Insulin-like Growth Factor Binding Protein-3 Research Articles

Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor-Binding Protein 7 Enhanced Risk Prediction for Initiation of Renal Replacement Therapy in Postoperative Patients with Acute Kidney Injury: A Prospective Cohort Study

Abstract Introduction: The current study is to identify the performance of urinary tissue inhibitors of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) for predicting renal replacement therapy (RRT) initiation and mortality in postoperative acute kidney injury (AKI) patients. Methods: Postoperative AKI patients were prospectively and consecutively enrolled. The biomarkers of urinary TIMP-2 and IGFBP7 were detected at the time AKI diagnosed (day 0) and 24 h later (day 1). The primary endpoint was the initiation of RRT, and the secondary endpoint was 30-day mortality. The receiver operating characteristic (ROC) curve was used to assess the performance of biomarkers for the prediction of RRT requirement. Results: There were 220 AKI patients enrolled in this study. Among the 220 patients, 33 (15.0%) initiated RRT during intensive care units period. Urinary (TIMP-2) × (IGFBP7), TIMP-2 and IGFBP7 on day 1 had fair performance for predict RRT initiation, the predictive area under the ROC curve (AUC) were 0.792 (0.732, 0.843), 0.784 (0.724, 0.837), and 0.770 (0.709, 0.824), respectively, with no significant difference. When they combined with clinically independent risk factors (nonrenal sequential organ failure assessment score, duration of surgery procedure, and serum creatinine at the time of AKI diagnosed) to construct predictive models for predicting RRT. The AUCs were greatly improved to be good. The best AUC was achieved by TIMP-2, which was 0.866 (0.814, 0.908). All of the biomarkers performed poor predictive values for predicting 30-day mortality. Conclusion: Urine concentrations of (TIMP-2) × (IGFBP7), TIMP-2 alone, and IGFBP7 alone on AKI day 1 show fair value for prediction of RRT initiation. However, they fail to predict 30-day mortality.

Insulin-like growth factor-binding protein-7 (IGFBP7) links senescence to heart failure

Heart failure (HF) is a rising global cardiovascular epidemic driven by aging and chronic inflammation. As elderly populations continue to increase, precision treatments for age-related cardiac decline are urgently needed. Here we report that cardiac and blood expression of IGFBP7 is robustly increased in patients with chronic HF and in an HF mouse model. In a pressure overload mouse HF model, Igfbp7 deficiency attenuated cardiac dysfunction by reducing cardiac inflammatory injury, tissue fibrosis and cellular senescence. IGFBP7 promoted cardiac senescence by stimulating IGF-1R/IRS/AKT-dependent suppression of FOXO3a, preventing DNA repair and reactive oxygen species (ROS) detoxification, thereby accelerating the progression of HF. In vivo, AAV9-shRNA-mediated cardiac myocyte Igfbp7 knockdown indicated that myocardial IGFBP7 directly regulates pathological cardiac remodeling. Moreover, antibody-mediated IGFBP7 neutralization in vivo reversed IGFBP7-induced suppression of FOXO3a, restored DNA repair and ROS detoxification signals and attenuated pressure-overload-induced HF in mice. Consequently, selectively targeting IGFBP7-regulated senescence pathways may have broad therapeutic potential for HF.

Protein-to-protein interaction of genes responsible for the economic trait of Madura Cattle: an in silico analysis

Our previous study found five genes consist of Insulin-like growth factor-1 (IGF-1), Growth hormone (GH1), Growth hormone receptor (GHR), Myostatin (MSTN), and Leptin (LEP) are responsible for the economic traits of Madura Cattle. This paper aimed to identify the protein-to-protein interaction of genes responsible for the economic traits of Madura Cattle. In silico study was done using STRING v.11.5 with Bos taurus IGF1, GH1, GHR, MSTN, and LEP as input analysis. Results show 24 biological processes, 3 molecular functions, and 6 KEGG pathways as potential protein interactions between genes. All genes are involved in six biological processes i.e. response to the hormone, response to oxygen-containing compound, cell surface receptor signalling pathway, regulation of signal transduction, positive regulation of the cellular metabolic process, and positive regulation of the macromolecule metabolic process. Five genes were predicted as functional partner genes, namely Leptin receptor (LEPR), Tyrosine-protein kinase receptor (INSR), Activin receptor type-2b precursor (ACVR2B), Insulin-like growth factor 1 receptor (IGF1R), and Insulin-like growth factor-binding protein 3 (IGFBP3). Based on the results, we can demonstrate the protein-to-protein interaction of IGF-1, GH, GHR, MSTN, and LEP genes which are potentially related to each other. Further experimental study is required to validate the interaction.

Ethanol alters the relationship between IGF-1 and bone turnover in male macaques.

Insulin-like growth factor 1 (IGF-1) influences bone turnover. Transient decreases in IGF-I levels and/or bioavailability may contribute to the detrimental effects of alcohol on bone. The goals of this non-human primate study were to i) evaluate the 20-h response of bone turnover markers to ethanol consumption and ii) assess how ethanol consumption influences the relationship between IGF-1 and these markers. Osteocalcin (bone formation), carboxyterminal cross-linking telopeptide of type 1 collagen (CTX, bone resorption), IGF-1, and IGF binding protein 1 (IGFBP-1) were measured in plasma from male rhesus macaques (N = 10, 8.4 ± 0.3 years) obtained at 12:00, 16:00, and 06:00 h during two phases: pre-ethanol (alcohol-naïve) and ethanol access. During the ethanol access phase, monkeys consumed 1.5 g/kg/day ethanol (4% w/v) beginning at 10:00 h. Osteocalcin and CTX were lower, and the ratio of osteocalcin to CTX was higher at each time point during ethanol access compared to the pre-ethanol phase. Pre-ethanol marker levels did not vary across time points, but markers varied during ethanol access. IGF-1 levels, but not IGFBP-1 levels, varied during the pre-ethanol phase. In contrast, IGF-1 levels were stable during ethanol access but IGFBP-1 levels varied. There were positive relationships between IGF-1 and turnover markers during the pre-ethanol phase, but not during ethanol access. In conclusion, chronic ethanol consumption reduces levels of bone turnover markers and blocks the normal positive relationship between IGF-1 and turnover markers and alters the normal relationship between IGF-1 and IGFBP-1. These findings support the hypothesis that chronic alcohol consumption leads to growth hormone/IGF-1 resistance.

Insulin-like Growth Factor Binding Protein 3 Increases Mouse Preimplantation Embryo Cleavage Rate by Activation of IGF1R and EGFR Independent of IGF1 Signalling

The viability of embryos cultured in vitro is poor compared to those that develop in vivo. The lack of maternally derived growth factors in vitro may contribute to this problem. Insulin-like growth factor binding protein 3 (IGFBP3) is one such growth factor that has been identified in the maternal reproductive system. This study examined the role of autocrine and exogenous IGFBP3 in mouse preimplantation embryos. Embryos expressed IGFBP3 across all stages of preimplantation development, and addition of exogenous IGFBP3 to embryo culture media increased the rate of development to the 2-, 4-, 5-, and 8-cell stages. Addition of inhibitors of the IGF1 and EGF receptors prevented this IGFBP3-mediated improvement in developmental rate, but the effect was not cumulative, indicating that both receptors are transactivated downstream of IGFBP3 as part of the same signalling pathway. Acute exposure to IGFBP3 increased phosphorylation of Akt and rps6 in 4-8 cell embryos, suggesting activation of the PI3-kinase/Akt pathway downstream of the IGF1 and EGFR receptors to promote cell proliferation and survival. In conclusion, addition of IGFBP3 to embryo culture media increases early cleavage rates independent of IGF1 signalling and therefore, IGFBP3 addition to IVF culture media should be considered.

Hepatic Oleate Regulates Insulin-like Growth Factor-Binding Protein 1 Partially through the mTORC1-FGF21 Axis during High-Carbohydrate Feeding.

Stearoyl-CoA desaturase-1 (SCD1) catalyzes the rate-liming step of monounsaturated fatty acid biosynthesis and is a key regulator of systemic glucose metabolism. Mice harboring either a global (GKO) or liver-specific deletion (LKO) of Scd1 display enhanced insulin signaling and whole-body glucose uptake. Additionally, GKO and LKO mice are protected from high-carbohydrate diet-induced obesity. Given that high-carbohydrate diets can lead to chronic metabolic diseases such as obesity, diabetes, and hepatic steatosis, it is critical to understand how Scd1 deficiency confers metabolically beneficial phenotypes. Here we show that insulin-like growth factor-binding protein 1 (IGFBP1), a hepatokine that has been reported to enhance insulin signaling, is significantly elevated in the liver and plasma of GKO and LKO mice fed a low-fat high-carbohydrate diet. We also observed that the expression of hepatic Igfbp1 is regulated by oleic acid (18:1n9), a product of SCD1, through the mTORC1-FGF21 axis both in vivo and in vitro.

Circadian gene Rev-erbα influenced by sleep conduces to pregnancy by promoting endometrial decidualization via IL-6-PR-C/EBPβ axis

BackgroundSleep disturbance can cause adverse pregnancy outcomes by changing circadian gene expression. The potential mechanisms remain unclear. Decidualization is critical for the establishment and maintenance of normal pregnancy, which can be regulated by circadian genes. Whether Rev-erbα, a critical circadian gene, affects early pregnancy outcome by regulating decidualization needs to be explored.MethodsQPCR, western blot and artificial decidualization mouse model were used to confirm the effect of sleep disturbance on Rev-erbα expression and decidualization. The regulatory mechanism of Rev-erbα on decidualization was assessed using QPCR, western blot, RNA-Seq, and Chip-PCR. Finally, sleep disturbance mouse model was used to investigate the effect of therapeutic methods targeting Rev-erbα and interleukin 6 (IL-6) on improving adverse pregnancy outcomes induced by sleep disturbance.ResultsDysregulation of circadian rhythm due to sleep disturbance displayed abnormal expression profile of circadian genes in uterine including decreased level of Rev-erbα, accompanied by defective decidualization. Rev-erbα could regulate decidualization by directly repressing IL-6, which reduced the expression of CCAAT/enhancer-binding protein β (C/EBPβ) and its target insulin-like growth factor binding protein 1 (IGFBP1), the marker of decidualization, by inhibiting progesterone receptors (PR) expression. Moreover, deficient decidualization, higher abortion rate and lower implantation number were exhibited in the mouse models with sleep disturbance compared with those in normal mouse. Pharmacological activation of Rev-erbα or neutralization of IL-6 alleviated the adverse effect of sleep disturbance on pregnancy outcomes.ConclusionsTaken together, Rev-erbα regulated decidualization via IL-6-PR-C/EBPβ axis and might be a connector between sleep and pregnancy outcome. Therapies targeting Rev-erbα and IL-6 might help improving adverse pregnancy outcomes induced by sleep disturbance.

Serum insulin-like growth factor binding protein 3 as a promising diagnostic and prognostic biomarker in esophagogastric junction adenocarcinoma

BackgroundEsophagogastric junction adenocarcinoma (EJA) lacks serum biomarkers to assist in diagnosis and prognosis. Here, we aimed to evaluate the diagnostic and prognostic value of serum insulin-like growth factor binding protein 3 (IGFBP3) in EJA patients.Methods320 participants were recruited from November 2016 to January 2020, who were randomly divided into a training cohort (112 normal controls and 102 EJA patients including 24 early-stage patients) and a validation cohort (56 normal controls and 50 EJA patients including 12 early-stage patients). We used receiver operating characteristics curve (ROC) to evaluate diagnostic value. The predictive performance of the nomogram was evaluated by the concordance index (C-index).ResultsSerum IGFBP3 levels were significantly lower in early-stage EJA or EJA patients than those in controls (P < 0.01). Measurement of serum IGFBP3 demonstrated an area under curve of 0.819, specificity 90.18% and sensitivity 43.14% in training cohort. Similar results were observed in validation cohort (0.804, 87.50%, 42.00%). Importantly, serum IGFBP3 had a satisfactory diagnostic value for early-stage EJA (0.822, 90.18%, 45.83% and 0.811, 84.48%, 50.00% in training and validation cohorts, respectively). Furthermore, survival analysis demonstrated that lower serum IGFBP3 level was related to poor prognosis (P < 0.05). Cox multivariate analysis revealed that serum IGFBP3 was an independent prognostic factor (HR = 0.468, P = 0.005). Compared with TNM stage, a nomogram based on serum IGFBP3, tumor size and TNM stage indicated an improved C-index in prognostic prediction (0.625 vs. 0.735, P = 0.001).ConclusionsWe found that serum IGFBP3 was a potential diagnostic and prognostic marker of EJA. Meanwhile, the nomogram might predict the prognosis of EJA more accurately and efficiently.

Associations of GHR, IGF-1 and IGFBP-3 expression in adipose tissue cells with obesity-related alterations in corresponding circulating levels and adipose tissue function in children

Components of the growth hormone (GH) axis, such as insulin-like growth factor-1 (IGF-1), IGF-1 binding protein-3 (IGFBP-3), GH receptor (GHR) and GH-binding protein (GHBP) regulate growth and metabolic pathways. Using our Leipzig Adipose Tissue (AT) Childhood Cohort and Leipzig Atherobesity Childhood Cohort (n=306), we asked if serum levels of these factors are altered with overweight/obesity and if this is related to gene expression of these factors in AT cells and/or increased fat mass in childhood obesity. Furthermore, we hypothesized that gene expression of GHR, IGF-1 and IGFBP-3 in AT is associated with overweight/obesity and AT function in children. Serum GHBP levels were increased in children with overweight/obesity throughout childhood, while for IGF-1 levels and the IGF-1/IGFBP-3 molar ratio this obesity-related elevation was only detectable until early puberty. Circulating levels did not correlate with gene expression of these factors in AT cells, which was decreased with overweight/obesity. Independent from body mass index, gene expression of GHR, IGF-1 and IGFBP-3 in AT cells was related to parameters of AT dysfunction, such as adipocyte hypertrophy, and increased insulin levels. Serum GHBP was associated with the percentage of liver fat and transaminase levels. We conclude that the obesity-related elevations in serum GHBP and IGF-1 are unlikely to be caused by increased subcutaneous AT mass and elevations in serum GHBP are more closely related to liver status in children. The diminished gene expression of these factors in AT cells with childhood obesity may contribute to early AT dysfunction and a deterioration of the metabolic state.

Insulin-like growth factor binding protein 5: Diverse roles in cancer.

Insulin-like growth factor binding proteins (IGFBPs) and the associated signaling components in the insulin-like growth factor (IGF) pathway regulate cell differentiation, proliferation, apoptosis, and adhesion. Of the IGFBPs, insulin-like growth factor binding protein 5 (IGFBP5) is the most evolutionarily conserved with a dynamic range of IGF-dependent and -independent functions, and studies on the actions of IGFBP5 in cancer have been somewhat paradoxical. In cancer, the IGFBPs respond to external stimuli to modulate disease progression and therapeutic responsiveness in a context specific manner. This review discusses the different roles of IGF signaling and IGFBP5 in disease with an emphasis on discoveries within the last twenty years, which underscore a need to clarify the IGF-independent actions of IGFBP5, the impact of its subcellular localization, the differential activities of each of the subdomains, and the response to elements of the tumor microenvironment (TME). Additionally, recent advances addressing the role of IGFBP5 in resistance to cancer therapeutics will be discussed. A better understanding of the contexts in which IGFBP5 functions will facilitate the discovery of new mechanisms of cancer progression that may lead to novel therapeutic opportunities.

Comparative accuracy of biomarkers for the prediction of hospital-acquired acute kidney injury: a systematic review and meta-analysis

BackgroundSeveral biomarkers have been proposed to predict the occurrence of acute kidney injury (AKI); however, their efficacy varies between different trials. The aim of this study was to compare the predictive performance of different candidate biomarkers for AKI.MethodsIn this systematic review, we searched PubMed, Medline, Embase, and the Cochrane Library for papers published up to August 15, 2022. We selected all studies of adults (> 18 years) that reported the predictive performance of damage biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP)), inflammatory biomarker (interleukin-18 (IL-18)), and stress biomarker (tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein-7 (TIMP-2 × IGFBP-7)) for the occurrence of AKI. We performed pairwise meta-analyses to calculate odds ratios (ORs) and 95% confidence intervals (CIs) individually. Hierarchical summary receiver operating characteristic curves (HSROCs) were used to summarize the pooled test performance, and the Grading of Recommendations, Assessment, Development and Evaluations criteria were used to appraise the quality of evidence.ResultsWe identified 242 published relevant studies from 1,803 screened abstracts, of which 110 studies with 38,725 patients were included in this meta-analysis. Urinary NGAL/creatinine (diagnostic odds ratio [DOR] 16.2, 95% CI 10.1–25.9), urinary NGAL (DOR 13.8, 95% CI 10.2–18.8), and serum NGAL (DOR 12.6, 95% CI 9.3–17.3) had the best diagnostic accuracy for the risk of AKI. In subgroup analyses, urinary NGAL, urinary NGAL/creatinine, and serum NGAL had better diagnostic accuracy for AKI than urinary IL-18 in non-critically ill patients. However, all of the biomarkers had similar diagnostic accuracy in critically ill patients. In the setting of medical and non-sepsis patients, urinary NGAL had better predictive performance than urinary IL-18, urinary L-FABP, and urinary TIMP-2 × IGFBP-7: 0.3. In the surgical patients, urinary NGAL/creatinine and urinary KIM-1 had the best diagnostic accuracy. The HSROC values of urinary NGAL/creatinine, urinary NGAL, and serum NGAL were 91.4%, 85.2%, and 84.7%, respectively.ConclusionsBiomarkers containing NGAL had the best predictive accuracy for the occurrence of AKI, regardless of whether or not the values were adjusted by urinary creatinine, and especially in medically treated patients. However, the predictive performance of urinary NGAL was limited in surgical patients, and urinary NGAL/creatinine seemed to be the most accurate biomarkers in these patients. All of the biomarkers had similar predictive performance in critically ill patients.Trial registrationCRD42020207883, October 06, 2020.

Abstract 12938: Intrathoracic Visceral Adiposity is Inversely Associated With Insulin Like Growth Factor Binding Protein 1: The Longenity Study

Introduction: Higher insulin-like growth factor binding protein 1 (IGFBP-1) level in serum has been variably associated with better insulin sensitivity and lower rates of obesity, diabetes mellitus, and atherosclerosis; suggesting that it may have a protective role in cardiometabolic aging. We hypothesized that epicardial, intrathoracic, or total thoracic adiposity (EAT, IAT, or TTA, respectively) measured on thoracic CT, were inversely associated with IGFBP-1, providing an assessment of cardiometabolic status by computed tomography (CT). Methods: Participants (n=104) were prospectively enrolled from the LonGenity study at Albert Einstein Institute of Aging. Participants were of Ashkenazi descent and ≥65 years, 53% were offspring of parents with exceptional longevity (OPEL) and 47% were offspring with usual survival (OPUS). Exclusion criteria were prior coronary artery bypass or stent, heart rate &gt; 100 beats/minute or not in sinus rhythm. Participants underwent a non-contrast gated CT. Adiposity was quantified using QFAT software (Cedars Sinai, CA). IGFBP-1 measures closest to the CT were used, ranging from 58 months before to 16 months after, with the majority within 1 year of the scan. Associations between IGFBP-1 and the adiposity were evaluated with linear regression with square-root of adiposity measures as the outcome. Each subject was weighted by the inverse of the years between CT and closest IGFBP-1 measurement. Results: IGFBP-1 levels were inversely associated with EAT (p =0.007), IAT (p = 0.003) and TTA (p = 0.003) after adjustment for age, sex, body mass index, OPEL/OPUS, diabetic medication, statin use, and high- and low-density lipoprotein levels. BMI explained 27.2% of the variation of TTA (p &lt; 0.001) and IGFBP-1 explained an additional 6% of the variation. There was no association of OPEL/OPUS status with adiposity measures. Conclusion: In conclusion, higher IGFBP-1 was associated with lower cross-sectional TTA, suggesting that IGFBP-1 may be indicative of a favorable cardiometabolic environment in aging. Future studies should evaluate the utility of IGFBP-1, epicardial and thoracic visceral adiposity as indicators of cardiometabolic disease.

CircSMARCA5 Is an Upstream Regulator of the Expression of miR-126-3p, miR-515-5p, and Their mRNA Targets, Insulin-like Growth Factor Binding Protein 2 (IGFBP2) and NRAS Proto-Oncogene, GTPase (NRAS) in Glioblastoma.

The involvement of non-coding RNAs (ncRNAs) in glioblastoma multiforme (GBM) pathogenesis and progression has been ascertained but their cross-talk within GBM cells remains elusive. We previously demonstrated the role of circSMARCA5 as a tumor suppressor (TS) in GBM. In this paper, we explore the involvement of circSMARCA5 in the control of microRNA (miRNA) expression in GBM. By using TaqMan® low-density arrays, the expression of 748 miRNAs was assayed in U87MG overexpressing circSMARCA5. Differentially expressed (DE) miRNAs were validated through single TaqMan® assays in: (i) U87MG overexpressing circSMARCA5; (ii) four additional GBM cell lines (A172; CAS-1; SNB-19; U251MG); (iii) thirty-eight GBM biopsies; (iv) twenty biopsies of unaffected brain parenchyma (UC). Validated targets of DE miRNAs were selected from the databases TarBase and miRTarbase, and the literature; their expression was inferred from the GBM TCGA dataset. Expression was assayed in U87MG overexpressing circSMARCA5, GBM cell lines, and biopsies through real-time PCR. TS miRNAs 126-3p and 515-5p were upregulated following circSMARCA5 overexpression in U87MG and their expression was positively correlated with that of circSMARCA5 (r-values = 0.49 and 0.50, p-values = 9 × 10-5 and 7 × 10-5, respectively) in GBM biopsies. Among targets, IGFBP2 (target of miR-126-3p) and NRAS (target of miR-515-5p) mRNAs were positively correlated (r-value = 0.46, p-value = 0.00027), while their expression was negatively correlated with that of circSMARCA5 (r-values = -0.58 and -0.30, p-values = 0 and 0.019, respectively), miR-126-3p (r-value = -0.36, p-value = 0.0066), and miR-515-5p (r-value = -0.34, p-value = 0.010), respectively. Our data identified a new GBM subnetwork controlled by circSMARCA5, which regulates downstream miRNAs 126-3p and 515-5p, and their mRNA targets IGFBP2 and NRAS.

Abstract 11642: Biologic Associations of the Senescence-Associated Secretory Phenotype (SASP) in Heart Failure (HF): Insights From Plasma Proteomics

Background: Cell senescence is involved in various age-related pathologies, including HF. The SASP is a characteristic secretory phenotype from senescent cells. We assessed biologic pathways associated with the SASP in human HF using a plasma proteomics approach. Methods: We measured 25 known SASP proteins among 2248 Penn HF Study (PHFS) participants using the SomaScan V4 assay. Factor analysis was used to extract the common variance among these proteins. Linear regression was used to assess the relationship of each factor to 4,746 other proteins, correcting for multiple comparisons, followed by pathway analyses. Results: Two underlying SASP factors were identified: Factor 1 was mainly represented by with matrix metallopeptidase 2, Tissue inhibitor of metalloproteinase 2 and Insulin Like Growth Factor Binding Protein 7. Factor 2 was correlated with cystatin C, Growth/differentiation factor-15 and Insulin-like Growth Factor Binding Protein-2. Both factors were associated with older age, male sex, lower BMI, higher prevalence of diabetes, higher prevalence of atrial fibrillation, lower estimated glomerular filtration rate and more advanced NYHA class. There was a lower prevalence of HF with recovered EF (as opposed to HF with reduced EF) among participants with higher levels of factor 1, but the prevalence of HF with preserved EF did not differ accordingly to levels of either factor. Factors 1 and 2 were associated with 1245 and 1509 proteins respectively. Both factors were associated with the coagulation system, complement system, acute phase response signaling, and retinoid X receptor (RXR) pathways that regulate cell metabolism ( Figure ). Conclusion: Higher levels of SASP are associated with older age, lower renal function and metabolic abnormalities in HF. Lower levels of SASP are associated with the presence of a recovered EF but not a preserved EF. Biologic pathways associated with SASP are predominantly related to inflammation and metabolic regulation.

HBP1 inhibits the development of type 2 diabetes mellitus through transcriptional activation of the IGFBP1 gene.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease that is highly prevalent worldwide and characterized by glucose and lipid metabolism disorders. However, the pathogenic mechanisms have not been fully established. Here, we found that HMG-box transcription factor 1 (HBP1) is involved in T2DM and that its deficiency in mice aggravates the features of diabetes. In addition, we undertook screening by RNA sequencing and found that HBP1 activates the transcription of the insulin-like growth factor binding protein 1 (IGFBP1) gene. Moreover, Insulin and palmitic acid reduced HBP1 protein expression and inhibited its binding to the IGFBP1 promoter. Furthermore, HBP1 reduced the serum free insulin-like growth factor 1 (IGF-1) concentration through IGFBP1 and inhibited the PI3K/AKT signaling pathway. This forms an insulin/HBP1/IGFBP1 negative feedback regulatory loop to dynamically regulate blood glucose and insulin concentrations. These findings have elucidated a mechanism whereby HBP1 and its negative feedback regulatory loop influence the development of T2DM, thereby providing a new theoretical basis and potential therapeutic target for T2DM.

A Bedside Test to Detect the Presence of Embryonic or Fetal Tissue in Vaginal Blood.

To evaluate a rapid bedside test that detects alpha-fetoprotein (AFP) and insulin-like growth factor-binding protein 1 (IGFBP-1) to identify the presence of embryonic or fetal tissue in vaginal blood. This was a prospective cohort study. Reproductive-aged individuals were recruited into three groups: a negative control group consisting of nonpregnant individuals undergoing dilation and curettage (D&C) or experiencing vaginal bleeding; a positive control group of individuals with confirmed intrauterine pregnancy undergoing D&C; and the study group of pregnant individuals with first-trimester bleeding. Lateral flow immunoassay strips capable of detecting both AFP and IGFBP-1 were used to test vaginal blood for the presence of embryonic or fetal tissue. Ninety individuals were recruited: 31 in the positive control group, 23 in the negative control group, and 36 in the study group, including 12 individuals with ectopic pregnancies, 16 with active miscarriages, four with threatened miscarriages, and four with complete miscarriages. Vaginal blood from 14 of the 16 individuals with active miscarriages was correctly positive for embryonic or fetal tissue. Vaginal blood from all individuals with ectopic pregnancies, threatened miscarriages, and complete miscarriages was negative for embryonic or fetal tissue. Overall, 45 of 47 individuals with confirmed embryonic or fetal tissue in vaginal blood correctly tested positive using the test strips, a test sensitivity of 95.7% (95% CI 85.5-99.5%). Of the 43 individuals with confirmed absence of embryonic or fetal tissue in their vaginal blood, 42 were correctly negative, a test specificity of 97.7% (95% CI 87.7-99.9%). A rapid test strip detecting both AFP and IGFBP-1 can accurately identify the presence of embryonic or fetal tissue in vaginal blood. When positive, this could aid in diagnosing miscarriage and ruling out ectopic pregnancy at the bedside.

IGFBP7 enhances trophoblast invasion via IGF-1R/c-Jun signaling in unexplained recurrent spontaneous abortion.

Insufficient trophoblast invasion at the maternal-fetal interface contributes to abortion-prone pregnancy. Our study shows that decreased levels of IGFBP7 in unexplained recurrent spontaneous abortion (URSA) trophoblast cells inhibit MMP2 and Slug expression as well as trophoblast invasion, suggesting that IGFBP7 should be considered a potential therapeutic protein target in URSA. Insufficient trophoblast invasion at the maternal-fetal interface contributes to abortion-prone pregnancy. Cyclosporine A (CsA) can exert therapeutic effects on URSA by promoting trophoblast invasion. A previous study showed decreased expression of insulin-like growth factor-binding protein 7 (IGFBP7) in the sera of recurrent spontaneous abortion patients. However, the role of IGFBP7 in URSA remains unknown. The aim of this study was to determine whether IGFBP7 modulates trophoblast invasion in URSA and the underlying molecular mechanisms. We found that IGFBP7 was expressed at lower levels in villous specimens from URSA patients. Manipulating IGFBP7 expression significantly affected the MMP2 and Slug expression in HTR-8/SVneo cells as well as trophoblast invasion in vitro. Inactivation of IGF-1R by IGFBP7 was observed, and IGF-1R inhibition increased the IGFBP7-induced MMP2 and Slug expression in HTR-8/SVneo cells. Moreover, the level of c-Jun was significantly upregulated in the URSA group. Silencing IGFBP7 increased the binding of downstream c-Jun to the MMP2 and Slug promoter regions in HTR-8/SVneo cells, thus suppressing transcription. In addition, increased expression of IGFBP7 in HTR-8/SVneo cells was observed upon CsA treatment. Knockdown of IGFBP7 inhibited the CsA-enhanced MMP2 and Slug expression in HTR-8/SVneo cells. Our results suggest that in normal pregnancy, IGFBP7 induces MMP2 and Slug expression via the IGF-1R-mediated c-Jun signaling pathway, thereby promoting trophoblast invasion. IGFBP7 depletion in URSA inhibits MMP2 and Slug expression as well as trophoblast invasion. Moreover, IGFBP7 participates in CsA-induced trophoblast invasion, suggesting that IGFBP7 is a potential therapeutic target for URSA.

Reduced IGFBP-2 related immunoreactivity in human serum correlates with arterial stiffness in a healthy Chinese population.

Circulating insulin-like growth factor binding protein 2 (IGFBP-2) is associated with metabolic changes in both physiological and pathological conditions. The aim of this study was to investigate the correlation between IGFBP-2 related immunoreactivity in serum and arterial stiffness in a healthy Chinese population. In this cross-sectional study, 360 healthy participants aged 37-87years were recruited from 1500 and were divided into three groups according to serum IGFBP-2 related immunoreactivity (Tertile I, 25.437ng/ml-120.870ng/ml; Tertile II, 120.871ng/ml-161.914ng/ml; Tertile III, 161.915ng/ml-321.636ng/ml). Arterial stiffness was evaluated by measuring the brachial-ankle pulse wave velocity (baPWV), ankle-brachial index (ABI), and carotid intima-media thickness (cIMT). The association between IGFBP-2 related immunoreactivity and arterial stiffness was estimated by multiple stepwise regression. Compared with the other two groups population, the individuals in Tertile I had significantly older age (62.66±13.30years, P<0.01), lower level of triglyceride (1.08±0.70mmol/l, P<0.01) and E/A (peak velocity of early filling and preak velocity of atrial filling ratio) (0.90±0.33, P<0.05). IGFBP-2 related immunoreactivity was inversely related with baPWV in the total population (r=-0.171, P<0.01) and in Tertile I (r=-0.275, P<0.01). After adjusting for age and the other confounders, no association was found between IGFBP-2 related immunoreactivity and baPWV in the total population. However, In Tertile I, reduced IGFBP-2 related immunoreactivity in serum was an independent risk factor of baPWV acceleration in three different adjustment models: Model 1 (no adjustment, P<0.01), Model 2 (adjusted for age, P<0.05), and Model 3 (adjusted for all variables, P<0.05). IGFBP-2 related immunoreactivity in serum is inversely associated with baPWV in a healthy Chinese population. This association did not change after adjustment for conventional risk factors for cardiovascular diseases in the subjects with the lowest IGFBP-2 related immunoreactivity. Consequently, reduction of IGFBP-2 related immunoreactivity may be a predictor of arterial stiffness. IGFBP-2 seems to be a potential intervention target in early atherosclerosis.

ODP399 Growth Hormone Peak did not predict presence of Pituitary Stalk Interruption Syndrome

Abstract Background Pituitary stalk interruption syndrome (PSIS) is a congenital abnormality of the pituitary gland characterized by a triad of the thin or interrupted pituitary stalk, aplasia, or hypoplasia of the anterior pituitary and absent or ectopic posterior pituitary. This can be associated with midline defects and pituitary endocrine deficiencies, ranging from isolated growth hormone deficiency to combined pituitary hormone deficiency. PSIS is a rare entity with an estimated incidence rate of 0.5/1,000,000 births. Clinical case: A 3-year-old neurodevelopmentally appropriate male was initially seen at the PCP office for growth failure. After birth, the patient appeared to have normal growth parameters, as he was in the 61st percentile for length and at the 19th percentile for weight. His growth velocity trended downwards, as he dropped to the 34th percentile at nine weeks old and the 2nd percentile by nine months old. PCP records showed that the patient was at the 10th percentile for height at one year old, but by 18-months, he had fallen below the 1st percentile. His mid-parental height was 175cm, between 25th and 50th percentile. Initial workup showed elevated TSH 9.12 mIU/ml (0.5-4.3 mIU/mL) with negative thyroid antibodies, thus started on 25 mcg of levothyroxine. The screen for systemic disease and inflammatory markers was negative. Insulin-like growth factor 1 (IGF-1) was low at &amp;lt;16 ng/mL (24-148 ng/mL) and insulin-like growth factor binding protein-3 (IGFBP-3) was normal at 1.2mcg/ml (0.7-3.6)A growth hormone (GH) stimulation test was obtained due to suboptimal growth, short stature, and undetectable IGF-1 level. The patient failed his GH stimulation study with a GH peak of 5.1 ng/mL (&amp;gt;10) after clonidine and 2ng/ml (&amp;gt;10) after arginine. A clinical and biochemical diagnosis of GHD was made, an MRI was ordered to evaluate for anatomic cause. Brain MRI showed an ectopic posterior pituitary gland with an absent infundibulum, suggesting PSIS. The patient was started on GH therapy with excellent response. He is currently growing well on a low dose of somatropin, around 0.234mg/kg/week. Conclusion PSIS is a congenital pituitary anatomical defect with a heterogeneous presentation. It is typically encountered in infancy and childhood, possibly progressing to panhypopituitarism by adulthood. Diagnosis can be delayed, as brain MRI imaging is not always obtained based on growth hormone peaks. As seen in our patient, the severity of GHD based on peak levels did not adequately predict the presence of brain anomalies. Historically, severe GHD (&amp;lt;5 ng/mL) is strongly associated with brain MRI abnormalities, but GH levels may not suffice to determine the severity of the disease. Based on our findings, we recommend obtaining brain MRI in all patients diagnosed with GHD to identify critical anatomical abnormalities, like PSIS, that require long-term close monitoring of pituitary function. Presentation: No date and time listed

ODP395 Relationship of serum total insulin-like growth factor-binding protein-3 with triglyceride to high-density lipoprotein cholesterol ratio and glucose tolerance in Korean children and adolescents

Abstract Objectives We investigated the relationships between serum IGF-I/ IGFBP-3 levels and degrees of triglyceride to high-density lipoprotein cholesterol (TG/HDL) ratio in Korean children and adolescents who underwentoral glucose tolerance test. Methods children and adolescents without known diabetes were checked an oral glucose tolerance test and collected the clinical and laboratory data. Serum IGF-I and total IGFBP-3 levels, TG/HDL ratio, total cholesterol, low-density lipoprotein cholesterol (LDL),AST, ALT, C-peptide levels, homeostasis model assessment of insulin resistance (HOMA-IR) index, and glycated hemoglobin (HbA1c) levels were measured. Results Serum TG/HDL ratio and IGF-I/ total IGFBP-3 levels were significantly higher in individuals with type 2 diabetes (DM) than in those with normal glucose tolerance (NGT) (P&amp;lt;0. 05). TG/HDL ratio was not related with age and IGF-I levels and it was correlated with serum IGFBP-3 levels, HbA1c, C-peptide, HOMA-IR, and body mass index. However, these relationships were altered in patients with insulin resistance state, especially in those with DM. In the DM group, TG/HDL ratio and total IGFBP-3 levels were positively correlated stronger than no-DM groups. In addition,TG/HDL ratio and total IGFBP-3 levels were positively correlated with total cholesterol and LDL levels but not with age. Conclusions TG/HDL ratio, the marker of small dense LDL particles, is related with IGFBP-3, especially in patients with type 2 diabetes. The IGF-I-IGFBP-3 axis, especially IGFBP-3, may play roles in the pathogenesis and metabolic control of lipid metabolism. Presentation: No date and time listed