GDF-15 Levels Research Articles

The effect of cachexia and anti-cancer therapies on GDF-15 levels in patients with pancreatic adenocarcinoma.

778 Background: Growth differentiation factor 15 (GDF15) is a novel biomarker in the setting of pancreatic adenocarcinoma (PDAC). Preliminary studies have found that downstream effects of GDF-15 promote the progression of pancreatic cancer. PDAC has a high prevalence of cachexia which is commonly treated with enzyme supplementation and nutritional support. Platinum-based therapies often used to treat PDAC increase the likelihood of patients experiencing cachexia. The purpose of this study was to observe the GDF-15 levels in respect to weight change of PDAC patients being treated with cachexia and anti-cancer therapies. Methods: Serum and Plasma samples were collected from locally advanced and advanced PDAC patients on 5 IRB approved studies from 2014-2024. Samples were analyzed using the R-PLEX Human GDF-15 Antibody Set. The study objective was compared using two-sample paired t-tests and Pearson correlation matrices. Elevated GDF-15 was determined as >1500 pg/mL. Results: Samples from 73 patients were utilized for this study (63% female; median age: 69; BMI: 23.31±4.96 kg/m 2 ). At baseline 71.8% (46/64) had elevated GDF-15, at Cycle 3 76% (25/33), and at Cycle 5 86% (25/29). In the total sample set, there was a slight negative correlation in the change of weight (-1.75 kg, p = 0.013) and GDF-15 (577.5 pg/mL, p = 0.278) from C1 to C3 (r = -0.185, p = 0.366). There was a slight negative correlation (r = -0.44, p = 0.076) in the difference of weight and GDF-15 from C1 to C3 in patients receiving chemotherapy. A strong negative correlation was observed in the change of GDF15 and weight from C1D1 to C1D8 in patients treated with platinum-based therapy (r = -0.530, p = 0.212) and a weak negative correlation (r = -0.421, p = 0.065) for patients with non-platinum-based therapy. There was a strong positive association (r = 0.993, p < 0.01) between the change in weight and GDF-15 from C1 to C5 in patients not receiving chemotherapy. There was no significant decrease in GDF-15 levels across the patients at all time points. Conclusions: Despite cachexia and anti-cancer treatment, the GDF-15 levels of PDAC patients continue to remain elevated in consecutive blood draws. Further research in GDF-15 kinetics is warranted. Clinical trial information: NCT02400398 , NCT03207724 , NCT04098237 , NCT05336266 , NCT04634539 . Weight and GDF-15 levels across different chemotherapy regimens. Baseline Cycle 1 Cycle 3 Cycle 5 BMI (kg/m2) Weight (kg) GDF15 (pg/mL) Weight (kg) GDF15 (pg/mL) Weight (kg) GDF15 (pg/mL) Chemotherapy 23.21 63.83 3243.25 63.44 3498.76 60.14 3201.33 No Chemotherapy 23.77 65.85 3113.73 62.32 2949.56 71.05 2944.54 Platinum Based 20.88 59.89 6527.78 51.7 3600.87 58.1 5152.50 Non-platinum-based chemotherapy 23.86 64.89 2442.14 64.67 3487.41 60.39 2957.43

The value of growth differentiation factor 15 as a biomarker for peripheral artery disease in diabetes patients

BackgroundGrowth differentiation factor 15 (GDF15) is significantly correlated with glycolipid metabolic disorders. Increased GDF15 levels are associated with obesity, insulin resistance, and diabetes as well as a poorer diabetes progression and prognosis. This is a prospective cohort study investigated the association between circulating GDF15 and diabetic peripheral artery disease.MethodsA total of 174 diabetic patients aged 20–80 were enrolled. Plasma GDF15 levels were measured using ELISA. Peripheral Artery Disease (PAD) was evaluated with the Ankle brachial index (ABI) and the Cardio-ankle vascular index (CAVI).ResultsWe found that diabetic patients with higher serum GDF15 levels (mean: 2521.5 pg/mL) had a higher incidence of peripheral artery disease. Multivariate logistic regression analysis indicated that patients with high serum GDF15 levels were at an increased risk of developing peripheral artery disease. High GDF15 levels were associated with ABI < 0.9 (right and left mean 19.5% p = 0.80, OR:1.13; 95%CI: [0.44–2.90]). Increased age (p = 0.025 OR:1.02; 95% CI [0.13–0.87]), family history (p = 0.001 OR:1.37; 95%CI: [0.37–5.05]), heart failure (p = 0.002 OR:4.96; 95%CI: [1.76–13.97]), sodium-glucose linked transporter 2 (SGLT 2) inhibitor use (p = 0.026), estimated glomerular filtration rate (eGFR) (p = < 0.001), and uric acid (p = < 0.001) was also positively associated with high GDF15 levels. Urine albumin-to-creatinine ratio (UACR) (p = < 0.010) was associated with higher GDF15 levels after one year of follow up.ConclusionsElevated GDF15 was significantly associated with worsening metabolic parameters and an increased risk of peripheral artery disease. Thus, it may be a stronger predictor of these outcomes in people with diabetes.

Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancer.

Phthalate exposure is linked to prostate enlargement through sex hormonal changes and oxidative stress. However, its role and action mechanism in prostate cancer remain unclear. This study examined two patient cohorts: 204 patients undergoing prostate biopsy (24 benign and 180 malignancies) and 85 with confirmed prostate cancer receiving robotic-assisted radical prostatectomy. Urine samples, collected with informed consent, were analyzed for urinary DEHP metabolites using HPLC-MS and ELISA. Patients with prostate cancer exhibited significantly higher urinary MEOHP and ΣDEHP metabolite levels than those who underwent benign biopsy (unpaired t-test, p = 0.027 and 0.039, respectively). MIR-5010 upregulation and MIR-205 downregulation were observed in two paired small RNA sequencing analyses (urine pellets of benign vs. malignant patients and PC3 cells without or with DEHP treatment), correlating with tumor staging in the TCGA prostate cancer cohort. Unlike MIR-205, a known tumor suppressor gene in prostate cancer, gene set enrichment analysis revealed that higher MIR-5010 expression was linked to increased Nrf-2 downstream signaling (enriched score: 0.35; p = 0.17). In vitro assays in prostate cancer cells showed that DEHP enhanced Nrf-2 protein expression and its downstream signaling molecules (i.e., SOD2, Heme oxygenase-1, and EGR-1) while increasing GDF15 mRNA expression via EGR-1 regulation in a dose- and time-dependent manner. Furthermore, urinary GDF15 levels were positively associated with urinary MEOHP and MEHP metabolites in the biopsy cohort (p = 0.0007 and 0.011, respectively) and with urinary oxidative stress marker 8-OHdG, aggressive marker VEGF, and CCL2/MCP-1 levels in the prostatectomy cohort (p = 0.0004, 0.006, and 0.0034, respectively). These findings suggest that phthalate exposure induces Nrf-2 and its downstream signaling (i.e., EGR-1/GDF-15) through microRNA regulation, contributing to prostate cancer aggressiveness.

Growth Differentiation Factor-15 IsAssociated With Congestion-Related Anorexia and Weight Loss in AdvancedHeartFailure.

Growth differentiation factor (GDF)-15 is a pleiotropic cytokine that is associated with appetite-suppressing effects and weight loss in patients with malignancy. This study aims to investigate the relationships between GDF-15 levels, anorexia, cachexia, and clinical outcomes in patients with advanced heart failure with reduced ejection fraction (HFrEF). In this observational, retrospective analysis, a total of 344 patients with advanced HFrEF (age 58 ± 10 years, 85% male, 67% NYHA functional class III), underwent clinical and echocardiographic examination, body composition evaluation by skinfolds and dual-energy x-ray absorptiometry, circulating metabolite assessment, Minnesota Living with HeartFailure Questionnaire, and right heart catheterization. The median GDF-15 level was 1,503ng/L (Q1-Q3: 955-2,332ng/L) (reference range:<1,200ng/L). Higher GDF-15 levels were associated with more prevalent anorexia and cachexia. Patients with higher GDF-15 had increased circulating free fatty acids and beta-hydroxybutyrate, lower albumin, cholesterol, and insulin/glucagon ratio, consistent with a catabolic state. Patients with higher GDF-15 had worse congestion and more severe right ventricular dysfunction. In multivariable Cox analysis, elevated GDF-15 was independently associated with risk of the combined endpoint of death, urgent transplantation, or left ventricular assist device implantation, even after adjusting for coexisting anorexia and cachexia (T3 vs T1 HR: 2.31 [95%CI: 1.47-3.66]; P< 0.001). In patients with advanced HFrEF, elevated circulating GDF-15 levels are associated with a higher prevalence of anorexia and cachexia, right ventricular dysfunction, and congestion, as well as an independently increased risk of adverse events. Further studies are warranted to determine whether therapies altering GDF-15 signaling pathways can affect metabolic status and clinical outcomes in advanced HFrEF.

Serum IL-27 and GDF15 levels in second trimester are associated with adverse pregnancy outcomes

Serum IL-27 and GDF15 levels in second trimester are associated with adverse pregnancy outcomes

Sleeve Gastrectomy Preferentially Increases GDF15 Plasma Levels in Patients With Obesity but Without Metabolic Syndrome.

The mechanisms by which bariatric/metabolic surgery induces weight loss and the amelioration of obesity-associated complications are far from being fully elucidated. Variations in circulating hormones involved in the regulation of energy balance are usually considered to explain the effects of surgery beyond the restrictive mechanism. Recent studies have shown that gastric bypass modulates the plasma levels of GDF15, a molecule with anorectic action potentially contributing to the body weight reduction observed after surgery. Here, we report that sleeve gastrectomy has different effects on GDF15 plasma levels in patients with obesity depending on the presence of metabolic syndrome (MetS). Patients with MetS showed higher GDF15 plasma levels at baseline, but they had no increase in hormone concentrations compared to patients without MetS. Furthermore, at baseline, a correlation between blood glucose and GDF15 was observed in patients with MetS, and between plasma insulin and GDF15 in patients without MetS. Considering this data, GDF15 seems a molecule reflecting the severity of metabolic derangements not directly involved in mechanisms of surgical weight loss, and its role in obesity physiopathology and treatment needs to be further investigated.

Association between DNA methylation predicted growth differentiation factor 15 and mortality: results from NHANES 1999–2002

BackgroundGrowth differentiation factor 15 (GDF15) is a crucial biomarker in various physiological and pathological processes. While elevated GDF15 levels are linked to increased mortality risk, the role of DNA methylation (DNAm)-predicted GDF15 in predicting mortality has not been extensively studied. The purpose of the study is to investigate the association between DNAm-predicted GDF15 levels and all-cause and cardiovascular disease (CVD) mortality in a nationally representative cohort.MethodsData from NHANES 1999–2002 were analyzed. DNAm-predicted GDF15 levels were estimated using a regression model. Weighted multivariate Cox regressions were employed to assess the relationship between DNAm-predicted GDF15 and mortality outcomes. Restricted cubic splines were used to explore dose-response relationships, and subgroup analyses were conducted to enhance result reliability.ResultsHigher DNAm-predicted GDF15 levels were significantly associated with increased all-cause mortality risk (HR = 1.08, 95% CI: 1.02–1.15). Participants in the highest DNAm-predicted GDF15 tertile showed significantly higher all-cause mortality risk (HR = 1.56, 95% CI: 1.16–2.10) and a 2.52-fold increased risk of cardiovascular mortality (HR = 2.52, 95% CI: 1.22–5.19). Kaplan-Meier curves revealed decreasing survival probability with higher DNAm-predicted GDF15 tertiles. Restricted cubic spline analysis demonstrated a non-linear dose-response relationship between DNAm-predicted GDF15 levels and cardiovascular mortality. The positive correlation between DNAm-predicted GDF15 and mortality remained robust in most of subgroups.ConclusionsDNAm-predicted GDF15 independently predicts all-cause and cardiovascular mortality. This association persists across multiple models and stratified subgroups, supporting GDF15’s value as a biomarker for mortality risk stratification. Future research should elucidate underlying biological mechanisms and evaluate GDF15’s clinical utility in guiding mortality risk reduction interventions.

Health implications of racial differences in serum growth differentiation factor levels among men with obesity.

Growth differentiation factor (GDF15) has been considered a biomarker and recently a hormonal driver for diseases in different populations. However, the role of GDF15 as a biomarker of health outcomes in obese men from different racial/ethnic background has not been evaluated. The objective of this study was to investigate the racial/ethnic differences on the relationship between GDF15 and markers of glucometabolic status, hormonal profile, body composition and bone mineral density (BMD) in obese men. One hundred ninety-three obese men from diverse racial/ethnic backgrounds were enrolled. BMD and body composition were measured by dual energy X-ray absorptiometry. Serum GDF15, osteocalcin, C-terminal telopeptide, sclerostin, adiponectin, leptin, estradiol, testosterone, follicle-stimulating hormone, luteinizing hormone, 25-hydroxyvitamin D, lipid profile, and hemoglobin A1C (A1C) were measured. Non-African Americans (NAA) had significantly higher GDF15 level than African Americans (AA). Level was also higher in patients with type 2 diabetes (T2DM). In both the groups GDF15 correlated with A1C and lean mass. However. GDF15 correlated with body fat, LDL total cholesteroland femoral neck BMD only in NAA and with appendicular lean mass only in AA. Ethnicity, total cholesterol and T2DM were found to be independent predictors of GDF15. We conclude that GDF15 may influence glucometabolic status, body composition and bone parameters which may affect cardiovascular risk and osteoporosis between races.

Identification of new bioactive molecules in platelet preparation, storage, and transfusion reactions for improved transfusion management

Platelet concentrates (PCs) intended for transfusion contain bioactive molecules that can be considered Biological Response Modifiers (BRMs), mainly originating from plasma regardless of the preparation process. During storage, NGAL and GDF-15 levels increase in single donor apheresis platelet concentrates (SDA-PC), whereas in buffy coat platelet concentrates (BC-PC), the levels of MIP1α, MCP-3, and HSAA increase, and GDF-15 levels decrease. These molecules, primarily released by leukocytes, may contribute to adverse reactions (ARs) following a PC transfusion. Notably, in SDA-PC or BC-PC transfusions that result in ARs, the levels of NGAL, HSAA, and GDF-15 are significantly elevated, while the levels of MDC and CX3CL1 are significantly reduced compared to transfusions without ARs. These biomarkers could potentially serve as predictors for PCs-induced ARs.

Oxidative damage and mitochondrial dysfunction in cystathionine beta-synthase deficiency

Cystathionine beta-synthase deficiency (CBSD) is the most prevalent inherited disorder of homocysteine metabolism in the transsulphuration pathway. Research have suggested oxidative stress and inflammation as candidate pathogenic mechanisms in CBSD. This study aims to evaluate mitochondrial dysfunction and oxidative stress biomarkers in cystathionine beta-synthase deficiency (CBSD) patients, which may aid in understanding the pathogenesis of CBSD and improving treatment. The study group comprised 23 patients with a diagnosis of CBSD and healthy controls. We analysed serum levels of NAD+ and NADH by fluorometric assay, FGF-21 and GDF-15 by ELISA, mitochondrial DAMPs by real time qRT-PCR, total homocysteine levels in plasma by enzymatic test and compared the results in CBSD group with healthy controls. In patient group, a positive correlation was found between the total homocysteine level and both GDF-15 and NAD+/NADH levels. Furthermore, there was a negative correlation between total homocysteine levels and both total NAD++NADH and NADH levels. The alterations in NAD+, FGF-21, GDF-15 levels, and NAD+/NADH ratio in patients suggest that oxidative damage coexists with mitochondrial dysfunction in CBSD. Assessment of oxidative damage and addition of anti-oxidant therapy together with mitochondrial support may have additional benefits in reducing long-term morbidity in CBSD patients.

ACVR2B polymorphism, Adiponectin, and GDF-15 levels as biomarkers for cachexia in gastrointestinal cancer

Reversing cancer cachexia remains a challenge. Genetic biomarkers for the early detection of the disease have been explored in order to enable the implementation of preventive measures. We therefore genotyped candidate genes based on cachexia phenotype and quantified adiponectin and GDF-15 levels in cachectic patients with gastrointestinal cancer. Patients with a diagnosis of gastrointestinal cancer were divided into a cachectic and a non-cachectic group after the start of chemotherapy. A control group (no cancer) was also included. We genotyped the following single nucleotide polymorphisms (SNPs) by quantitative PCR: FOXO3 (rs1935949), FOXO3 (rs4946935), ACVR2B (rs2268757), and SELP (rs6136). In addition, we quantified adiponectin and GDF-15 levels by ELISA. The rs2268757 SNP in the ACVR2B gene was associated with the weight loss phenotype in cachectic patients with gastrointestinal cancer (non-cachectic, P = 0.004). Plasma adiponectin levels were higher in cachectic patients compared to controls (P = 0.01) and non-cachectic patients (P = 0.004). GDF-15 was also elevated in cachectic patients compared to controls (P < 0.0001) and non-cachectic patients (P = 0.001). Analysis by sex showed elevated adiponectin levels in men (control, P = 0.01) and cachectic women (control, P = 0.04; non-cachectic, P = 0.01), as well as elevated GDF-15 levels in men (control, P = 0.002) and cachectic women (control, P = 0.002; non-cachectic, P = 0.007). However, there was no significant difference in the levels of these cytokines between cachectic men and women. The results suggest the rs2268757 SNP in the ACVR2B gene, adiponectin, and GDF-15 as potential biomarkers of cachexia in gastrointestinal cancer.

Older patients affected by COVID-19: investigating the existence of biological phenotypes

IntroductionCOVID-19 provides an opportunity to examine biological phenotypes (observable morphological, functional and biological characteristics) in individuals who experience the same acute condition, potentially revealing differences in response to acute external stressors. The aim our study was to investigate biological phenotypes in older patients hospitalized for COVID-19, exploiting a panel of aging biomarkers.MethodsData were gathered from the FRACOVID Project, an observational multicenter study, aimed to evaluate the impact of frailty on health-related outcomes in patients 60 + with COVID-19 in Northern Italy. A hierarchical cluster analysis was run using log-transformed and scaled values of TNF-a, IL-1 beta, IL-6, PAI-1, GDF-15, NT-proBNP, and Cystatin C evaluated at admission.ResultsEighty-one participants (mean age 75.3 years; 60.5% male) were evaluated. Frailty was identified in 42% of the sample and 27.2% were unable to ambulate outdoors. The mean hospital stay was 24.7 days, with an in-hospital mortality rate of 18.5%. Three biological phenotypes were found: (1) ‘inflammatory’, with high inflammatory biomarkers; (2) ‘organ dysfunction’, characterized by elevated cystatin C and NT-proBNP, and lower inflammatory markers; and (3) ‘unspecific’, with lower NT-proBNP and GDF-15 levels, and intermediate concentrations of other biomarkers. The ’organ dysfunction’ phenotype showed the highest mean age and prevalence of frailty, disability, and chronic diseases. The ‘inflammatory‘ phenotype showed the highest burden of respiratory and systemic signs and symptoms of infection.ConclusionBiological phenotypes might be used to identify different clinical and functional phenotypes in individuals affected by COVID-19.

Biomarker-enhanced cardiovascular risk prediction in patients with cancer: a prospective cohort study.

Continuously improving cancer-specific survival puts a growing proportion of cancer patients at risk of major adverse cardiovascular events (MACE), but tailored tools for cardiovascular risk prediction remain unavailable. To assess a broad panel of cardiovascular biomarkers and risk factors for the prediction of MACE and cardiovascular death in cancer patients. In total, 2192 patients with newly diagnosed or recurrent cancer were followed prospectively for the occurrence of 2-year MACE and 5-year cardiovascular death. Univariable and multivariable risk models were fit to assess independent associations of cardiovascular risk factors and biomarkers with adverse outcomes, and a risk score was developed. Traditional cardiovascular risk factors and selected cancer types were linked to higher MACE risk. While levels of Lp(a), CRP, and GDF-15 did not associate with MACE, levels of ICAM-1, P-/E-/L-selectins, and NT-proBNP were independently linked to 2-year MACE risk. A clinical risk score was derived, assigning+1 point for male sex, smoking, and age of ≥60 years and+2 points for atherosclerotic disease, yielding a bootstrapped C-statistic of 0.76 (95% CI: 0.71-0.81) for the prediction of 2-year MACE. Implementation of biomarker data conferred improved performance (0.83, 95% CI: 0.78-0.88), with a simplified model showing similar performance (0.80, 95% CI: 0.74-0.86). The biomarker-enhanced and simplified prediction models achieved a C-statistic of 0.82 (95% CI: 0.71-0.93) and 0.74 (95% CI: 0.64-0.83) for the prediction of 5-year cardiovascular death. Biomarker-enhanced risk prediction strategies allow the identification of cancer patients at high risk of MACE and cardiovascular death. While external validation studies are ongoing, this first-of-its-kind risk score may provide the basis for personalized cardiovascular risk assessment across cancer entities.

Elevated GDF-15 is associated with stroke severity, myocardial injury and poor clinical outcome in patients after acute ischemic stroke

Abstract Background GDF-15 is emerging as a biomarker of cardiometabolic risk and disease burden. Increased concentrations of circulating GDF-15 are associated with increased mortality in patients with acute coronary syndromes or heart failure. Purpose We aimed to describe relation between GDF-15 elevation with stroke severity, myocardial injury and poor clinical outcome in patients after acute ischemic stroke (AIS). Methods Patients after AIS were enrolled in our study. Blood samples were obtained from patients at the time of admission, 24 and 48 hours later to determine the plasma levels of GDF-15 and high-sensitive troponin I (hs-cTnI). Receiver-operating characteristic (ROC) curve analysis was used to determine the diagnostic accuracy and optimal elevation cut-off values of GDF-15 on day 1 for the severity of acute stroke defined by NIHSS score. The optimal cut off in our group was 1776 pg/ml (Sensitivity 0,8, Specificity 0,52). Myocardial injury was defined by fourth universal definition of myocardial infarction using hs-cTnI. Demographic characteristics, clinical data, functional outcome, and all-cause mortality at 1 year were compared between groups according to GDF-15 levels. National Institutes of Health Stroke Scale (NIHSS) at the time of admission and the modified Rankin Scale (mRS) 90 days following the patient’s discharge from the hospital were used to assess stroke severity and clinical outcome. All analyses were performed with SPSS 29.0 (SPSS Inc). Results Between August 2020 and August 2022, 177 patients after AIS were enrolled. Elevated GDF-15 was observed in 71 patients (40,1%). Most common comorbidities included arterial hypertension, dyslipidemia, type 2 DM and atrial fibrillation. In analysis, we observed a connection between elevated GDF-15 with unfavourable outcome evaluated by mRS at 90 days (HR 2.57, 95% CI 1,44 to 4,57, p=0.001) and with all-cause death at 1 year (HR 4.479, 95% CI 1,81 to 11,09, p=0.001). GDF-15 elevation was associated with myocardial injury (Figure 1C). Moreover, individuals with moderate to severe and severe strokes (NIHSS 16-42) displayed higher GDF-15 levels compared to those with minor to moderate stroke (Figure 1D). The Kaplan-Meier survival curve accentuated a significantly elevated all-cause mortality among patients with increased GDF-15 (p &amp;lt; 0.001) (Figure 2). In multivariate regression analysis elevated GDF-15 was associated with atrial fibrillation and high-sensitive troponin I elevation. Conclusion The conclusions drawn suggest that heightened GDF-15 is associated with increased stroke severity, myocardial injury and unfavourable outcome.

Effects of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on mitochondrial-derived peptide-c and on markers of neurohumoral activation

Abstract Background/Introduction Type-2 diabetes mellitus (T2DM) is associated with increased prevalence of cardiovascular disease. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on mitochondrial-derived peptide-c (MOTS-c), N-terminal pro B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, oxidant and antioxidant biomarkers and cardiovascular function of T2DM patients. Methods A total of 160 T2DM patients were randomized to insulin (n = 40), liraglutide (n = 40), empagliflozin (n = 40) or their combination (GLP-1RA+SGLT-2i) (n = 40) as add-on to metformin. We measured at baseline, at 4 and at 12 months of treatment: a) plasma levels of MOTS-c, NT-proBNP and GDF-15, b) thiobarbituric acid reactive substances (TBARS), as an oxidant biomarkers, and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), as an antioxidant biomarker, and c) global left ventricular longitudinal strain (GLS) and global work index (GWI) using speckle-tracking imaging. Results Twelve months after treatment, treatment with SGLT-2i and GLP-1RA+SGLT-2i improved MOTS-c (14.89 ± 11.27 vs. 7.26 ± 4.21 ng/mL, p=0.009, 6.49 ± 3.91 vs. 5.6 ± 3.38 ng/mL, p=0.029, respectively), while treatment with insulin and GLP-1RA had a neutral effect on this biomarker (p &amp;gt; 0.05; Table). GLP-1RA, SGLT-2i and their combination showed a greater reduction of NT-proBNP (-43.1% vs. -54.2% vs. -56.9% vs. -14.7%; Figure) and GDF-15 (-14.8% vs. -15.2% vs. -16.1% vs. -0.9%) than insulin (p &amp;lt; 0.05 for all comparisons), despite the fact that all patient achieved adequate glycemic control. GLP-1RA or GLP-1RA+SGLT-2i provided a remarkable reduction of TBARS and increase of GLS and GWI compared to insulin or SGLT-2i (p &amp;lt; 0.05). In all patients, at 4 and at 12 months, the percentage reduction of NT-proBNP was associated with the improvement of TBARS, GLS and GWI (p &amp;lt; 0.05). The percentage reduction of GDF-15 was correlated with the increase of ABTS and with the improvement of GLS at 4 and 12 months (p &amp;lt; 0.05). In SGLT-2i group, the percentage increase of MOTS-c was related with the percentage reduction of GDF-15 (r = 0.81, p = 0.005) at 12 months. Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i and their combination resulted in reduction of cardiac biomarkers in parallel with a greater decrease of oxidative stress than insulin in T2DM. SGLT-2i appears more effective in the improvement of MOTS-c and markers of neurohumoral activation.TableFigure

Integrating aging biomarkers and immune function to predict kidney health: insights from the future of families and child wellbeing study.

Biomarkers of biological aging predict health outcomes more accurately than chronological age. This study examines the relationship between aging biomarkers, immune function, and kidney health using the Future of Families and Child Wellbeing Study Biomarker Dataset. Using Wave 5 (year 9) and Wave 6 (year 15), we examined biomarker data from a total of 4898 individuals. The panel of aging biomarkers, comprised of epigenetic clocks (GrimAge, Horvath), immune function markers (CD8 + T cells, plasmablasts), and metabolic indicators (GDF-15, leptin), was evaluated in depth. We used principal component analysis (PCA) and K-means clustering for subtype identification. A random forest regressor was employed to predict kidney function using Cystatin C levels, and the importance of features was assessed. Three clusters with unique biological age and immune function profiles were identified. Cluster 1 had younger biological age markers. In Cluster 2, both GrimAge and GDF-15 levels were significantly increased, indicating an elevated risk for age-related diseases. According to predictive modeling, GrimAge, Pack Years, and immune function markers had the strongest influence on Cystatin C levels (R2 = 0.856). The incorporation of immune aging markers enhanced the predictive power, emphasizing the importance of immunosenescence in renal health. Aging biomarkers and immune function significantly impact kidney health prediction. The study results call for the utilization of extensive biomarker tests for individualized elderly care and early recognition of kidney deterioration. Clinical practice can be improved by incorporating biological age assessments for the prevention and management of age-related diseases.

Elevated plasma level of arginine and its metabolites at labor among women with preeclampsia: A prospective cohort study.

Preeclampsia complicates 3-5% of all pregnancies and is associated with higher levels of asymmetric (ADMA) and symmetric (SDMA) dimethylarginines. Dimethylarginines are inhibitors of nitric oxide, which is a uterine smooth muscles relaxant. Women with hypertensive disorders experience a shorter labor duration compared to normotensive women. However, very little is known about the possible biochemical mechanisms behind differences in labor duration. In this study we aimed to investigate if women with preeclampsia had higher levels of arginines (ADMA, SDMA and L-arginine) at labor than controls, and also investigate the association between arginines and labor duration. The study was based on data from the Swedish, Uppsala County population-based, prospective cohort BASIC, between 2009 and 2018. Arginines were analyzed by Ultra-High Performance Liquid Chromatography using plasma samples taken at labor from women with preeclampsia (n=47) and normotensive pregnancy (n=90). We also analyzed inflammation markers CRP, TNF-R1, TNF-R2 and GDF-15. Women with preeclampsia had higher levels of ADMA (p<0.001), SDMA (p<0.001), L-arginine (p<0.001), TNF-R1 (p<0.001), TNF-R2 (p=0.03) and GDF-15 (p<0.01) compared to controls. Further, ADMA and SDMA, not inflammation markers, were negatively correlated to labor duration in preeclampsia. No correlations were observed when comparing arginines and inflammation markers. Among women with preeclampsia, our novel findings of higher level of arigines, negative correlation of arginines to duration of labor and absence of correlation of arginines to inflammation markers might support the theory that it is not inflammation but arginines which could be associated with shorter duration of labor in preeclampsia.

Hepatocyte-specific GDF15 overexpression improves high-fat diet-induced obesity and hepatic steatosis in mice via hepatic FGF21 induction

GDF15 and FGF21, stress-responsive cytokines primarily secreted from the liver, are promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interaction between GDF15 and FGF21 remains unclear. We examined the effects of hepatocyte-specific GDF15 or FGF21 overexpression in high-fat diet (HFD)-fed mice for 8 weeks. Hydrodynamic injection of GDF15 or FGF21 sustained high circulating levels of GDF15 or FGF21, respectively, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and hepatic steatosis. In addition, GDF15 treatment led to early reduction in body weight despite no change in food intake, indicating the role of GDF15 other than appetite loss. GDF15 treatment increased liver-derived serum FGF21 levels, whereas FGF21 treatment did not affect GDF15 expression. GDF15 promoted eIF2α phosphorylation and XBP1 splicing, leading to FGF21 induction. In murine AML12 hepatocytes treated with free fatty acids (FFAs), GDF15 overexpression upregulated Fgf21 mRNA levels and promoted eIF2α phosphorylation and XBP1 splicing. Overall, continuous exposure to excess FFAs resulted in a gradual increase of β-oxidation-derived reactive oxygen species and endoplasmic reticulum stress, suggesting that GDF15 enhanced this pathway and induced FGF21 expression. GDF15- and FGF21-related crosstalk is an important pathway for the treatment of MASLD.

Ferroptosis related CPT1A and GDF15 gene polymorphisms are risk factors for lung adenocarcinoma: A case-control study

BackgroundFerroptosis is not only a consequence of inflammation, but also a dynamic process. Recent bioinformatics analysis suggests that ferroptosis related genes might be associated with lung adenocarcinoma (LUAD). CPT1A and GDF15 are critical for the process of ferroptosis and development of inflammation; however, little study focused on the mutation level of these genes in patients with LUAD. MethodsThe candidate SNPs in CPT1A and GDF15 were genotyped in 320 pairs of LUAD patients and controls using Mass ARRAY platform. Moreover, the different expression of CPT1A and GDF15 in LUAD cases and healthy controls were validated by qRT-PCR and ELISA. ResultsThe rs80356779 G > A, rs3019594 C > T, rs888663 T > G and rs4808793 G > C all exhibited an increased risk of the disease (p < 0.05). Moreover, the rs80356779-GA, rs3019594-TT, rs888663-TG and rs4808793-CC genotypes were all related to different levels of increase in LUAD risk (p < 0.05). Genetic model results showed that rs80356779 G > A, rs888663 T > G and rs4808793 G > C were associated with LUAD susceptibility under dominant and additive models (p < 0.05), while rs3019594 C > T was correlated with an elevated risk of the disease in all three models (p < 0.05). Additionally, patients with rs80356779 G > A and rs3019594 C > T exhibited lower expression and serum concentration of CPT1A compared with wile types, and patients with rs888663 T > G and rs4808793 G > C exhibited higher serum and expression level of GDF15. ConclusionThe results provided new clues for the role of ferroptosis in LUAD and new potential targets for screening of susceptible population.

Growth Differentiation Factor 15 during pregnancy and postpartum as captured in blood, cerebrospinal fluid and placenta: A cohort study on associations with maternal mental health

IntroductionGrowth Differentiation Factor 15 (GDF15) increases substantially during pregnancy and is primarily produced by the placenta. Elevated levels of GDF15 have been associated with mental health problems in non-perinatal populations, higher corticosterone levels, and decreased estrogen receptor activity. However, the role of GDF15 in mental health during the perinatal transition remains unknown. This longitudinal study is the first to evaluate pregnancy levels of GDF15 in cerebrospinal fluid (cGDF15), plasma (pGDF15) and placenta GDF15 mRNA, along with mapping plasma GDF15 (pGDF15) level changes from late pregnancy to early postpartum. Moreover, we aimed to evaluate the association between pregnancy cGDF15 levels and cortisol early postpartum, evaluate the association between pregnancy cGDF15 levels and mental health in pregnancy and postpartum, and evaluate the association between pGDF15 and estrogens and high-sensitivity C-reactive protein (CRP). MethodsWe included data from 95 women scheduled for a planned cesarean section and obtained cerebrospinal fluid (CSF) and plasma levels of GDF15. We quantified GDF15 mRNA levels in placenta biopsies. Estrogens, high-sensitivity CRP, and mental health measures were further collected on the day or one day before the cesarean section. At five weeks postpartum, mental health measures and saliva samples for cortisol analyses were collected. Correlation analyses for GDF15 in CSF, plasma, and placenta mRNA were performed, along with association analyses for pregnancy cGDF15, Cortisol Awakening Response, and mental health outcomes. ResultsWe demonstrated a strong correlation between cGDF15 and pGDF15 (r=0.52; p<0.001) and found that both cGDF15 and pGDF15 correlated with placenta GDF15 mRNA*placental weight (r=0.62, p<0.001 and r=0.44, p=0.008, respectively). During late pregnancy, both estradiol (E2) and estriol (E3) were significantly associated with pGDF15 levels (E2: p=0.002; E3: p(corrected)<0.001). Finally, we found that cGDF15 levels were not associated with self-reported mental well-being or the Cortisol Awakening Response or absolute cortisol at awakening postpartum. ConclusionThis novel study points to the unique hormonal landscape during the perinatal transition and the specific role of GDF15 in pregnancy, which appears uncoupled with perinatal mental health and cortisol outcomes. Our data also strongly imply that the overall amount of circulating GDF15 in late pregnancy is closely related to placenta size.