GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma / 医学前沿

Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.

Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons / 神经科学通报·英文版

Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. It is widely distributed in the central and peripheral nervous systems. Whether and how GDF-15 modulates nociceptive signaling remains unclear. Behaviorally, we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats. Electrophysiologically, we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia (DRG) neurons. Furthermore, GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents, and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction. GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels, suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel. Immunohistochemistry results showed that activin receptor-like kinase-2 (ALK2) was widely expressed in DRG medium- and small-diameter neurons, and some of them were Nav1.8-positive. Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors. Inhibition of PKA and ERK, but not PKC, blocked the inhibitory effect of GDF-15 on Nav1.8 currents. These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK, which mediate the peripheral analgesia of GDF-15.

Regulation of Systemic Glucose Homeostasis by T Helper Type 2 Cytokines

Obesity results in an inflammatory microenvironment in adipose tissue, leading to the deterioration of tissue protective mechanisms. Although recent studies suggested the importance of type 2 immunity in an anti-inflammatory microenvironment in adipose tissue, the regulatory effects of T helper 2 (Th2) cytokines on systemic metabolic regulation are not fully understood. Recently, we identified the roles of the Th2 cytokine (interleukin 4 [IL-4] and IL-13)-induced adipokine, growth differentiation factor 15 (GDF15), in adipose tissue in regulating systemic glucose metabolism via signal transducer and activator of transcription 6 (STAT6) activation. Moreover, we showed that mitochondrial oxidative phosphorylation is required to maintain these macrophage-regulating autocrine and paracrine signaling pathways via Th2 cytokine-induced secretion of GDF15. In this review, we discuss how the type 2 immune response and Th2 cytokines regulate metabolism in adipose tissue. Specifically, we review the systemic regulatory roles of Th2 cytokines in metabolic disease and the role of mitochondria in maintenance of type 2 responses in adipose tissue homeostasis.

Correlation between GDF-15 gene polymorphism and the formation of collateral circulation in acute ST-elevation myocardial infarction

Summary Objective: To explore the correlation between growth differentiation factor 15 (GDF-15) -3148C/G polymorphism and the formation of collateral circulation in acute ST-elevation myocardial infarction (STEMI) in Han population of Taiyuan area. Method: The present study included 92 STEMI patients and 56 normal controls based on coronary angiography; STEMI group was divided into collateral group and non-collateral group according to Rentrop's grading method. Polymerase chain reaction (PCR) and DNA sequencing methods were used to detect and analyze the GDF-15 -3148C/G polymorphism in all participants. Results: There was significant difference in GDF-15 -3148C/G CC and GC distribution between STEMI group and control group (p=0.009); the allele frequencies between these two groups were also significant different (p=0.016); and the risk genotype for STEMI was CC with increased OR=2.660. For STEMI group, GDF-15 -3148C/G CC and GC distribution was also significantly different between patients with and without collateral (p=0.048), and CC genotype significantly promote the formation of collateral circulation. However, there were no significant differences in allele frequencies between these two subgroups of STEMI. Conclusion: There was correlation between GDF-15-3148C/G polymorphism and the formation of collateral circulation in patients with acute STEMI.

Strain auricular izquierdo y biomarcadores cardíacos como predictores de accidente cerebrovascular en pacientes con fibrilación auricular de reciente comienzo / Left atrial strain and biomarkers for stroke in patients with recent onset atrial fibrillation

Introducción: La miopatía y fibrosis auricular representan el sustrato protrombótico y proarrítmico en pacientes con fibrilación auricular (FA). Estudios recientes muestran relación entre el strain auricular izquierdo (SAI), eventos cardiovasculares y recurrencia en pacientes con FA. La asociación entre SAI y bio-marcadores cardíacos como predictores de accidente cerebrovascular silente (ACVs) en pacientes con FA de reciente comienzo (FArc) no ha sido estudiada. Objetivo: Determinar si la asociación entre SAI y biomarcadores cardíacos contribuye a la predicción de ACV en pacientes con FArc. Métodos: Se realizó un estudio prospectivo que permitió reclutar 57 pacientes con FArc (primer episodio de < de 8 semanas de evolución). Obtenido consentimiento informado (CI) se realizó recolección de datos clínicos y muestras de sangre para determinación de Pro-BNP, Dimero-D y GDF-15. Se realizó resonancia nuclear magnética cerebral (RNMc) y ecocardiograma transtorácico (ETT) durante los primeros 3 días de inclusión y en ritmo sinusal. Para la evaluación de SAI se consideró la curva de deflexión positiva durante la sístole ventricular (SAIs), derivada de speckle tracking, considerando el promedio de 5 ciclos. Se utilizó Mann Whitney U test y Spearman Rho para análisis estadístico. Resultados: La edad promedio fue 70±8,2 años y el 70% fueron hombres. El CHA2DS2-VASc score promedio fue 3,1±1 y el promedio de pro-BNP, Di-mero-D y GDF-15 fue 96,1±12,4 pg/ml, 990±140 ng/ ml y 12 ng/ml respectivamente. 15% de los pacientes (n=9) presentaban ACVs en la RNMc al momento del diagnóstico. Se observó, además, que los pacientes con ACV presentaban un SAIs más bajo que los pacientes sin eventos (5,5±1,1% y 14,6±7,3% respectivamente p=0.04). Adicionalmente, se encontró una correlación significativa entre SAIs y pro-BNP, Dimero-D y GDF-15. Conclusiones: En este trabajo se evidenció que el 15% de los pacientes con FArc presenta ACVs al momento del diagnóstico. El SAIs bajo se correlaciona de forma inversa con los biomarcadores de sobrecarga, trombogénesis, fibrosis auricular y presencia de ACV silente. Estos resultados pueden ser utilizados para una mejor estratificación del riesgo de ACV en pacientes con FA.

Introduction: Atrial myopathy and fibrosis constitute a pro-arrhythmic and pro-thromboembolic substrate in patients with atrial fibrillation (AF). Recent studies using left atrial strain (LAS) have shown that LAS contributes to predict AF recurrence in patients with paroxysmal AF. The association between LAS and cardiac biomarkers in predicting silent stroke (SS) in patients with new AF has not been studied. Aim: The association of LAS and cardiac biomarkers contribute to predict SS in patients with new AF. Methods: We have prospectively evaluated 57 consecutive patients with new AF (first episode with less than 8 weeks of evolution). Baseline clinical characteristics and blood samples for determinations of Pro-BNP, D-Dimer and GDF-15 were obtained. Brain magnetic resonance (BMRI) and 2D Echo were performed within 3 days. In sinus rhythm, the positive deflection during ventricular systole of the LAS curve derived from speckle tracking was considered (mean of 5 cycles) (LASS). Mann Whitney U test and Spearman Rho were used for statistical analysis. Results: Mean age was 70±8,2 years, 70% were men. The mean CHA2DS2-VASc score was 3,1±1. Mean pro-BNP, D-Dimer and GDF-15 were 96,1±12,4 pg/ml, 990±140 ng/ml and 12 ng/ml, respectively. Fifteen percent of patients (n=9) had evidence of previous SS in BMRI. Patients with SS had significantly less LASS than patients without events (5,5±1,1% and 14,6±7,3% respectively p=0,04). In addition, a significant correlation between LASs and pro-BNP, D-Dimer and GDF-15 was found. Conclusion: Evidence of SS was found in 15% of patients with new AF. This was associated with LASs impairment, which was inversely correlated with cardiac biomarkers of LV overload, thrombogenesis and LA fibrosis. These findings could be utilized for a better risk stratification of stroke in patients with new AF.

Growth Differentiation Factor 15 Predicts Chronic Liver Disease Severity

BACKGROUND/AIMS: Growth differentiation factor 15 (GDF-15) belongs to the transforming growth factor-β superfamily. GDF-15 is emerging as a biomarker for several diseases. The aim of this study was to determine the clinical performances of GDF-15 for the prediction of liver fibrosis and severity in chronic liver disease. METHODS: The serum GDF-15 levels were examined via enzyme immunoassay in 145 patients with chronic liver disease and 101 healthy individuals. The patients with chronic liver disease consisted of 54 patients with chronic hepatitis, 44 patients with compensated liver cirrhosis, and 47 patients with decompensated liver cirrhosis. RESULTS: Of the patients with chronic liver diseases, the decompensated liver cirrhosis patients had an increased serum GDF-15 (3,483 ng/L) level compared with the patients with compensated liver cirrhosis (1,861 ng/L) and chronic hepatitis (1,232 ng/L). The overall diagnostic accuracies of GDF-15, as determined by the area under the receiver operating characteristic curves, were as follows: chronic hepatitis=0.656 (>574 ng/L, sensitivity, 53.7%; specificity, 79.2%), compensated liver cirrhosis=0.886 (>760 ng/L, sensitivity, 75.6%; specificity, 92.1%), and decompensated liver cirrhosis=0.984 (>869 ng/L, sensitivity, 97.9%; specificity, 94.1%). CONCLUSIONS: This investigation represents the first study to demonstrate the availability of GDF-15 in chronic liver disease. GDF-15 comprised a useful biomarker for the prediction of liver fibrosis and severity in chronic liver disease.

Effects of growth differentiation factor-15 (GDF-15) on neurological systems, cardiovascular diseases, and cancer progression / 生理学报

Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor beta superfamily. GDF-15 expression is dramatically upregulated during acute brain injury, cancer, cardiovascular disease, and inflammation, suggesting its potential value as a disease biomarker. It has been suggested that GDF-15 has neurotropic effects in the nervous system. Our studies showed that GDF-15 modulated the expression of neuronal Kand Caion channels and increased the release of excitatory transmitter in the medial prefrontal cortex of mice. GDF-15 is also involved in the complex modulation of cancer and cardiovascular disease. Here, we reviewed studies involving the modulation of GDF-15 expression and its mechanisms, the primary pathological and physiological functions of GDF-15 in neurological and cardiovascular systems, and its role in cancer progression. The biological effects and the values of GDF-15 in basic research and clinical applications were also addressed.

Association between Growth Differentiation Factor 15 (GDF15) and Cardiovascular Risk in Patients with Newly Diagnosed Type 2 Diabetes Mellitus

We investigated an association between serum Growth Differentiation Factor 15 (GDF15) level and cardiovascular risk in patients with newly diagnosed type 2 diabetes mellitus (T2D). A total of 107 participants were screened for T2D and divided into a T2D group and a control group (without diabetes). We used the Framingham risk score (FRS) and the New Pooled Cohort Equation score to estimate the 10-year risk of atherosclerotic cardiovascular disease. Serum GDF15 levels were measured using an enzyme-linked immunosorbent assay. Correlation analyses were performed to evaluate the associations between GDF15 level and cardiovascular risk scores. The mean serum GDF15 level was elevated in the T2D group compared to the control group (P < 0.001). A positive correlation was evident between serum GDF15 level and age (r = 0.418, P = 0.001), the FRS (r = 0.457, P < 0.001), and the Pooled Cohort Equation score (r = 0.539, P < 0.001). After adjusting for age, LDL-C level, and body mass index (BMI), the serum GDF15 level was positively correlated with the FRS and the New Pooled Cohort Equation score. The serum GDF15 level is independently associated with cardiovascular risk scores of newly diagnosed T2D patients. This suggests that the level of GDF15 may be a useful predictive biomarker of cardiovascular risk in newly diagnosed T2D patients.

Effect of Atorvastatin on Growth Differentiation Factor-15 in Patients with Type 2 Diabetes Mellitus and Dyslipidemia

BACKGROUND: Elevated serum levels of growth differentiation factor-15 (GDF-15) are associated with type 2 diabetes. Therefore, the effects of atorvastatin on metabolic parameters and GDF-15 levels in patients with type 2 diabetes and dyslipidemia were evaluated. METHODS: In this prospective randomized trial from February 2013 to March 2014, 50 consecutive type 2 diabetic patients with a low density lipoprotein cholesterol (LDL-C) levels > or =100 mg/dL were enrolled. The patients were divided into two groups based on the amount of atorvastatin prescribed, 10 mg/day (n=23) or 40 mg/day (n=27). The effect of atorvastatin on metabolic parameters, including lipid profiles and GDF-15 levels, at baseline and after 8 weeks of treatment were compared. RESULTS: The baseline metabolic parameters and GDF-15 levels were not significantly different between the two groups. After 8 weeks of treatment, the total cholesterol (TC) and LDL-C levels were significantly decreased in both groups. The mean changes in TC and LDL-C levels were more significant in the 40 mg atorvastatin group. The GDF-15 level was decreased in the 10 mg atorvastatin group, from 1,460.6+/-874.8 to 1,451.0+/-770.8 pg/mL, and was increased in the 40 mg atorvastatin group, from 1,271.6+/-801.0 to 1,341.4+/-855.2 pg/mL. However, the change in the GDF-15 level was not statistically significant in the 10 or 40 mg atorvastatin group (P=0.665 and P=0.745, respectively). CONCLUSION: The GDF-15 levels were not significantly changed after an 8-week treatment with atorvastatin in type 2 diabetic patients.

Macrophage Inhibitory Cytokine-1 as a Novel Diagnostic and Prognostic Biomarker in Stage I and II Nonsmall Cell Lung Cancer / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Increased level of serum macrophage inhibitory cytokine-1 (MIC-1), a member of transforming growth factor-μ superfamily, was found in patients with epithelial tumors. This study aimed to evaluate whether serum level of MIC-1 can be a candidate diagnostic and prognostic indicator for early-stage nonsmall cell lung cancer (NSCLC).</p><p><b>METHODS</b>A prospective study enrolled 152 patients with Stage I-II NSCLC, who were followed up after surgical resection. Forty-eight patients with benign pulmonary disease (BPD) and 105 healthy controls were also included in the study. Serum MIC-1 levels were measured using an enzyme-linked immunosorbent assay, and the association with clinical and prognostic features was analyzed.</p><p><b>RESULTS</b>In patients with NSCLC, serum protein levels of MIC-1 were significantly increased compared with healthy controls and BPD patients (all P< 0.001). A threshold of 1000 pg/ml of MIC-1 was found in patients with early-stage (Stage I and II) NSCLC, with sensitivity and specificity of 70.4% and 99.0%, respectively. The serum levels of MIC-1 were associated with age (P = 0.001), gender (P = 0.030), and T stage (P = 0.022). Serum MIC-1 threshold of 1465 pg/ml was found in patients with poor early outcome, with sensitivity and specificity of 72.2% and 66.1%, respectively. The overall 3-year survival rate of NSCLC patients with high serum levels of MIC-1 (≥1465 pg/ml) was lower than that of NSCLC patients with low serum MIC-1 levels (77.6% vs. 94.8%). Multivariate Cox regression survival analysis showed that a high serum level of MIC-1 was an independent risk factor for reduced overall survival (hazard ratio = 3.37, 95% confidential interval: 1.09-10.42, P= 0.035).</p><p><b>CONCLUSION</b>The present study suggested that serum MIC-1 may be a potential diagnostic and prognostic biomarker for patients with early-stage NSCLC.</p>

Growth Differentiation Factor 15 Expression in Astrocytes After Excitotoxic Lesion in the Mouse Hippocampus

Growth differentiation factor 15 (GDF15) is, a member of the transforming growth factor beta (TGF-beta) superfamily of proteins. Although GDF15 is well established as a potent neurotrophic factor for neurons, little is known about its role in glial cells under neuropathological conditions. We monitored GDF15 expression in astrocyte activation after a kainic acid (KA)-induced neurodegeneration in the ICR mice hippocampus. In control, GDF15 immunoreactivity (IR) was evident in the neuronal layer of the hippocampus; however, GDF15 expression had increased in activated astrocytes throughout the hippocampal region at day 3 after the treatment with KA. LPS treatment in astrocytes dramatically increased GDF15 expression in primary astrocytes. In addition, LPS treatment resulted in the decrease of the IkappaB-alpha degradation and increase of the phosphorylation level of RelA/p65. These results indicate that GDF15 has a potential link to NF-kappaB activation, making GDF15 a valuable target for modulating inflammatory conditions.

Growth Differentiation Factor 15 Inhibits Elevated Expression of Matrix Metalloproteinase 1 Induced by Pooled Serum in Patients with Coroanry Artery Ectasia / 中国医学科学院学报

<p><b>OBJECTIVE</b>To observe the effects of coroanry artery ectasia (CAE) patients' pooled serum on the main proteinases and extracellular matrix (ECM) synthesis and explore whether the growth differentiation factor 15(GDF 15) can regulate the characteristic changes induced by CAE patients' pooled serum.</p><p><b>METHODS</b>Serum samples were collected from 32 CAE patients, 30 patients with coronary heart disease (CHD), and 31 subjects with normal coronary arteries (CON) and then mixed in the same volumes by groups. Then human umbilical vein smooth muscle cells were cultured with the media containing 25% pooled serum. After having been disposed, proteinase system and ECM synthesis system were detected in the cell and culture media samples. GDF15 or GDF15 antibodies was added into the 25% pooled serum in each group to observe if GDF 15 could impact the characteristic changes induced by CAE patients' pooled serum.</p><p><b>RESULTS</b>The expression of matrix metalloproteinases (MMP) 1 mRNA in CAE group was significantly higher than CON group (P=0.002) and CHD group (P=0.000), the secretory MMP1 protein and total MMPs activity in culture media were also upregulated in CAE group (both P<0.01). After adding GDF 15 into the culture media (GDF15+CAE group), the MMP1 mRNA ,secretory MMP1 protein, and total MMPs activity were significantly lower than CAE group (all P<0.01), while in the GDF15 antibody+CAE group, the MMP1 mRNA and total MMPs activities were significantly higher than in GDF15+CAE group (both P<0.01), but the secretory MMP1 protein was not different from GDF 15+CAE group (P>0.05).</p><p><b>CONCLUSION</b>The vascular smooth muscle cells may participate in the CAE process mainly by regulating MMPs system but not the elastase 2 or ECM synthesis system, and GDF15 may be an compensatory factor to prohibit the over-destruction of coronary ECM induced by MMPs.</p>

Expression of serum GDF15 and its clinical significance in multiple myeloma patients / 中南大学学报(医学版)

OBJECTIVE@#To determine the serum level of the growth differentiation factor 15 (GDF15) in multiple myeloma (MM) patients and analyze its level with other clinical parameters, and to investigate its significance in the formation, development and prognosis assessment of MM.@*METHODS@#We used enzyme-linked immunosorbent assay (ELISA) to measure the serum level of GDF15 in an MM group (24 pre-treatment patients) and in 20 healthy controls. All patients' clinical data were collected.@*RESULTS@#The serum GDF15 level was significantly higher in the MM group [(1.37±0.64) ng/mL] than in the normal control group [(0.14±0.06) ng/mL, P0.05). After 3 cycles of chemotherapy, patients with a>50% reduction of M protein had a significant reduction of GDF15, while for the patients whose M protein did not decrease obviously, their corresponding serum GDF15 level increased.@*CONCLUSION@#The serum GDF15 level may reflect the tumor burden in the MM patients, which increases obviously, is related with ISS, positively correlated with serum M protein level, β2- microglobulin level, serum creatinine and negatively with hemoglobin concentration and platelet count. The change of serum GDF15 level has some relation with the extent of M protein reduction, suggesting it may be used as a marker for therapy response.

Prognostic Value of Serum Growth Differentiation Factor-15 in Patients with Chronic Obstructive Pulmonary Disease Exacerbation / 결핵및호흡기질환

BACKGROUND: Information regarding prognostic value of growth differentiation factor 15 (GDF-15) and heart-type fatty acid-binding protein (H-FABP) in patients with chronic obstructive pulmonary disease (COPD) exacerbation is limited. The aim of this study was to investigate whether serum levels of GDF-15 and H-FABP predict an adverse outcome for COPD exacerbation. METHODS: Clinical variables, including serum GDF-15 and H-FABP levels were compared in prospectively enrolled patients with COPD exacerbation that did or did not experience an adverse outcome. An adverse outcome included 30-day mortality and need for endotracheal intubation or inotropic support. RESULTS: Ninety-seven patients were included and allocated into an adverse outcome (n=10) or a control (n=87) group. Frequencies of mental change and PaCO2>37 mm Hg were significantly higher in the adverse outcome group (mental change: 30% vs. 6%, p=0.034 and PaCO2>37 mm Hg: 80% vs. 22%, p1,600 pg/mL) was more common in the adverse outcome group (80% vs. 43%, p=0.041). However, serum H-FABP level and frequency of serum H-FABP elevation (>755 pg/mL) did not differ between the two groups. Multivariate analysis showed that an elevated serum GDF-15 and PaCO2>37 mm Hg were significant predictors of an adverse outcome (odds ratio [OR], 25.8; 95% confidence interval [CI], 2.7-243.8; p=0.005 and OR, 11.8; 95% CI, 1.2-115.3; p=0.034, respectively). CONCLUSION: Elevated serum GDF-15 level and PaCO2>37 mm Hg were found to predict an adverse outcome independently in patients with COPD exacerbation, suggesting the possibility that serum GDF-15 could be used as a prognostic biomarker of COPD exacerbation.

GDF15 Is a Novel Biomarker for Impaired Fasting Glucose

BACKGROUND: Growth differentiation factor-15 (GDF15) is a protein that belongs to the transforming growth factor beta superfamily. An elevated serum level of GDF15 was found to be associated with type 2 diabetes mellitus (T2DM). T2DM is an inflammatory disease that progresses from normal glucose tolerance (NGT) to impaired fasting glucose (IFG). Hence, we aimed to validate the relationship between GDF15 and IFG. METHODS: The participants were divided into the following three groups: NGT (n=137), IFG (n=29), and T2DM (n=75). The controls and T2DM outpatients visited the hospital for routine health check-ups. We used fasting blood glucose to detect IFG in nondiabetic patients. We checked the body mass index (BMI), C-reactive protein level, metabolic parameters, and fasting serum GDF15 level. RESULTS: Age, BMI, triglyceride, insulin, glucose, homeostatic model assessment-insulin resistance (HOMA-IR), and GDF15 levels were elevated in the IFG and T2DM groups compared to the NGT group. In the correlation analysis between metabolic parameters and GDF15, age and HOMA-IR had a significant positive correlation with GDF15 levels. GDF15 significantly discriminated between IFG and NGT, independent of age, BMI, and HOMA-IR. The serum levels of GDF15 were more elevated in men than in women. As a biomarker for IFG based on the receiver operating characteristic curve analysis, the cutoff value of GDF15 was 510 pg/mL in males and 400 pg/mL in females. CONCLUSION: GDF15 had a positive correlation with IR independent of age and BMI, and the serum level of GDF15 was increased in the IFG and T2DM groups. GDF15 may be a novel biomarker for detecting IFG in nondiabetic patients.

Value of plasma growth differentiation factor-15 in diagnosis and evaluation of type 2 diabetic nephropathy / 南方医科大学学报

<p><b>OBJECTIVE</b>To detect the plasma level of growth differentiation factor-15 (GDF-15) in patients of type 2 diabetic nephropathy and assess its value in diagnosis and evaluation of type 2 diabetic nephropathy.</p><p><b>METHODS</b>Thirty type 2 diabetic patients with normoalbuminuria, 20 with microalbuminuria, and 30 with macroalbuminuria, diagnosed according to Mogensen's criteria, were examined for plasma GDF-15 level using enzyme-linked immunosorbent assay.</p><p><b>RESULTS</b>The patients with macroalbuminuria had significantly higher plasma GDF-15 level than those with microalbuminuria and normoalbuminuria [1773.9 (1099.1-2357.4) pg/ml vs 864.0 (636.1-994.3) pg/ml and 704.5 (548.8-975.8) pg/ml, respectively, P<0.01], and patients with microalbuminuria had higher GDF-15 level than those with normoalbuminuria (P>0.05). Plasma GDF-15 level was found to increase early in the stage of mild renal dysfunction (60≤GFR<90 ml·min(-1)·1.73 m(-2)) with a median level of 999.5 (769.2-1372.1) pg/ml. Partial correlation analysis showed that plasma GDF-15 level was positively correlated with diabetic durations, mAlb, BUN and sCr (r=0.246, 0.493, 0.390, and 0.471, respectively, P<0.05), and negatively with eGFR (r=-0.438) and Alb (r=-0.397) (P<0.01). Multivariate linear regression analysis showed that a high plasma GDF-15 level was an independent risk factor for increased mAlb. In the diagnosis of renal dysfunction (eGFR<90 ml·min(-1)·1.73 m(-2)), the area under the receiver-operating characteristic curve (AUC) of GDF-15 was 0.801, significantly higher than that of mAlb (0.717, P<0.05). With the cut-off value of 733.78 pg/ml, plasma GDF-15 level had a sensitivity of 88.1% and a specificity of 58.1% for renal dysfunction diagnosis.</p><p><b>CONCLUSION</b>In patients with type 2 diabetic nephropathy, plasma GDF-15 level increases with the Mogensen stage, and as a independent risk factor for increased mAlb, it is significantly correlated with mAlb and eGFR, and serves, suggesting its value in early diagnosis, evaluation and prediction of the outcomes of type 2 diabetic nephropathy.</p>

Stress-induced growth-differentiation factor 15 plays an intriguing role in cardiovascular diseases / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To provide an overview of the current knowledge of growth-differentiation factor 15 (GDF-15) in heart disease.</p><p><b>DATA SOURCES</b>To identify relevant publications, we searched PubMED database combining the textual terms of heart, cardiac, cardiovascular disease with GDF-15.</p><p><b>STUDY SELECTION</b>Well-controlled, relatively large-scale, retrospective studies as well as meaningful individual cases were all selected as materials.</p><p><b>RESULTS</b>GDF-15 is a distant member of the transforming growth factor-β cytokine superfamily. In myocardium, GDF-15 is weakly expressed under physiological conditions. However, its expression level is increased in response to pathological stress. Growing evidence indicate that elevated levels of GDF-15 is a promising prognostic biomarker in cardiovascular diseases. Moreover, GDF-15 exhibits the properties of endogenous anti-hypertrophy of cardiomyocytes and protecting the heart suffering from ischemia and reperfusion insult.</p><p><b>CONCLUSION</b>Ve GDF-15 may be a promising biomarker for evaluation and management of patient with cardiovascular diseases, and have potential protective properties on myocardium.</p>

Plasma concentration of growth-differentiation factor-15 in children with congenital heart disease: relation ship to heart function and diagnostic value in heart failure / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the correlation between growth differentiation factor-15(GDF-15) and cardiac function in pediatric patients with congenital heart disease, and the diagnostic value of GDF-15 in heart failure(HF).</p><p><b>METHODS</b>From March 2011 to May 2012, 97 pediatric patients with congenital heart disease(CHD) who consecutively attended Chengdu Women's & Children's Central Hospital were enrolled in the study and assigned to HF (patients with heart failure, n=71) and Non-HF(patients without heart failure, n=26) groups. HF was defined as patients presenting with modified Ross score≥3. Plasma concentrations of GDF-15 and NT-proBNP were determined using ELISA. Left ventricular ejection fraction(LVEF) was tested by echocardiography. The correlation between GDF-15 and modified Ross score, LVEF and NT-proBNP was evaluated with Spearman's analysis. The area under the receiver-operating characteristic(ROC) curve for GDF-15 was examined, and the cut-off concentration of GDF-15 for diagnosing HF was detected.</p><p><b>RESULTS</b>The HF group demonstrated higher levels of GDF-15 and NT-proBNP, and a lower LVEF level (P<0.01) than the Non-HF group. Plasma GDF-15 level was positively correlated with modified Ross score and plasma NT-proBNP concentration (r=0.705, r=0.810 respectively; P<0.01), and negatively correlated with LVEF(r=-0.391, P<0.01). According to ROC analysis, the AUC of GDF-15 for detection of HF was 0.757. Sensitivity and specificity was 68.8% and 71.2% respectively for the cut-off value of 1306 ng/mL.</p><p><b>CONCLUSIONS</b>Plasma GDF-15 levels are significantly elevated in children with HF induced by CHD. Plasma GDF-15 levels are related to cardiac function, LVEF and plasma concentration of NT-proBNP. GDF-15 may potentially indicate HF in pediatric patients with CHD.</p>

Effect of GDF15 on iron overloading and erythropoiesis / 中国实验血液学杂志

Ineffective erythropoiesis is recognized as the principal reason of non-transfusional iron overload. In the process of expanded erythropoiesis, the apoptosis of erythroblasts induces the up-regulation of GDF15. GDF15 suppresses hepcidin production by the hepatocytes. Subsequently, low hepcidin levels increase iron absorption from the intestine resulting in iron overload. Physiological dose of GDF15 can promote the growth and differentiation of erythroid progenitors, but the high dose of GDF15 can suppress the secretion of hepcidin. The regulation of GDF15 may also be related to iron levels, epigenetic regulation and hypoxia. In this article the GDF15 and its expression and distribution, roles of GDF15 in erythropoiesis and iron overload, as well as the regulation factors of GDF15 are reviewed.

Correlation between serum growth differentiation factor-15 and TIMI risk scores in patients with unstable angina pectoris / 南方医科大学学报

<p><b>OBJECTIVE</b>To explore the correlation between serum levels of growth differentiation factor-15 (GDF-15) and Thrombolysis in Myocardial Infarction (TIMI) risk scores in patients with unstable angina pectoris (UA).</p><p><b>METHODS</b>The serum levels of GDF-15 in 97 patients with UA and 30 healthy volunteers were measured using enzyme-linked immunosorbent assay (ELISA) and compared between 3 patient groups with different TIMI scores to analyze relationship between serum GDF-15 levels and TIMI risk scores.</p><p><b>RESULTS</b>The serum levels of GDF-15 in UA patients were significantly higher than those in the healthy volunteers (P<0.01). GDF-15 levels also differed significantly between patients with different TIMI scores (P<0.01), and showed a significant positive correlation to TIMI risk scores.</p><p><b>CONCLUSION</b>Serum levels of GDF-15 can be used as an index for evaluating the severity of UA.</p>