age [SD]: 63 [12] years; male: 52 [65%]) underwent randomization. Over 12 months, the Theranova group demonstrated a significantly smaller decrease in GFR than the high-flux group (least squares mean difference of change [95% confidence interval], −1.4 [−2.4 to −0.5] ml/min per 1.73 m2). Theranova maintained greater 24-hour urine volume until 9 months, not at 12 months, compared with the high-flux dialyzer. The reduction ratio for κ/λ free light chains, TNF-α, and growth differentiation factor-15 was higher in the Theranova group than in the high-flux group. The increase in the kidney injury marker, IGF-binding protein 7, was attenuated in the Theranova group. Hospitalization rate and mortality did not differ between the two groups. This trial suggests that expanded hemodialysis using the Theranova dialyzer slowed decline in residual kidney function compared with a high-flux dialyzer in patients starting treatment with long-term hemodialysis.

In situ Detection of Insulin-Like Growth Factor-1, Insulin-Like Growth Factor-Binding Protein-3, and Leptin in Human Placental and Immature Fetus Tissues

Background: Gestational hypertension (HTN) can impair fetal growth and development. The purpose of this study was to look at the histological changes and level of expression of insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3), and leptin in placental and fetal tissue from women with pregnancy HTN. Methods: Collection of tissue biopsy samples was from 60 women and divided into four groups: placenta-positive control (normal birth), placenta-negative control (a prior abortion), placenta and fetus (from dilation and curettage procedures), and miscarried placentas and fetuses from pregnancies exacerbated by high pressure. Histological and immunohistochemical markers for IGF-1, IGFBP-3, and leptin were done. Results: Women with gestational HTN had significant tissue alterations in their placentas, including increasing blood vessel thickness, fibrinoid exudate, chorangiosis, villus hypovascularization, and stromal fibrinoid necrosis. Immunohistochemical examination demonstrated a significant link between HTN and increased expression of IGF-1, IGFBP-3, and leptin, with greater expression in the HTN group than in the control group. Conclusion: Pregnancy HTN causes histological changes in the placenta, which may lead to poor fetal outcomes. The abnormal regulation of IGF-1, IGFBP-3, and leptin in the placenta and fetal tissues of women with HTN implies that these development factors may play a role in predicting and controlling high blood pressure-related births.

Cortisol reduces insulin-like growth factor-1 (Igf1) and alters liver Igf binding protein (Igfbp) and muscle myogenic gene expression in blue rockfish (Sebastes mystinus)

Cortisol reduces insulin-like growth factor-1 (Igf1) and alters liver Igf binding protein (Igfbp) and muscle myogenic gene expression in blue rockfish (Sebastes mystinus)

Role of Insulin-Like Growth Factor-1 and Adiponectin in The Association between Dietary Intake, Physical Activity, and Metabolic Syndrome in Malayaustronesia Children and Adolescent: A Systematic Review Protocol

Background: Risk factors of metabolic syndromes develop in childhood and tacks across life, which may lead them to a higher risk of getting cardiovascular diseases and premature deaths. A healthy diet and being physically active are supposed to modify the risk of metabolic syndromes (MetS). However, those observations primarily work in adult samples and the biological mechanisms that link that behavioral factor and MetS in children and adolescents still need to be explored. Asian people are more likely to get MetS than their white counterparts, but study in Malay-Austronesia children is minimal. Objectives: This study aims to comprehensively review and appraise studies that elucidate biological factors (insulin-like growth factor-1 and adiponectin) that possibly mediate the relationship between those risk factors and MetS in Malay-Austronesia children. Methods: The search will be performed in PubMed, Scopus, Web of Science, Google Scholar, and local databases Garuda (Garba Rujukan Digital, Indonesian) and Mycite (Malaysian citation index). All prospective cohort studies that examine the association of one of the behavioral factors (dietary intakes OR physical activity) AND one of the biological factors (Insulin-like growth factor OR adiponectin) with MetS or its components in healthy children with the exposures start from the age of 1 and 12 years of age and outcomes begin from 1 year and two months until the age of 18 years old are eligible. Only literature in English and local languages from inception to 31 December 2023 that match eligibility criteria will be included. National Institute of Health tool for observational studies will be used to assess the quality of included studies. This work was registered to PROSPERO CRD42023471481. Results: The findings may shed light on how the predefined biological factors mediate those behavioural factors on MetS in children. The findings will also be published in a peer-reviewed journal. Conclusion: This review utilizes relevant databases to optimize the searching of eligible studies. Eligible studies will be extracted by more (four) researchers who work independently with a predefined data extraction template. There are possibility some studies report significant finding on IGF-1 binding protein instead of total IGF-1 or its molar ratio will challenge the statistical analysis.

High-temperature exposure during the early embryonic stage lowers core body temperature after growth via a hypothalamic Igfbp2-dependent mechanism

The mechanisms underlying individual differences in core body temperature (Tc) are unexplained by genetic factors and poorly understood. Here, we investigated whether the environmental temperature during early development affects postnatal Tc. Mouse embryos were cultured from pronuclear to blastocyst stage in either standard (37 °C) or high (38 °C) temperature, and the Tc of each grown-up adult was measured. The adult 38 °C-incubated mice showed lower Tc than the 37 °C group without changes in activity levels. In the hypothalamus of the 38 °C group, insulin-like growth factor 1 (Igf1) and IGF binding protein 2 (Igfbp2) gene expression increased. The decrease in Tc in the wild-type 38 °C group was alleviated by brain neuron-specific Igfbp2 knockout. This suggests that IGFBP2 binds to IGF-1 and, inhibits its binding to the receptor, thereby interfering with the thermogenic signaling of IGF-1. These results suggest that one of the factors determining individual postnatal Tc is the ambient temperature of embryos at an early developmental stage, which could affect epigenetic changes, such as DNA methylation, leading to alterations in the Igf1 and Igfbp2 gene expressions in adulthood.

Levels of parathyroid hormone and IGF binding protein 1 and associations with mortality and hip fractures in older women

In this study we examined the effect of simultaneously elevated levels of parathyroid hormone (PTH) (≥ 65 ng/mL) and high levels of insulin-like growth factor-binding protein 1 (IGFBP-1) on the 10-year risk of all-cause mortality and hip fractures. Blood tests for levels of PTH and IGFBP-1 was collected at baseline in 338 community-dwelling women in Stockholm aged between 69 and 79 years. Data on hip fractures and all-cause mortality over the next 10 years were retrieved from healthcare registers. The participants were divided into four groups depending on their levels of PTH and IGFBP-1: (A) normal PTH and low IGFBP-1; (B) normal PTH and high IGFBP-1; (C) elevated PTH and low IGFBP-1; (D) elevated PTH and high IGFBP-1. Group D was used as reference. Cox proportional hazard regression (HR) model was used to compare age-adjusted association with hip fractures and all-cause mortality of the four groups. The group with elevated levels of PTH and high IGFBP-1 had a two to three times higher risk of all-cause mortality compared to the other groups but we found no association with hip fractures.

Serum HIF-1α, IGF-1 and IGFBP-3 correlate to recurrence and overall survival in early-stage hepatocellular carcinoma patients.

Aim: Recurrence of hepatocellular carcinoma (HCC) after ultrasound-guided microwave ablation (UGMWA) was a critical issue. Therefore, it is significant to identify the role of hypoxia-inducible factor 1 α (HIF-1α), insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) in recurrence.Materials & methods: HCC patients receiving UGMWA were divided into recurrence and no-recurrence groups. The preoperative and postoperative risk factors were compared between these two groups.Results: Preoperative and postoperative serum levels of HIF-1α, IGF-1 and IGFBP-3 were closely associated with the recurrence of HCC. Serum HIF-1α level was increased, while serum levels of IGF-1 and IGFBP-3 were decreased in HCC patients with recurrence.Conclusion: HIF-1α, IGF-1 and IGFBP-3 were associated with and predicted the recurrence of HCC after UGMWA, respectively or in combination.

Abstract 4141892: Insulin-like growth factor binding protein 7 induces cell senescence in vitro and is associated with cell senescence in the advanced atheroma.

BACKGROUND: Cellular senescence, an irreversible cell cycle arrest, has been associated with coronary heart disease (CHD). Senescent cells (SC) secrete proinflammatory molecules contributing to CHD. Insulin-like growth factor I (IGF1) protects against developing cell senescence and atherogenesis. IGF1 binding protein 7 (BP7) binds IGF1 and also interacts with IGF1 receptor (IGF1R), suppressing intracellular IGF1 signaling. HYPOTHESIS: SC secrete BP7, and BP7 promotes cell senescence via suppression of IGF1 signaling. METHODS: Cell senescence was induced by treatment of smooth muscle cells (SMC) with Bleomycin. Cell proliferation was quantified by live cell analysis system. BP7 levels were measured by Westerns in cell lysates and conditioned medium (CM) and by immunohistochemistry in atherosclerotic pigs. BP7/IGF1R binding was quantified by proximity ligation assay (PLA). RESULTS: Bleomycin arrested SMC proliferation at 16h, upregulated senescence markers (beta-galactosidase and γH2A.X histone), and elevated BP7 levels in CM (3-fold increase, P&lt;0.05) showing that SC secrete and upregulate BP7. We obtained CM from SC and used it to treat non-senescent SMC. CM inhibited IGF1-induced Akt phosphorylation in non-senescent cells, and CM incubation with BP7 antibody reversed this effect, indicating that BP7 mediates CM inhibitory effect on IGF1 signaling. BP7 overexpression (with pCMV-IGFBP7 vector) or inhibition of IGF1R (using Ganitumab, IGF1R antibody) suppressed cell proliferation, and upregulated senescence markers. BP7 overexpression also blocked IGF1-induced cell proliferation and migration (both are P&lt;0.05) consisted with BP7 inhibitory effect on IGF1 signaling. Increased BP7 levels was detected in SMC in the fibrous cap (FC) in porcine plaque compared to BP7 level in vascular media (1.8-fold increase, P&lt;0.05). BP7 upregulation in plaque correlated with elevated PLA signal indicating increased BP7/IGF1R binding. We used spatial transcriptomics to profile gene expression in the porcine atheroma. BP7 upregulation was detected in FC cluster (P&lt;0.001) and it was co-localized with increased senescence module score. CONCLUSIONS: SC upregulate BP7 and BP7 inhibits IGF1 signaling. Upregulated BP7 induces senescence in vitro and it was associated with SC in the advanced coronary plaque. Our results suggest a novel role of BP7 in senescence and atherogenesis and identify BP7 as a potential target for anti-atherogenic therapy.

IGF2/IGFBP4 reduces apoptosis and increases free cholesterol of chicken granulosa cells in vitro

IGF2/IGFBP4 reduces apoptosis and increases free cholesterol of chicken granulosa cells in vitro

Interactions between androgen and IGF1 axes in prostate tumorigenesis.

Androgen signalling through the androgen receptor (AR)is essential for prostate tumorigenesis. However, androgen signalling pathways also interact with other growth factor-mediated signalling pathways to regulate the prostatic cell cycle, differentiation, apoptosis and proliferation in the initiation and progression of prostate cancer. Insulin-like growth factor 1 (IGF1) is one of the most prominent growth factors in prostate tumorigenesis. Clinical and experimental evidence has demonstrated that IGF1 signalling supports both androgen-dependent and androgen-independent prostate tumorigenesis, suggesting that improved understanding of the interactions between the IGF1 and androgen axes might aid the development of new therapeutic strategies. Available data have shown a dynamic role of androgen-AR signalling in the activation of IGF1-signalling pathways by augmenting transcription of the IGF1 receptor in prostatic basal epithelial cells and by increasing IGF1 secretion through the suppression of IGF-binding protein 3 expression in prostatic stromal cells. In turn, IGF1 stimulates Wnt-β-catenin signalling in prostatic basal progenitors to promote prostatic oncogenic transformation and prostate cancer development. These findings highlight the cooperative, autocrine and paracrine interactions that underlie the oncogenic effects of androgens and IGF1 and open up new opportunities for therapeutic targeting.

8015 Growth Hormone Axis Dysfunction in PMM2-CDG: Exploring the Role of Dynamic Tests for the Management of Short Stature in Two Pediatric Cases

Abstract Disclosure: G. Del Medico: None. E. Procopio: None. L. Ferri: None. A. Barbato: None. A. Morrone: None. S. Stagi: None. PMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) and is caused by defective phosphomannomutase2 (PMM2) activity. According to the 2019 guidelines, approximately half of PMM2-CDG patients exhibit short stature and low serum levels of insulin-like growth factor-1 (IGF-1), IGF binding protein 3 (IGFBP3), and acid-labile subunit (ALS). Despite this, there is no expert consensus on the endocrinological management of this condition. We investigated the growth hormone (GH) axis in two 12-year-old female patients with PMM2-CDG. The first patient was compound heterozygote for the most common PMM2 gene variants in Italy, p.(Leu32Arg) and p.(Arg141His). She presented with short stature (&amp;lt; 2 Standard Deviation Score, SDS) and low serum levels of IGF-1 and IGF-BP3 (&amp;lt; 2.5° for age and sex). Bone age was significantly delayed. Tanner stage was prepubertal. Somatotropic response to GH stimulation testing (Levodopa) was normal. After the IGF-1 generation test with recombinant GH, serum IGF-1 increased by 115%. The second patient was compound heterozygote for the known PMM2 pathogenetic variant p.(Ala108Val) and the novel p.(Thr171Asnfs*11) variant (only case described in literature). She presented short stature (&amp;lt; 2 SDS) with near-to-normal IGF-1 and IGF-BP3 serum levels (2.5° for age and sex). Bone age was slightly delayed. Tanner stage was prepubertal. She also exhibited severe obesity, hypertriglyceridemia, and hepatic steatosis. Her somatotropic response to two GH stimulation tests (Levodopa and Arginine) was deficient, probably because of her significant overweight. IGF-1 serum levels didn’t increase after the IGF-1 generation test. Hypoglycosylation in PMM2-CDG impairs the IGF1 system on multiple levels. It destabilizes the ternary complex formed by IGF-1 and glycoproteins IGFBP3 and ALS, therefore reducing the half-life of circulating IGF-1. Hypoglycosylation also reduces IGF1 production by impairing its precursor proIGF-1Ea and its cellular secretion. As a result, PMM2-CDG patients have GH insensitivity, with normal GH production but low levels of IGF-1. However, there is a lack of information in the literature on the use of dynamic tests and hormonal therapies (GH and rhIGF-1) in CDG. The IGF-1 generation test in our patients showed partial GH sensitivity in the first patient and GH insensitivity in the second patient. These observations suggest variability. Some PMM2-CDG patients may benefit from an extended trial with GH therapy, while for GH-insensitive patients a trial with recombinant IGF-1 might be considered. This is one of the first reports that explores the potential role of dynamic tests in PMM2-CDG. As the biochemical effects of hypoglycosylation on the GH-IGF1 pathway are becoming clearer more clinical research is needed to reach a consensus on the management and treatment of short stature in these patients. Presentation: 6/3/2024

6996 Optimal Growth Hormone Response Despite Low Insulin-Like Growth Factor-1: Clinical Picture of an A67T IGF-1 Variant

Abstract Disclosure: E.M. Bomberg: Research Investigator; Self; Novo Nordisk. Z. Wu: Employee; Self; Quest Diagnostics. I. Motorykin: Employee; Self; Quest Diagnostics. J. Torkelson: None. N. Schmitz: None. A. Drilling: None. M.J. McPhaul: Employee; Self; Quest Diagnostics. B.S. Miller: Advisory Board Member; Self; Abbvie, Ascendis Pharma, Biomarin, Bristol-Myers Squibb, Eton Pharmaceuticals, EMD Serono, Endo Pharmaceuticals, GenSci, Novo Nordisk, Pfizer, Inc., Provention Bio, Sanofi, Tolmar. Consulting Fee; Self; Abbvie, Ascendis Pharma, Biomarin, Bristol-Myers Squibb, Eton Pharmaceuticals, EMD Serono, Endo Pharmaceuticals, GenSci, Provention Bio, Sanofi, Tolmar. Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Abbvie, Aeterna Zentaris, Amicus, Foresee Pharmaceuticals, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Inc., Prevail Therapeutics, Sangamo Therapeutics. Research Investigator; Self; Alexion Pharmaceuticals, Inc., Abbvie, Aeterna Zentaris, Amicus, Foresee Pharmaceuticals, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Inc., Prevail Therapeutics, Sangamo Therapeutics. Speaker; Self; Biomarin, Novo Nordisk, Pfizer, Inc., Tolmar. Introduction: Insulin-like growth factor-1 (IGF-1) measurements are used for growth hormone (GH) deficiency screening and helpful in monitoring GH treatment effectiveness. However, IGF-1 variants have been reported with mass spectrometry (MS)-based assays, potentially limiting interpretation of reported results. Clinical Case: A 14-year-old male presented for short stature. Evaluation was non-revealing aside from low serum IGF-1 measured via liquid chromatography (LC)-MS assay (58 ng/mL; -3.8 standard deviation score [SDS]), and IGF-Binding Protein 3 (3.7 ug/mL; -1.7 SDS). Height was 148.2 cm (1st percentile, -2.08 SDS; mid-parental height 172.7 cm [31st percentile, -0.48 SDS]), pubertal exam Tanner stage 2, and bone age 2.5 years delayed. A GH stimulation test showed a peak GH of 8.1 ug/L; brain MRI was normal. GH was started at 0.29 mg/kg/wk. One month later, IGF-1 remained low (89 ng/mL; -3.2 SDS) and GH was increased to 0.36 mg/kg/wk, and over time to 0.52 mg/kg/wk due to persistently low IGF-1 (-2.9 to -2.3 SDS), despite reports of good compliance and significant catch-up growth (height increased to 19th percentile, -0.84 SDS). He reported no significant side effects during GH treatment. At 17.5 years old, he returned to clinic reporting self-discontinuing GH 1 month prior. Height was at the 27th percentile (171.5 cm, -0.59 SDS), he was fully pubertal, IGF-1 128 ng/mL (-3.1 SDS), and bone age 1.5 years delayed. Further review of IGF-1 linked reports accompanying lab values directly entered into the electronic health record (EHR; starting 2021) described the presence of a rare heterozygous IGF-1 functional variant with unknown clinical significance based on MS data. Concentration of the variant was expected to be identical to that reported for the wild type IGF-1 protein, potentially explaining the lower than expected values. Analysis of the raw LC-MS data (variant peak at m/z 1098.09, isotopic peak index [IP6], relative retention time [rRT]=0.00 min) was consistent with either an A67T or A70T IGF-1 variant. To resolve this ambiguity, the specimen was reanalyzed with an LC-tandem MS/MS fragmentation method, which identified distinguishing peaks at m/z 503.28 (y5 ion) and 305.18 (y3 ion) characteristic of A67T, a known benign variant. Conclusions: Benign IGF-1 variants should be considered in cases of unexplained low IGF-1 levels, including when these remain low despite increasing GH doses, good adherence, and optimal growth velocity. Presence of IGF-1 variants should not affect GH stimulation results (e.g., GH levels), however, may lower reported IGF-1 levels used to determine need for diagnostic testing and followed when monitoring GH response. Careful review of IGF-1 lab reports and full abstraction of these into the EHR should be performed. Knowing a variant is benign could help providers set lower wild-type IGF-1 targets when monitoring GH response to avoid unnecessarily high GH doses. Presentation: 6/3/2024