Insulin Growth Factor Binding Protein Research Articles

Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells.

Hyperglycaemia influences the development of glomerular endothelial cell damage and nowhere is this more evident than in the progression of diabetic kidney disease (DKD). While the Set7 lysine methyltransferase is a known hyperglycaemic sensor, its role in endothelial cell function in the context of DKD remains poorly understood. Single-cell transcriptomics was used to investigate Set7 regulation in a mouse model of DKD, followed by validation of findings using pharmacological and shRNA inhibition of Set7. Set7 knockout (Set7KO) improved glomerular structure and albuminuria in a mouse model of diabetes. Analysis of single cell RNA-seq (scRNA-seq) data showed dynamic transcriptional changes in diabetic renal cells. Set7KO controls phenotype switching of GEN cell populations through transcriptional regulation of IGFBP5 (Insulin growth factor binding protein 5). Chromatin immunoprecipitation assays confirmed the expression of the IGFBP5 gene was associated with mono- and di-methylation of histone H3 lysine 4 (H3K4me1/2). The generalisability was investigated in human renal and circulating hyperglycaemic cells exposed to TGFβ1. We show that the highly selective Set7 inhibitor, PFI-2, attenuated indices associated with renal cell damage and mesenchymal transition; specifically (i) reactive oxygen species production, (ii) IGFBP5 gene regulation, and (iii) expression of mesenchymal markers. Furthermore, renal benefit observed in Set7KO diabetic mice closely correspond in human GEN cells with PFI-2 inhibition or Set7 shRNA silencing. Set7 regulates the phenotypic endothelial-mesenchymal transition (EDMT) switch and suggest that targeting the lysine methyltransferase could protect glomerular cell injury in DKD.

Skin advanced glycation end-products as indicators of the metabolic profile in diabetes mellitus: correlations with glycemic control, liver phenotypes and metabolic biomarkers

IntroductionThe production of advanced glycation end-products (AGEs) is a key pathomechanism related to the complications of diabetes mellitus. The measurement of HbA1c as one of the AGEs is widely used in the clinic, but also other proteins undergo glycation in the course of diabetes. Here, we measure skin AGEs (SAGEs) in patients with diabetes type 1 (DM1) and type 2 (DM2) and correlate them with metabolic markers as well as non-invasively measured liver fibrosis and steatosis.Patients and methodsIn this cross-sectional study, a total of 64 patients with either DM1 or DM2 and 28 healthy controls were recruited. SAGEs were measured using autofluorescence (AGE Reader). Liver fibrosis and steatosis were quantified using transient elastography, which determines liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). FGF19, FGF21 and GDF-15 were measured in blood samples using ELISA.ResultsSAGEs were elevated in both groups of patients with diabetes as compared to healthy controls (both p < 0.001) and were higher in patients with DM2 in comparison to DM1 (p = 0.006). SAGEs correlated positively with HbA1c (r = 0.404, p < 0.001), CAP (r = 0.260, p = 0.016) and LSM (r = 0.356, p < 0.001), and negatively with insulin growth factor binding protein 3 (p < 0.001). We also detected a positive correlation between GDF15 and SAGEs (r = 0.469, p < 0.001).ConclusionsSAGEs are significantly elevated in patients with both DM types 1 and 2 and correlate with metabolic markers, including HbA1c and GDF15. They might also help to detect patients with advanced liver injury in the setting of diabetes.

Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia model

Cancer cachexia is a tumour-induced wasting syndrome, characterised by extreme loss of skeletal muscle. Defective mitochondria can contribute to muscle wasting; however, the underlying mechanisms remain unclear. Using a Drosophila larval model of cancer cachexia, we observed enlarged and dysfunctional muscle mitochondria. Morphological changes were accompanied by upregulation of beta-oxidation proteins and depletion of muscle glycogen and lipid stores. Muscle lipid stores were also decreased in Colon-26 adenocarcinoma mouse muscle samples, and expression of the beta-oxidation gene CPT1A was negatively associated with muscle quality in cachectic patients. Mechanistically, mitochondrial defects result from reduced muscle insulin signalling, downstream of tumour-secreted insulin growth factor binding protein (IGFBP) homologue ImpL2. Strikingly, muscle-specific inhibition of Forkhead box O (FOXO), mitochondrial fusion, or beta-oxidation in tumour-bearing animals preserved muscle integrity. Finally, dietary supplementation with nicotinamide or lipids, improved muscle health in tumour-bearing animals. Overall, our work demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting in cancer cachexia.

Polymorphism of IGFBP7 gene (g.72351183 A&gt;C) and its association with mineral content and cholesterol of Indonesian lamb meat

The genetic improvement of sheep for higher productivity and meat quality is strongly needed due to the increasing demand for meat sheep. Insulin growth factor binding protein 7 (IGFBP7) has been reported as a potential gene which has a substantial role in meat quality. The objective of the study was to identify IGFBP7 gene polymorphisms and their association with minerals and cholesterol in Indonesian lamb meat. The study used 130 rams consisting of local and crossbred sheep. The local sheep were Javanese thin-tailed, Javanese fat-tailed, and Jonggol sheep. The crossbred sheep were Compass agrinak, Composite garut agrinak and Bahtera agrinak sheep. The identification of polymorphism was using PCR-RFLP method. The association analysis was obtained using a general linear model. The results showed that IGFBP7 (g.72351183 A&gt;C) was polymorphic in local and crossbred sheep. The IGFBP7 was significantly associated with cholesterol in crossbred (P&lt;0.01), whereas the AA genotype had the lowest cholesterol. Cholesterol in crossbred sheep also was higher (P&lt;0.01) compared to local sheep for all observed genotypes. IGFBP7 gene was not significantly associated with minerals and cholesterol (P&gt;0.05) in local sheep. It is concluded that IGFBP7 gene seems promising as a genetic marker for cholesterol level in Indonesian crossbred sheep.

[Clinical and genetic analysis of a child with maternal uniparental disomy of chromosome 20].

To explore the clinical and genetic characteristics of a boy with isolated maternal uniparental disomy of chromosome 20 [UPD(20)mat]. A child who was admitted to the Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology on April 8,2021. was selected as the study subject. Phenotypic and endocrinological findings of the child were retrospectively analyzed. Whole exome sequencing (WES) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were carried out for detecting the UPD sequences and copy number variations. Both of his parents were verified by Sanger sequencing. Relevant literature was systematically reviewed. The child, a 3-year-and-8-month-old boy born to a 41-year-old mother by Cesarean delivery at 36+2 gestational weeks due to oligohydramia, had a birth weight of 2 300 g and length of 46 cm. He was admitted to the NICU for feeding difficulties which had persisted despite of clinical management. At the age of 3.75, he had a height of 92.5 cm (< 3rd percentile; 25th ~ 50th percentile at 2.5 years) and a weight of 10.8 kg (< 3rd percentile; 50th percentile at 15 months). He had also presented with growth retardation, short stature, attention deficit and hyperactivity disorder (ADHD), mild mental retardation, and speech and language development disorders. He had simian creases in both hands but no additional dysmorphic signs, and his motor development was normal. Serum insulin, thyroid-stimulating hormone, and insulin growth factor binding protein 3 levels were within the normal ranges, though insulin growth factor-1 (IGF-1) was slightly decreased. Since that time he had continuously used atomoxetine hydrochloride capsules to control his ADHD. WES and MS-MLPA revealed the existence of UPD (20)mat. The UPD(20)mat syndrome is characterized by feeding difficulties, growth retardation and short stature. The child in our case has been accompanied by ADHD and speech and language development disorders, which required long-term treatment. For women with advanced maternal age and suggestive phenotypes, genetic testing and counseling should be conducted.

Biomarker profiles of favorable ventricular remodeling in heart failure patients with reduced ejection fraction: Insights from the echocardiographic substudy of the VICTORIA trial

Abstract Background Favorable ventricular remodeling, defined as a decrease in left ventricular end-systolic volume indexed (LVESVI) to body surface area or an increase in left ventricular ejection fraction (LVEF), is associated with improved clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Because the underlying biomarker correlates remain unclear, we investigated circulating biomarker profiles and their relationship to ventricular remodeling. Methods We studied 419 high-risk patients with worsening HFrEF from the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial with core-lab assessed echocardiograms and measurements of 92 biomarkers (Olink CVD III panel). Biomarkers were measured in plasma using proximity extension assays and conventional ELISAs. Paired biomarkers (in 306 patients) and echocardiographic measurements (in 419 patients) were available at baseline and 8 months post-randomization. We evaluated the association of biomarkers at baseline and their temporal changes with favorable cardiac remodeling. Favorable remodeling was prespecified as a 5% LVEF absolute increase or 15% LVESVI relative decrease between baseline and 8 months. Reported p-values for protein changes are adjusted for the false discovery rate (FDR) at 0.05 to account for multiple comparisons. Results Of 419 patients (median age 66 [interquartile range 57-74] years, 27.4% women), 206 (49.2%) had favorable remodeling and 213 (50.8%) did not. Patients with favorable remodeling had a lower median body mass index (26.5 vs 28.3 kg/m2, P = 0.010), lower prevalence of diabetes (36.4% vs 47.4%, P = 0.022) and coronary artery disease (39.3% vs 62.0%, P&amp;lt;0.001). After correcting for multiple testing, no baseline biomarker levels differed between patients with and without favorable remodeling. Between baseline and 8 months, however, there was a significant decrease in biomarkers relating to inflammation and cardiac metabolism with favorable remodeling compared with those without (Figure). Particularly NT-proBNP (ratio 0.46, 95%confidence interval [CI] 0.38-0.57), TNF Superfamily Member 13b (ratio 0.85, 95%CI 0.80-0.91), growth differentiation factor-15 (ratio 0.76, 95%CI 0.68-0.84), cathepsin D (ratio 0.88, 95%CI 0.82-0.94), and insulin growth factor binding protein 7 (ratio 0.81, 95%CI 0.74-0.88) showed a significantly larger decrease in those with than those without favorable remodeling (Figure and Table). Conclusion Our results suggest favorable cardiac remodeling occurs in half of high-risk HFrEF with recent worsening. We provide new insights into the clinical phenoype and associated inflammatory and cardiac metabolism changes. These findings may help identify potential treatment targets for future drug discovery.

Plasma IGFBP-2 levels reveal heterogeneity in hepatic fat content in adults with excess visceral adiposity.

Obesity is frequently accompanied by a fatty liver. However, some individuals with high abdominal fat levels nevertheless have low levels of liver fat. Reasons for such discordant phenotypes are unclear. In this paper, we report that among asymptomatic individuals with high levels of visceral fat, low concentrations of IGFBP-2 in the circulation were associated with significantly higher hepatic fat content compared to those with high IGFBP-2 levels. We conclude that quantification of plasma IGFBP-2 concentrations may be useful to identify the early risk for liver fat accumulation in apparently healthy individuals without cardiovascular symptoms. Although excess visceral adiposity (VAT) is generally associated with increased liver fat (LF), recent evidence has revealed heterogeneity in LF content among adults with visceral obesity, potentially contributing to specific differences in cardiometabolic outcomes. Reasons for such discordant VAT-LF phenotypes are largely unknown. The present study aimed at assessing whether circulating levels of insulin growth-factor binding protein-2 (IGFBP-2) could be a useful biomarker in the identification of heterogenous and discordant VAT-LF phenotypes. A sample of 308 middle-aged Caucasian apparently healthy men and women without cardiovascular symptoms were studied for the present cross-sectional analyses. Fasting plasma glucose and lipid levels were assessed and an oral glucose tolerance test was performed. Hepatic fat fraction (HFF) was measured using magnetic resonance spectroscopy whereas VAT was assessed by magnetic resonance imaging. Plasma IGFBP-2 levels were quantified by ELISA. Participants were then classified on the basis of median VAT (81 mL) and IGFBP-2 levels (233 ng/mL). Individuals with high levels of VAT were characterized by higher waist circumference, lower insulin sensitivity, as well as by higher plasma triglyceride and lower HDL-cholesterol levels. Plasma IGFBP-2 levels were inversely correlated with HFF (r = -0.39, p < 0.0001). Among men and women with high levels of VAT, those with low levels of IGFBP-2 had significantly higher HFF (7.5 ± 0.7%), compared to participants with high IGFBP-2 concentrations (3.2 ± 0.5%, p < 0.0001). In the presence of excess VAT, high IGFBP-2 concentrations are associated with low levels of LF. Although additional studies will be necessary to establish causality and further clarify the clinical implications of these observations, these findings are concordant with a novel function of IGFBP-2 in modulating susceptibility to non-alcoholic fatty liver disease (NAFLD) in the presence of visceral obesity.

Contrast-associated acute kidney injury and cardiovascular events: a secondary analysis of the PRESERVE cohort.

Contrast-associated acute kidney injury (CA-AKI) has been associated with a higher risk of cardiovascular (CV) events. We studied the risk of CV events in chronic kidney disease (CKD) patients undergoing angiography and whether biomarkers can predict such events. We also explored whether CA-AKI mediates the association of pre-angiography estimated glomerular filtration rate (eGFR) on CV events. We analysed participants from the Prevention of Serious Adverse Events following the Angiography (PRESERVE) trial. Urinary tissue inhibitor of matrix metalloproteinase [TIMP]-2 and insulin growth factor binding protein [IGFBP]-7, plasma brain-type natriuretic peptide (BNP), high sensitivity C-reactive protein (hs-CRP), and serum cardiac troponin-I (Tn-I) were assayed before and after angiography. We assessed the composite risk of CV events by day 90. Of the 922 participants, 119 (12.9%) developed CV events, and 73 (7.9%) developed CA-AKI. Most cases of CA-AKI (90%) were stage 1. There were no differences in urinary [TIMP-2]•[IGFBP7] concentrations or the proportion of patients with CA-AKI among those with and without CV events. Higher BNP, Tn-I, and hs-CRP were associated with CV events, but their discriminatory capacity was modest (AUROC <0.7). CA-AKI did not mediate the association of the pre-angiography eGFR on CV events. Most episodes of CA-AKI are stage 1 AKI and are not associated with CV events. Less severe CA-AKI episodes also did not mediate the risk of pre-angiography eGFR on CV events. Our findings suggest that most CV events after contrast procedures are due to underlying CKD and CV risk factors rather than less severe CA-AKI episodes and should help enhance the utilization of clinically indicated contrast procedures among high-risk patients with CKD. Further research is required to examine whether moderate-to-severe CA-AKI episodes are associated with CV events.

Acute Kidney Injury and Sepsis after Cardiac Surgery: The Roles of Tissue Inhibitor Metalloproteinase-2, Insulin-like Growth Factor Binding Protein-7, and Mid-Regional Pro-Adrenomedullin.

Identifying a panel of markers detecting kidney injury before the glomerular filtration rate reduction is a challenge to improving the diagnosis and management of acute kidney injury (AKI) in septic patients. This study evaluated the roles of tissue inhibitor metal proteinase-2, insulin growth factor binding protein-7 (TIMP2*IGFBP7), and mid-regional pro-adrenomedullin (MR-proADM) in patients with AKI. This study was prospectively conducted in an intensive care unit (ICU) enrolling 230 patients who underwent cardiac surgery. Biomarkers were evaluated before and after 4 h of the cardiac surgery. Whereas urine and creatinine alterations appeared at 23.2 (12.7-36.5) hours after cardiac surgery, urinary TIMP2*IGBP7 levels were higher at 4 h in AKI patients (1.1 ± 0.4 mg/L vs. 0.08 ± 0.02 mg/L; p < 0.001). Its concentration > 2 mg/L increases AKI risk within the following 24 h, clearly identifying the population at high risk of renal replacement therapy (RRT). In patients with sepsis, MR-proADM levels were 2.3 nmol/L (0.7-7.8 nmol/L), with the highest values observed in septic shock patients (5.6 nmol/L (3.2-18 nmol/L)) and a better diagnostic profile than procalcitonin and C-reactive protein to identify septic patients. MR-proADM values > 5.1 nmol/L and urine TIMP2*IGBP7 levels > 2 mg/L showed a significantly faster progression to RRT, with a mean follow-up time of 1.1 days. TIMP2*IGBP7 and MR-proADM precociously diagnose AKI in septic patients after cardiac surgery, giving prognostic information for RRT requirement.

The identification and validation of target genes of IGFBP3 protein in sheep skeletal muscle cells

This study aimed to identify the target genes of IGFBP3（insulin growth factor binding protein）protein and to investigate its target genes effects on the proliferation and differentiation of Hu sheep skeletal muscle cells. IGFBP3 was an RNA-binding protein that regulates mRNA stability. Previous studies have reported that IGFBP3 promotes the proliferation of Hu sheep skeletal muscle cells and inhibits differentiation, but the downstream genes that bind to it have not been reported yet. We predicted the target genes of IGFBP3 through RNAct and sequencing data, and verified by qPCR and RIP（RNA Immunoprecipitation）experiments, and demonstrated GNAI2（G protein subunit alpha i2）as one of the target gene of IGFBP3. After interference with siRNA, we carried out qPCR, CCK8, EdU, and immunofluorescence experiments, and found that GNAI2 can promote the proliferation and inhibit differentiation of Hu sheep skeletal muscle cells. This study revealed the effects of GNAI2 and provided one of the regulatory mechanisms of IGFBP3 protein underlying sheep muscle development.

Kidney Cell Cycle Arrest and Cardiac Biomarkers and Acute Kidney Injury Following Angiography: The Prevention of Serious Adverse Events Following Angiography (PRESERVE) Study

Recent studies in patients with chronic kidney disease (CKD) indicate that most cases of contrast-associated acute kidney injury (CA-AKI) are mild and are not associated with elevation in kidney injury biomarkers. We used highly sensitive kidney cell cycle arrest and cardiac biomarkers to assess the risk of CA-AKI and major adverse kidney events in patients with CKD undergoing angiography. A retrospective study. A subset of 922 participants from the Prevention of Serious Adverse Events following Angiography trial. Pre- and postangiography urinary tissue inhibitor of matrix metalloproteinase [TIMP]-2 and insulin growth factor binding protein [IGFBP]-7 were measured in 742 subjects, and plasma β natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP), and serum troponin (Tn) in 854 participants using samples obtained 1-2 hours before and 2-4 hours after angiography. CA-AKI and major adverse kidney events. We fitted logistic regression to examine association and area under the receiver operating characteristic curves for risk prediction. There were no differences in postangiography urinary [TIMP-2]•[IGFBP7], plasma BNP, serum Tn, and hs-CRP concentrations among patients with and without CA-AKI and major adverse kidney events. However, higher pre- and postangiography median plasma BNP (pre: 200.0 vs 71.5, pg/mL, P=0.05; post: 165.0 vs 81pg/mL, P=0.02); serum Tn (pre: 0.03 vs 0.01, ng/mL, P<0.001; post, 0.04 vs 0.02, ng/mL, P=0.01); and hs-CRP (pre: 9.55 vs 3.40mg/L, P=0.01; post: 9.90 vs 3.20mg/L, P=0.002) concentrations were associated with major adverse kidney events, although their discriminatory capacity was only modest (area under the receiver operating characteristic curves<0.7). Most participants were men. Most mild CA-AKI cases are not associated with urinary cell cycle arrest biomarker elevation. Significant elevation in preangiography cardiac biomarkers may reflect patients with more significant cardiovascular disease that may predispose to poor long-term outcomes independent of CA-AKI status.

ODP315 Hypoglycemia: Neuroendocrine Tumor of the Pancreas with Liver Metastasis and Transformation to Insulinoma

Abstract Background Neuroendocrine tumors (NETs) are rare, can be found in any part of the body including the gastrointestinal tract, lung, and pancreas and have potential for metastasis. Clinical Case A 39-year-old male with stage IV high grade neuroendocrine tumor of the pancreas with metastasis to the liver and lymph nodes whose disease progressed despite treatment with systemic therapy who presented with severe hypoglycemia. Diagnosis and management of his hypoglycemia was difficult. For the diagnosis, patient's serum blood glucose did not always correlate with his capillary blood glucose via finger sticks, which lead to a delay in his diagnosis. Also, his diagnosis was not straight forward as he did not respond adequately to the glucagon following a serum glucose of less than 55 mg/dL (normal 70-110 mg/dL) during a diagnostic fast. Once critical labs were obtained, it took days for the results. In the interim, his hypoglycemia was managed with dextrose infusions at 10%, 20% and as high as 50%, frequent meals, and high dose steroids, yet he still had daily symptomatic hypoglycemia. A diagnosis of insulinoma was made with the following critical lab results: insulin 70.4 uIU/mL (2.6-24.9), C-peptide 12.6 ng/mL (1.1-4.4), proinsulin 407.6 pmol/L (0. 0-10. 0), beta-hydroxybutyrate &amp;lt;0. 050 mmol/L (0. 02-0.27), insulin antibodies &amp;lt;5. 0 uU/mL, negative sulfonylurea screen, insulin-growth factor-1 (IGF-1) 77 ng/mL (90-278), and insulin-growth factor binding protein three (IGF-BP3) 2133 ug/L (2571-5982). Patient was treated with both diazoxide and hepatic artery embolization to reduce tumor burden. His dose of diazoxide was titrated to maintain normoglycemia. He had mild tumor lysis syndrome that did not require dialysis. His hypoglycemia resolved within a few days of treatment and was discharged from the hospital with a continuous glucose monitor (CGM), diazoxide and hydrocortisone. It is our belief that transformation of the liver lesions to insulinoma was the cause of his hypoglycemia. Conclusion We recommend that patients with metastases from their neuroendocrine tumor who develop hypoglycemia be evaluated for insulinoma and if found should be treated with diazoxide and if not surgical candidates to consider hepatic artery embolization. Presentation: No date and time listed

Exosome-associated microRNA-375 induces cell proliferation by regulating IGFBP4 upon hepatitis C virus infection.

Hepatitis C virus (HCV) infection is one of the most common causes of liver cancer. HCV infection causes chronic disease followed by cirrhosis, which often leads to hepatocellular carcinoma (HCC). In this study, we investigated the roles of exosome-associated miRNAs in HCV-induced disease pathology. Small RNA sequencing was performed to identify miRNAs that are differentially regulated in exosomes isolated from patient sera at two different stages of HCV infection: cirrhosis and hepatocellular carcinoma. Among the differentially expressed miRNAs, miR-375 was found to be significantly upregulated in exosomes isolated from patients with cirrhosis and HCC. A similar upregulation was observed in intracellular and extracellular/exosomal levels of miR-375 in HCV-JFH1 infected Huh7.5 cells. The depletion of miR-375 in infected cells inhibited HCV-induced cell migration and proliferation, suggesting a supportive role for miR-375 in HCV pathogenesis. miR-375, secreted through exosomes derived from HCV-infected cells, could also be transferred to naïve Huh7.5 cells, resulting in an increase in cell proliferation and migration in the recipient cells. Furthermore, we identified Insulin growth factor binding protein 4 (IGFBP4), a gene involved in cell growth and malignancy, as a novel target of miR-375. Our results demonstrate the critical involvement of exosome-associated miR-375 in HCV-induced disease progression.

Low IGF1 and high IGFBP1 predict diabetes onset in prediabetic patients.

Some individuals develop type 2 diabetes mellitus (T2DM) despite significant metabolic improvements through lifestyle intervention. We tested the hypotheses that insulin growth factor 1 (IGF1) and its binding proteins 1 and 2 predict the onset of T2DM in prediabetes patients and determine the capacity for metabolic regeneration. We measured fasting serum IGF1, insulin growth factor-binding protein 1 (IGFBP1) and IGFBP2 in three randomized controlled lifestyle intervention trials, covering at least 1 year of intervention period and 1 year of additional follow-up. Within a sample of 414 high-risk prediabetes patients (58% women; 28-80 years), we analyzed fasting serum concentrations of IGF1, IGFBP1 and IGFBP2 in relation to diabetes incidence and metabolic parameters over 2 years. Three hundred and forty-five subjects finished the first year of intervention. The interventions significantly improved body weight (BMI: -3.24%, P < 0.001), liver fat (-36.8%, P < 0.001), insulin sensitivity (IS) (homeostatic model assessment-insulin resistance: -6.3%, P < 0.001) and insulin secretion (disposition index: +35%, P < 0.001) in the cohort. Fourteen percent developed T2DM within 2 years. Mean IGFBP1 levels at baseline were lower in prediabetes compared to a healthy population. Also, prediabetes patients with obesity and nonalcoholic fatty liver disease had lower IGFBP1. Those with impaired glucose tolerance had higher IGFBP1 compared to those with only impaired fasting glucose. Baseline IGF1 was lower (122.5 vs 146.6 µg/L) and IGFBP1 was higher (3.32 vs 2.09 µg/L) in subjects who developed T2DM (n = 57), resulting in a significant prediction of diabetes incidence (hazard ratio (HR) IGF1: 0.991 µg/L, P = 0.003; HR IGFBP1: 1.061 µg/L, P = 0.002). This translates into a 20% and 9% difference in T2DM incidence for IGF1 and IGFBP1, respectively. Despite reduced weight, visceral fat and hepatic fat in response to 1 year of lifestyle intervention, those who developed T2DM had not improved insulin sensitivity, glucose tolerance or IGFBP1. Lower IGF1 and higher IGFBP1 in prediabetes predicted the incidence of T2DM, indicating an impairment of beta-cell function, which explains the unresponsiveness to lifestyle intervention.

Gold Nanoparticles Disrupt the IGFBP2/mTOR/PTEN Axis to Inhibit Ovarian Cancer Growth.

By exploiting the self-therapeutic properties of gold nanoparticles (GNPs) a molecular axis that promotes the growth of high-grade serous ovarian cancer (HGSOC), one of the deadliest gynecologic malignancies with poorly understood underlying molecular mechanisms, has been identified. The biodistribution and toxicity of GNPs administered by intravenous or intraperitoneal injection, both as a single dose or by repeated dosing over two weeks are first assessed; no biochemical or histological toxicity to vital organs is found. Using an orthotopic patient-derived xenograft (PDX) model of HGSOC, the authors then show that GNP treatment robustly inhibits tumor growth. Investigating the molecular mechanisms underlying the GNP efficacy reveals that GNPs downregulate insulin growth factor binding protein 2 (IGFBP2) by disrupting its autoregulation via the IGFBP2/mTOR/PTEN axis. This mechanism is validated by treating a cell line-based human xenograft tumor with GNPs and an mTOR dual-kinase inhibitor (PI-103), either individually or in combination with GNPs; GNP and PI-103 combination therapy inhibit ovarian tumor growth similarly to GNPs alone. This report illustrates how the self-therapeutic properties of GNPs can be exploited as a discovery tool to identify a critical signaling axis responsible for poor prognosis in ovarian cancer and provides an opportunity to interrogate the axis to improve patient outcomes.

Abstract CT571: Plasma proteomic markers prognostic or predictive for survival of patients with newly diagnosed glioblastoma who were treated in a phase II trial with standard care and the addition of the novel patient-specific dendritic cell vaccine AV-GBM-1

Abstract Standard aggressive therapy for primary newly diagnosed glioblastoma (GBM), which includes surgical resection followed by concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ) and then maintenance TMZ, is associated with poor survival rates. Adding treatment with AV-GBM-1, a personal vaccine consisting of autologous dendritic cells (DC) pulsed with autologous tumor antigens (ATA) may improve survival. AV-GBM-1 is produced by incubating ATA with autologous DC. ATA are from a lysate of irradiated autologous GBM cells that were self-renewing in serum-free medium with factors that favor survival and proliferation of tumor initiating cells, i.e., stem cells and early progenitor cells. After recovery from RT/TMZ, GBM patients were injected subcutaneously with AV-GBM-1 admixed in granulocyte-macrophage colony-stimulating factor (GM-CSF) at weeks 1, 2, 3, 8, 12, 16, 20, and 24. This study examined changes in plasma proteomics before and after injections of AV-GBM-1. 57 patients were treated during November 2018 to October 2020. Median progression-free and overall survival were 10.3 and 16.0 months respectively. Plasma samples obtained at baseline (week-0), and just prior to the third injection (week-2) were cryopreserved and subsequently analyzed for 448 proteomic markers using quantitative, multiplex enzyme-linked immunosorbent assays (Raybiotech, Inc., Norcross, GA.). 54 patients had a baseline week-0 sample prior to the 1st vaccination; 50 had a week-2 sample just prior to the 3rd dose; 49 had paired samples for both time-points. The averages of paired samples were measured for all patients and for cohorts defined by median survival that were compared by 2-tail T-Tests. After two weekly injections there were significant (p&amp;lt;0.01) increases in thymus and activation-regulated chemokine (TARC, CCL17), chemerin, lipocalin-2 and angiopoietin, and decreases in thrombospondin-5, angiotensinogen, and beta-fibroblast growth factor. The changes in TARC are due to GM-CSF. 25 patients survived more than 15 months and 24 less than 15 months. Prognostic baseline markers associated with longer survival were higher CD14 (p=0.009), higher tissue-inhibitor of metalloproteinases (TIMP-1), and higher insulin growth factor binding proteins (IGFBP) 1 and 2 (p&amp;lt;0.02). The only markers that appeared predictive for survival (p&amp;lt;0.05) based on changes from baseline to week-2 were increased lipocalin-2, associated with longer survival (p=0.0369), and decreased brain-derived neurotrophic factor (BDNF) associated with shorter survival (p=0.0186). Because of the large number of analyses, these results are considered hypothesis generating and not definitive. Citation Format: Daniela A. Bota, David E. Piccioni, Christopher M. Duma, Renato V. LaRoca, Santosh Kesari, Mehrdad Abedi, Robert D. Aiken, Aleksandra J. Poole, Gabriel I. Nistor, Robert O. Dillman. Plasma proteomic markers prognostic or predictive for survival of patients with newly diagnosed glioblastoma who were treated in a phase II trial with standard care and the addition of the novel patient-specific dendritic cell vaccine AV-GBM-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT571.

Long-term treatment with chloroquine increases lifespan in middle-aged male mice possibly via autophagy modulation, proteasome inhibition and glycogen metabolism.

Previous studies have shown that the polyamine spermidine increased the maximum life span in C. elegans and the median life span in mice. Since spermidine increases autophagy, we asked if treatment with chloroquine, an inhibitor of autophagy, would shorten the lifespan of mice. Recently, chloroquine has intensively been discussed as a treatment option for COVID-19 patients. To rule out unfavorable long-term effects on longevity, we examined the effect of chronic treatment with chloroquine given in the drinking water on the lifespan and organ pathology of male middle-aged NMRI mice. We report that, surprisingly, daily treatment with chloroquine extended the median life span by 11.4% and the maximum life span of the middle-aged male NMRI mice by 11.8%. Subsequent experiments show that the chloroquine-induced lifespan elevation is associated with dose-dependent increase in LC3B-II, a marker of autophagosomes, in the liver and heart that was confirmed by transmission electron microscopy. Quite intriguingly, chloroquine treatment was also associated with a decrease in glycogenolysis in the liver suggesting a compensatory mechanism to provide energy to the cell. Accumulation of autophagosomes was paralleled by an inhibition of proteasome-dependent proteolysis in the liver and the heart as well as with decreased serum levels of insulin growth factor binding protein-3 (IGFBP3), a protein associated with longevity. We propose that inhibition of proteasome activity in conjunction with an increased number of autophagosomes and decreased levels of IGFBP3 might play a central role in lifespan extension by chloroquine in male NMRI mice.

Hepatic Stearoyl‐CoA desaturase deficiency‐mediated induction of the insulin‐like growth factor‐binding protein 1 requires FGF21

Stearoyl‐CoA desaturase‐1 (SCD1) catalyzes the rate‐limiting step in the biosynthesis of monounsaturated acids and is a key regulator of systemic glucose metabolism. Hepatic deletion of Scd1protects mice from high‐carbohydrate diet (HCD)‐induced hepatic steatosis and adiposity in part by suppressing hepatic lipogenesis, increasing adipose tissue lipogenesis, and increasing systemic glucose uptake. However, the mechanism leading to these phenotypes is unclear. 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 alters metabolic pathways to produce metabolically beneficial phenotypes. Here we show that hepatic SCD1 deficiency enhances tissue glucose uptake and is correlated with dramatic increases in the expression and plasma levels of the fibroblast growth factor 21 (FGF21), and Insulin growth factor binding protein‐1 (IGFBP1), both liver derived insulin‐sensitizing hormones that are known to regulate whole body lipid and glucose homeostasis. Feeding both male and female LKO mice with triolein, but not tristearin, supplemented HCD reduced Fgf21 and Igfbp1 expression and restored plasma glucose levels. Inhibition of SCD activity in primary hepatocytes induced the expression of Fgf21 and Igfbp1 which was repressed by treatment with oleate but not stearate. Moreover, we show that the hepatic stearoyl‐CoA desaturase deficiency‐mediated induction of the Igfbp1 is through the oleate‐FGF21 axis.

Association of 71 cardiovascular disease-related plasma proteins with pulmonary function in the community.

RationaleIt has been speculated that shared mechanisms underlie respiratory and cardiovascular diseases (CVD) including systemic inflammation or mutual risk factors. In this context, we sought to examine the associations of CVD-related plasma proteins with lung function as measured by spirometry in a large community-based cohort of adults.MethodsThe study included 5777 Framingham Heart Study participants who had spirometry and measurement of 71 CVD-related plasma proteins. The association of plasma proteins with lung function was assessed cross-sectionally and longitudinally using models accounting for familial correlations. Linear mixed models were used for the following measurements: FEV1%predicted, FVC%predicted, and FEV1/FVC ratio with secondary analyses examining obstructive and restrictive physiology at baseline and their new onset during follow up.Measurements and main resultsAmong the 71 CVD-related plasma proteins, 13 proteins were associated in cross-sectional analyses with FEV1%predicted, 17 proteins were associated with FVC%predicted, and 1 protein was associated with FEV1/FVC. The proteins with the greatest inverse relations to FEV1%predicted and FVC%predicted included leptin, adrenomedullin, and plasminogen activator inhibitor-1; in contrast there were three proteins with positive relations to FEV1%predicted and FVC%predicted including insulin growth factor binding protein 2, tetranectin, and soluble receptor for advanced glycation end products. In longitudinal analyses, three proteins were associated with longitudinal change in FEV1 (ΔFEV1) and four with ΔFVC; no proteins were associated with ΔFEV1/FVC.ConclusionOur findings highlight CVD-related plasma proteins that are associated with lung function including markers of inflammation, adiposity, and fibrosis, representing proteins that may contribute both to respiratory and CVD risk.

Insulin growth factor binding protein-3 enhances dental implant osseointegration against methylglyoxal-induced bone deterioration in a rat model.

PurposeThe aim of this study was to determine the effect of insulin growth factor binding protein-3 (IGFBP-3) on the inhibition of glucose oxidative stress and promotion of bone formation near the implant site in a rat model of methylglyoxal (MGO)-induced bone loss.MethodsAn in vitro study was performed in MC3T3 E1 cells treated with chitosan gold nanoparticles (Ch-GNPs) conjugated with IGFBP-3 cDNA followed by MGO. An in vivo study was conducted in a rat model induced by MGO administration after the insertion of a dental implant coated with IGFBP-3.ResultsMGO treatment downregulated molecules involved in osteogenic differentiation and bone formation in MC3T3 E1 cells and influenced the bone mineral density and bone volume of the femur and alveolar bone. In contrast, IGFBP-3 inhibited oxidative stress and inflammation and enhanced osteogenesis in MGO-treated MC3T3 E1 cells. In addition, IGFBP-3 promoted bone formation by reducing inflammatory proteins in MGO-administered rats. The application of Ch-GNPs conjugated with IGFBP-3 as a coating of titanium implants enhanced osteogenesis and the osseointegration of dental implants.ConclusionsThis study demonstrated that IGFBP-3 could be applied as a therapeutic component in dental implants to promote the osseointegration of dental implants in patients with diabetes, which affects MGO levels.