Plasma Growth Differentiation Factor-15 Research Articles

GDF15 ameliorates sepsis-induced lung injury via AMPK-mediated inhibition of glycolysis in alveolar macrophage

Growth differentiation factor 15 (GDF15) as a stress response cytokine is involved in the development and progression of several diseases associated with metabolic disorders. However, the regulatory role and the underlying mechanisms of GDF15 in sepsis remain poorly defined. Our study analyzed the levels of GDF15 and its correlations with the clinical prognosis of patients with sepsis. In vivo and in vitro models of sepsis were applied to elucidate the role and mechanisms of GDF15 in sepsis-associated lung injury. We observed strong correlations of plasma GDF15 levels with the levels of C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), and lactate as well as Sequential Organ Failure Assessment (SOFA) scores in patients with sepsis. In the mouse model of lipopolysaccharide-induced sepsis, recombinant GDF15 inhibited the proinflammatory responses and alleviated lung tissue injury. In addition, GDF15 decreased the levels of cytokines produced by alveolar macrophages (AMs). The anti-inflammatory effect of glycolysis inhibitor 2-DG on AMs during sepsis was mediated by GDF15 via inducing the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α) and the expression of activating transcription factor 4 (ATF4). Furthermore, we explored the mechanism underlying the beneficial effects of GDF15 and found that GDF15 inhibited glycolysis and mitogen-activated protein kinases (MAPK)/nuclear factor-κB (NF-κB) signaling via promoting AMPK phosphorylation. This study demonstrated that GDF15 inhibited glycolysis and NF-κB/MAPKs signaling via activating AMP-activated protein kinase (AMPK), thereby alleviating the inflammatory responses of AMs and sepsis-associated lung injury. Our findings provided new insights into novel therapeutic strategies for treating sepsis.

Convalescent Growth Differentiation Factor-15 and Long-Term Outcomes after an Acute Coronary Syndrome.

Growth differentiation factor-15 (GDF-15) has been shown to be associated with adverse clinical outcomes in patients after an acute coronary syndrome when measured soon after an event. Although dynamic in the acute phase after myocardial injury, GDF-15 has been shown to remain stable during convalescence. In this study, we aimed to assess the value of GDF-15 as a long-term prognostic marker for clinical outcomes when measured in the convalescent phase following an acute coronary syndrome. GDF-15 concentrations were measured in 1945 patients who were recruited between 2002 and 2009 to the Coronary Disease Cohort Study. For this analysis, follow-up was curtailed at 10 years and association of GDF-15 with all-cause death, cardiovascular death, recurrent myocardial infarction, and heart failure hospitalizations were assessed with multivariate Cox proportional hazard regression analysis. After 10 years of follow-up, there were 648 deaths (348 from cardiovascular causes), 500 admissions for myocardial infarction, and 436 for heart failure. Four-month convalescent GDF-15 demonstrated a robust independent association with all endpoints, which remained after adjustment for Global Registry of Acute Coronary Events score and other convalescent biomarkers. When compared to the lowest quartile of GDF-15 concentrations, those in the highest quartile had a 3-fold increased risk of all-cause death. Convalescent plasma GDF-15 is a strong and independent predictor of 10-year all-cause death, cardiovascular death, recurrent myocardial infarction, and heart failure admission following an acute coronary syndrome. ACTRN12605000431628.

Proteomics validate circulating GDF-15 as an independent biomarker for COVID-19 severity.

Growth differentiation factor 15 (GDF-15) was originally described as a stress-induced cytokine, and a biomarker of aging and cardiovascular diseases. We hypothesized that circulating GDF-15 would be associated with COVID-19 disease severity. Herein, we explored this hypothesis in a large cohort of COVID-19 patients. Blood samples were collected from 926 COVID-19 adult patients and from 285 hospitalized controls from the Biobanque Québécoise de la COVID-19 (BQC19). COVID-19 severity was graded according to the WHO criteria. SOMAscan proteomics assay was performed on 50µL of plasma. ELISA were performed on 46 selected participants with left-over plasma to validate differences in plasma GDF-15 levels. Statistical analyses were conducted using GraphPad Prism 9.0 and SPSS. P values < 0.01 were considered significant. Proteomics showed that plasma GDF-15 levels were higher in COVID-19 patients compared to hospitalized controls. GDF-15 levels increased with COVID-19 severity. COVID-19 patients presenting with comorbidities including diabetes, cancer, chronic obstructive pulmonary disease (COPD) and cardiovascular disease had higher GDF-15 levels. ELISA revealed significant elevation of GDF-15 until 30 days after hospitalization. Plasma GDF-15 elevation was correlated with older age. Moreover, GDF-15 levels correlated with pro-inflammatory cytokine interleukin-6 (IL-6) and inflammation marker C-reactive protein (CRP) as well as soluble levels of its putative receptor CD48. No association was established between anti-SARS-CoV-2 IgG levels and plasma GDF-15 levels. This study confirms GDF-15 as a biomarker for COVID-19 severity. Clinical evaluation of GDF-15 levels could assist identification of persons at high-risk of progressing to severe disease, thus improving patient care.

Estimation of plasma growth differentiation factor 15 level in de novo acute myeloid leukemia patients

Abstract: BACKGROUND: Acute myeloid leukemia (AML) is a diversified disorder, characterized by clonal proliferation of myeloid precursors in peripheral blood (PB) and bone marrow (BM). Growth differentiation factor 15 (GDF15) is a member of transforming growth factor-β superfamily that has an important role in cancer prognosis and pathophysiology and it can induce apoptosis and inhibit growth and invasion of tumor. OBJECTIVES: The aim of this study was to estimate the GDF15 plasma levels in patients with de novo AML and their association with patients’ survival. MATERIALS AND METHODS: A cross-section samples from 60 adult patients who were newly diagnosed with de novo AML from September 2022 to September 2023 were included. Other 30 healthy adult individuals were involved as controls. The measurement of plasma GDF15 level was established by the ELISA technique using the human GDF15 ELISA kit. RESULTS: Plasma (GDF15) was higher in AML patients, and it was associated with inferior overall survival (OS). Plasma (GDF15) level shows positive correlation with age, hemoglobin level, and insignificant correlation with the BM and PB blast percentages, total white blood cell count, sex, and platelets. CONCLUSIONS: Plasma GDF15 levels in AML patients were high at the diagnosis and were associated with inferior OS.

GDF15 is a dynamic biomarker of the integrated stress response in the central nervous system.

Characterize Growth Differentiation Factor 15 (GDF15) as a secreted biomarker of the integrated stress response (ISR) within the central nervous system (CNS). We determined GDF15 levels utilizing invitro and invivo neuronal systems wherein the ISR was activated. Primarily, we used the murine model of vanishing white matter disease (VWMD), a neurological disease driven by persistent ISR in the CNS, to establish a link between levels of GDF15 in the cerebrospinal fluid (CSF) and ISR gene expression signature in the CNS. GDF15 was also determined in the CSF of VWM patients. GDF15 expression was increased concomitant to ISR activation in stress-induced primary astrocytes as well as in retinal ganglion cells following optic nerve crush, while treatment with 2Bact, a specific eIF2B activator, suppressed both the ISR and GDF15. In the VWMD model, CSF GDF15 levels corresponded with the magnitude of the ISR and were reduced by 2BAct. In VWM patients, mean CSF GDF15 was elevated >20-fold as compared to healthy controls, whereas plasma GDF15 was undifferentiated. These data suggest that CSF GDF15 is a dynamic marker of ISR activation in the CNS and may serve as a pharmacodynamic biomarker for ISR-modulating therapies.

Effect of a 6-Week Carbohydrate-Reduced High-Protein Diet on Levels of FGF21 and GDF15 in People With Type 2 Diabetes.

Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are increased in type 2 diabetes and are potential regulators of metabolism. The effect of changes in caloric intake and macronutrient composition on their circulating levels in patients with type 2 diabetes are unknown. To explore the effects of a carbohydrate-reduced high-protein diet with and without a clinically significant weight loss on circulating levels of FGF21 and GDF15 in patients with type 2 diabetes. We measured circulating FGF21 and GDF15 in patients with type 2 diabetes who completed 2 previously published diet interventions. Study 1 randomized 28 subjects to an isocaloric diet in a 6 + 6-week crossover trial consisting of, in random order, a carbohydrate-reduced high-protein (CRHP) or a conventional diabetes (CD) diet. Study 2 randomized 72 subjects to a 6-week hypocaloric diet aiming at a ∼6% weight loss induced by either a CRHP or a CD diet. Fasting plasma FGF21 and GDF15 were measured before and after the interventions in a subset of samples (n = 24 in study 1, n = 66 in study 2). Plasma levels of FGF21 were reduced by 54% in the isocaloric study (P < .05) and 18% in the hypocaloric study (P < .05) in CRHP-treated individuals only. Circulating GDF15 levels increased by 18% (P < .05) following weight loss in combination with a CRHP diet but only in those treated with metformin. The CRHP diet significantly reduced FGF21 in people with type 2 diabetes independent of weight loss, supporting the role of FGF21 as a "nutrient sensor." Combining metformin treatment with carbohydrate restriction and weight loss may provide additional metabolic improvements due to the rise in circulating GDF15.

GDF15 AND REDUCED PHYSICAL FUNCTION FOLLOWING TOTAL KNEE REPLACEMENT: A STUDY OF PHYSICAL RESILIENCE AND AGING

Abstract The metabolic and inflammatory cytokine growth-differentiation factor 15 (GDF15) increases with age and negatively associates with physical and cognitive function in older adults. We hypothesized GDF15 also negatively associates with resilient outcomes after surgery. This hypothesis was tested in the SPRING study of physical resiliency after total knee replacement by assessing relationships between pre-operative plasma GDF15 levels and postoperative resilience measures including short physical performance battery (SPPB) scores, fatigability, and grip strength. GDF15 analyses and physical resilience were assessed in 127 SPRING participants (age 70±6 yrs, n=83 women). Baseline GDF15 levels correlated with age (r=0.263, P&amp;lt; 0.05); age-adjusted analyses were applied. In total, pre-operative GDF15 levels did not significantly correlate with functional measures at any timepoint. However, in men (n=44), GDF15 levels correlated with age (r=0.408, P&amp;lt; 0.05) and significant age-adjusted correlations were observed in fatigue (r=0.368, P&amp;lt; 0.05), gait speed (r=-0.428, P&amp;lt; 0.05), and SPPB score (r=-0.329, P&amp;lt; 0.05). Additionally, GDF15 levels correlated with chair stands at six months (r=-0.398, P&amp;lt; 0.05), SPPB score at six months (r=-0.384, P&amp;lt; 0.05), and gait speed after one year (r=-0.487, P&amp;lt; 0.05). GDF15 did not significantly correlate with changes in SPPB score (P&amp;gt;0.05). There were no significant correlations between GDF15 and any of these functional measures in women (r-value range: -0.259 to 0.107; p-value range: 0.112 to 0.969). Elevated pre-operative GDF15 appears to correlate with worsening physical function following knee replacement in men, but not women. Further investigation is necessary to understand the relationship between GDF15 and the biology of physical resiliency.

GDF15 is a major determinant of ketogenic diet-induced weight loss

A ketogenic diet (KD) has been promoted as an obesity management diet, yet its underlying mechanism remains elusive. Here we show that KD reduces energy intake and body weight in humans, pigs, and mice, accompanied by elevated circulating growth differentiation factor 15 (GDF15). In GDF15- or its receptor GFRAL-deficient mice, these effects of KD disappeared, demonstrating an essential role of GDF15-GFRAL signaling in KD-mediated weight loss. Gdf15 mRNA level increases in hepatocytes upon KD feeding, and knockdown of Gdf15 by AAV8 abrogated the obesity management effect of KD in mice, corroborating a hepatic origin of GDF15 production. We show that KD activates hepatic PPARγ, which directly binds to the regulatory region of Gdf15, increasing its transcription and production. Hepatic Pparγ-knockout mice show low levels of plasma GDF15 and significantly diminished obesity management effects of KD, which could be restored by either hepatic Gdf15 overexpression or recombinant GDF15 administration. Collectively, our study reveals a previously unexplored GDF15-dependent mechanism underlying KD-mediated obesity management.

Vascular endothelial growth factor-D plasma levels in fluid overload and cardiac function evaluation of elderly patients with cardiovascular disease.

This study aimed to investigate the clinical significance of vascular endothelial growth factor (VEGF) subtypes and growth differentiation factor-15 (GDF-15) plasma levels in evaluating the fluid overload and cardiac function of elderly patients with cardiovascular disease. The plasma levels of VEGF-C, VEGF-D, and GDF-15 were measured using ELISA. Their correlations with N-terminal pro B-type natriuretic peptide (NT-Pro BNP) and echocardiography data were analyzed. 1. Higher plasma levels of VEGF-D and GDF-15 were observed in elderly patients with cardiovascular disease and heart failure(P < .01). VEGF-D plasma levels were higher in patients with chronic heart failure than those with acute myocardial infarction (P < .01). VEGF-D plasma levels were positively correlated with amino-terminal pro-B type natriuretic peptide (NT-pro BNP) (P < .001). VEGF-D plasma levels were positively correlated with echocardiographic parameters, including left atrial diameter, left ventricular end-diastolic diameter and left ventricular ejection fraction, in patients with cardiovascular disease (P < .01). 2. VEGF-C plasma levels were higher in acute myocardial infarction group (P < .05). The plasma levels of VEGF-C were not correlated with either VEGF-D or NT-pro BNP plasma levels. VEGF-C plasma levels had no correlation with echocardiographic parameters. 3. GDF-15 plasma levels were positively correlated with sera biomarkers of cardiac injury (creatine kinase isoenzyme MB and cardiac troponin I). GDF-15 plasma levels were positively correlated with urinary biomarkers of tubular injury (N-acetyl-β-galactosidase and α1-microglobulin). Both GDF-15 and NT-pro BNP plasma levels were correlated with age, estimated glomerular filtration rate (eGFR), and nutritional biomarkers (albumin and hemoglobin plasma levels). VEGF-D plasma levels is a potential biomarker of fluid overload and cardiac function in elderly patients with cardiovascular disease. Age, nutrition, and kidney injury are factors influencing both GDF-15 and NT-pro BNP plasma levels in estimating cardiac function and fluid overload.

Longitudinal Associations Between ATPase Inhibitory Factor 1, Growth Differentiation Factor-15, and Nutritional Status in Older Adults From the MAPT Study.

Weight and appetite regulation have been associated with the expression and secretion of ATPase inhibitory factor 1 (IF1) and growth differentiation factor-15 (GDF-15), 2 potential biomarkers for age-related mitochondrial dysfunction. The aim was to explore the associations between these biomarkers and nutritional variables in the Multidomain Alzheimer Preventive Trial study. IF1 and GDF-15 plasma levels were quantified at 1-year follow-up. The nutritional status was measured using the Mini Nutritional Assessment (MNA) score variation between baseline and 1- and 2-year visits; appetite loss was extracted from the MNA. Bodyweight was measured every 6 months until the third year and then yearly until the fifth year of follow-up, and weight loss was established if the loss was greater than 5% or 10% within the past 6 or 12 months, respectively. Bidirectional associations of IF1 and GDF-15 levels with malnutrition, appetite, and weight loss were examined. The interactions between individual IF1 and GDF-15 with sex were explored. Four hundred and forty-eight participants had MNA data and 1 045 had weight loss data. All the associations between IF1 levels and the MNA score, appetite loss, and weight loss were nonsignificant. Higher GDF-15 levels were cross-sectionally associated with appetite loss at the first year of follow-up, and the GDF-15 highest quartile was associated with nearly 80% higher risks of weight loss over 4 years. Interactions between IF1 and GDF-15 levels, and between these 2 markers and sex were not significantly associated with the outcomes. GDF-15 plasma levels were related to key malnutrition criteria.

Circulating Growth Differentiation Factor 15 as a Biomarker in Patients with Unresected Locally Advanced Non-Small Cell Lung Cancer Treated with Chemo-Radiotherapy with or without Metformin

Growth differentiation factor 15 (GDF15) is a member of the TGFβ family suggested to have prognostic value in cancer. Plasma GDF15 levels are elevated in humans during cellular stress, chronic diseases, and cancer and in response to cytotoxic (chemotherapy and radiation) or metabolic (metformin) therapies. Currently, the effect of combined metformin and cytotoxic treatment on circulating GDF15 is not known, and it is unclear whether GDF15 can serve as a biomarker in patients receiving such therapy. To examine this question, we analyzed circulating GDF15 levels in stage IIIA or IIIB NSCLC patients that participated in the randomized phase II clinical trial OCOG-ALMERA (NCT02115464). In OCOG-ALMERA patients were randomized to treatment with concurrent platinum-based chemotherapy and chest radiotherapy (60-66 Gy), with or without consolidation chemotherapy (CRT) or the same treatment plus metformin (2000mg/d). Dosimetric parameters and survival outcomes were collected by the trial. EDTA Plasma was collected from patients at baseline, 2 weeks into CRT treatment, at completion of CRT and 6 months after treatment initiation and assayed for GDF15 using an ELISA method. Statistical analyses were conducted to explore potential associations between plasma GDF15 with survival and dosimetric parameters. Fifteen patients from the metformin arm and 18 from the control arms provided EDTA plasma for this analysis. Average baseline GDF15 levels for all participants were elevated compared to those reported for healthy individuals. Baseline plasma GDF15 was statistically prognostic for RFS and OS (hazard ratio = 1.19, 95% CI = 1.06 to 1.34, p = 0.005). GDF15 levels increased during CRT treatment reaching the highest value at the end of cytotoxic therapy. Addition of metformin to CRT treatment was associated with further increase in circulating GDF15 (p<0.001). Plasma GDF15 levels at 2 weeks of CRT were positively correlated with size of the radiotherapy clinical target volume and volumes of esophagus and heart receiving high dose radiotherapy. This work suggests that GDF15 may be a promising prognostic marker to predict response to standard chemoradiation therapy in NSCLC. Future studies should aim to validate these results in larger datasets and examine whether GDF15 may have value as early biomarker of radiation toxicity in lung cancer patients.

Associations of circulating GDF15 with combined cognitive frailty and depression in older adults of the MARK-AGE study.

Growth differentiation factor-15 (GDF15) might be involved in the development of cognitive frailty and depression. Therefore, we evaluated cross-sectional associations of plasma GDF15 with combined cognitive-frailty-and-depression in older (i.e. ≥ 55years) and younger adults of the MARK-AGE study. In the present work, samples and data of MARK-AGE ("European study to establish bioMARKers of human AGEing") participants (N = 2736) were analyzed. Cognitive frailty was determined by the global cognitive functioning score (GCF) and depression by the Self-Rating Depression Scale (SDS score). Adults were classified into three groups: (I) neither-cognitive-frailty-nor-depression, (II) either-cognitive-frailty-or-depression or (III) both-cognitive-frailty-and-depression. Cross-sectional associations were determined by unadjusted and by age, BMI, sex, comorbidities and hsCRP-adjusted linear and logistic regression analyses. Cognitive frailty, depression, age and GDF15 were significantly related within the whole study sample. High GDF15 levels were significantly associated with both-cognitive-frailty-and-depression (adjusted β = 0.177 [0.044-0.310], p = 0.009), and with low GCF scores and high SDS scores. High GDF15 concentrations and quartiles were significantly associated with higher odds to have both-cognitive-frailty-and-depression (adjusted odds ratio = 2.353 [1.267-4.372], p = 0.007; and adjusted odds ratio = 1.414 [1.025-1.951], p = 0.035, respectively) independent of age, BMI, sex, comorbidities and hsCRP. These associations remained significant when evaluating older adults. We conclude that plasma GDF15 concentrations are significantly associated with combinedcognitive-frailty-and-depression status and, with cognitive frailty and depressive symptoms separately in old as well as young community-dwelling adults.

GDF-15 at admission predicts cardiovascular death, heart failure, and bleeding outcomes in patients with CAD.

We aimed to investigate the independent associations between growth differentiation factor 15 (GDF-15) level at admission and cardiovascular (CV) death, thrombotic events, heart failure (HF), and bleeding outcomes in patients with coronary artery disease (CAD). We measured the plasma concentrations of GDF-15 centrally in patients from the BIomarker-based Prognostic Assessment for patients with Stable angina and acute coronary Syndrome (BIPass) registry, which consecutively enrolled patients with CAD from November 2017 to September 2019 at five tertiary hospitals in China. The outcomes included CV death, thrombotic events [myocardial infarction (MI) and ischaemic stroke], HF events [acute HF during hospitalization and hospitalization for HF post-discharge (A/H HF) and cardiogenic shock], and bleeding outcomes [non-coronary artery bypass grafting-related major bleeding and clinically significant bleeding (CSB)] during the 12month follow-up period after hospitalization. Among 6322 patients with CAD {65.4% male, median age 63.7 [inter-quartile range (IQR)] 56.0-70.1years}, the median concentration of plasma GDF-15 at admission was 1091 (IQR 790.5-1635.0) ng/L. Higher concentrations of GDF-15 were associated with an increased risk of CV death [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.35-2.88, P<0.001], A/H HF (HR 2.69, 95% CI 1.92-3.77, P<0.001), cardiogenic shock (HR 1.46, 95% CI 1.04-2.05, P=0.029), and CSB (HR 1.48, 95% CI 1.22-1.79, P<0.001), but not for MI or stroke, after adjusting for clinical risk factors and prognostic biomarkers. Adding GDF-15 to the model with risk factors and biomarkers improved the net reclassification for CV death, A/H HF, cardiogenic shock, and CSB. In patients with CAD, admission levels of GDF-15 were associated with an increased 1year risk of CV death, HF, and bleeding outcomes, but not with thrombotic events. GDF-15 may be a prognostic biomarker for CV death, HF, and bleeding outcomes and could be used to refine the risk assessment of these specific clinical outcomes. ClinicalTrials.gov Identifier: NCT04044066.

Rare PMP22 variants in mild to severe neuropathy uncorrelated to plasma GDF15 or neurofilament light

Charcot-Marie-Tooth disease (CMT) is a heterogeneous set of hereditary neuropathies whose genetic causes are not fully understood. Here, we characterize three previously unknown variants in PMP22 and assess their effect on the recently described potential CMT biomarkers’ growth differentiation factor 15 (GDF15) and neurofilament light (NFL): first, a heterozygous PMP22 c.178G > A (p.Glu60Lys) in one mother-son pair with adult-onset mild axonal neuropathy. The variant led to abnormal splicing, confirmed in fibroblasts by reverse transcription PCR. Second, a de novo PMP22 c.35A > C (p.His12Pro), and third, a heterozygous 3.2 kb deletion predicting loss of exon 4. The latter two had severe CMT and ultrasonography showing strong nerve enlargement similar to a previous case of exon 4 loss due to a larger deletion. We further studied patients with PMP22 duplication (CMT1A) finding slightly elevated plasma NFL, as measured by the single molecule array immunoassay (SIMOA). In addition, plasma GDF15, as measured by ELISA, correlated with symptom severity for CMT1A. However, in the severely affected individuals with PMP22 exon 4 deletion or p.His12Pro, these biomarkers were within the range of variability of CMT1A and controls, although they had more pronounced nerve hypertrophy. This study adds p.His12Pro and confirms PMP22 exon 4 deletion as causes of severe CMT, whereas the previously unknown splice variant p.Glu60Lys leads to mild axonal neuropathy. Our results suggest that GDF15 and NFL do not distinguish CMT1A from advanced hypertrophic neuropathy caused by rare PMP22 variants.

Urinary growth differentiation factor 15 predicts renal function decline in diabetic kidney disease

Sensitive biomarkers can enhance the diagnosis, prognosis, and surveillance of chronic kidney disease (CKD), such as diabetic kidney disease (DKD). Plasma growth differentiation factor 15 (GDF15) levels are a novel biomarker for mitochondria-associated diseases; however, it may not be a useful indicator for CKD as its levels increase with declining renal function. This study explores urinary GDF15’s potential as a marker for CKD. The plasma and urinary GDF15 as well as 15 uremic toxins were measured in 103 patients with CKD. The relationship between the urinary GDF15-creatinine ratio and the uremic toxins and other clinical characteristics was investigated. Urinary GDF15-creatinine ratios were less related to renal function and uremic toxin levels compared to plasma GDF15. Additionally, the ratios were significantly higher in patients with CKD patients with diabetes (p = 0.0012) and reduced with statin treatment. In a different retrospective DKD cohort study (U-CARE, n = 342), multiple and logistic regression analyses revealed that the baseline urinary GDF15-creatinine ratios predicted a decline in estimated glomerular filtration rate (eGFR) over 2 years. Compared to the plasma GDF15 level, the urinary GDF15-creatinine ratio is less dependent on renal function and sensitively fluctuates with diabetes and statin treatment. It may serve as a good prognostic marker for renal function decline in patients with DKD similar to the urine albumin-creatinine ratio.

Growth differentiation factor‑15 in patients with gestational diabetes mellitus and its relationship with microalbuminuria.

Gestational diabetes mellitus (GDM) is a common pregnancy-related complication and growth differentiation factor-15 (GDF-15) is involved in a number of diseases; therefore, the aim of the present study was to investigate the level and clinical significance of serum GDF-15 levels in patients with GDM. A total of 237 pregnant women at 20-24 weeks of gestation were selected and assigned to a normal pregnancy group (70 patients) and a GDM group (167 patients) according to the presence or absence of GDM. The general clinical data of the two groups were collected. Fasting plasma glucose, 1-h plasma glucose, 2-h plasma glucose, glycated hemoglobin, fasting insulin, 24-h urinary albumin and serum GDF-15 levels were measured. The results showed that the body mass index (BMI) of the GDM group was higher than that of the normal pregnancy group. Fasting plasma glucose, 1-h plasma glucose, 2-h plasma glucose, fasting insulin, glycated hemoglobin and GDF-15 levels and the positive rate of microalbuminuria were significantly higher in the GDM group compared with the normal pregnancy group. GDF-15 levels were positively correlated with BMI, fasting plasma glucose, glycated hemoglobin, homeostasis model assessment-insulin resistance and fasting insulin levels. Logistic regression analysis suggested that elevated GDF-15 levels are an independent risk factor for microalbuminuria. In conclusion, serum GDF-15 levels are strongly associated with GDM and elevated GDF-15 levels are an independent risk factor for microalbuminuria. Serum GDF-15 may act as a novel biomarker for predicting microalbuminuria in GDM patients.

Dietary medium-chain fatty acids reduce food intake via the GDF15-GFRAL axis in mice

ObjectiveMedium chain fatty acids (MCFAs), which are fatty acids with chain lengths of 8–12 carbon atoms, have been shown to reduce food intake in rodents and humans, but the underlying mechanisms are unknown. Unlike most other fatty acids, MCFAs are absorbed from the intestine into the portal vein and enter first the liver. We thus hypothesized that MCFAs trigger the release of hepatic factors that reduce appetite. MethodsThe liver transcriptome in mice that were orally administered MCFAs as C8:0 triacylglycerol (TG) was analyzed. Circulating growth/differentiation factor 15 (GDF15), tissue Gdf15 mRNA and food intake were investigated after acute oral gavage of MCFAs as C8:0 or C10:0 TG in mice. Effects of acute and subchronic administration of MCFAs as C8:0 TG on food intake and body weight were determined in mice lacking either the receptor for GDF15, GDNF Family Receptor Alpha Like (GFRAL), or GDF15. ResultsHepatic and small intestinal expression of Gdf15 and circulating GDF15 increased after ingestion of MCFAs, while intake of typical dietary long-chain fatty acids (LCFAs) had no effect. Plasma GDF15 levels also increased in the portal vein with MCFA intake, indicating that in addition to the liver, the small intestine contributes to the rise in circulating GDF15. Acute oral provision of MCFAs decreased food intake over 24 h compared with a LCFA-containing bolus, and this anorectic effect required the GDF15 receptor, GFRAL. Moreover, subchronic oral administration of MCFAs reduced body weight over 7 days, an effect that was blunted in mice lacking either GDF15 or GFRAL. ConclusionsWe have identified ingestion of MCFAs as a novel nutritional approach that increases circulating GDF15 in mice and have revealed that the GDF15-GFRAL axis is required for the full anorectic effect of MCFAs.

Increased plasma endostatin and GDF15 in indolent non-Hodgkin lymphoma.

Increased microvascular density correlates with more advanced disease and unfavorable overall survival in non-Hodgkin lymphoma (NHL), suggesting that angiogenesis is important for disease progression. However, studies of anti-angiogenic agents in NHL patients, have generally not shown favorable outcomes. The aim of this study was to investigate whether plasma levels of a subset of angiogenesis-associated proteins are increased in indolent B-cell derived NHL (B-NHL) and to investigate whether the levels differ between patients with asymptomatic versus symptomatic disease. Plasma levels of growth differentiation factor 15 (GDF15), endostatin, matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), long pentraxin 3 (PTX3), and galectin 3 (GAL-3) were measured by ELISA in 35 patients with symptomatic indolent B-NHL, 41 patients with asymptomatic disease, and 62 healthy controls. Bootstrap t-tests were used to assess the relative differences in biomarker levels between groups. Group differences were visualized using a principal component plot. Mean plasma endostatin and GDF15 levels were significantly higher in symptomatic and asymptomatic lymphoma patients than in controls. Symptomatic patients had higher mean MMP9 and NGAL than controls. The finding of increased plasma endostatin and GDF15 in patients with asymptomatic indolent B-NHL suggests that increased angiogenic activity is an early event in indolent B-NHL disease progression.

Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake and body weight

Metformin, the most widely prescribed medication for obesity-associated type 2 diabetes (T2D), lowers plasma glucose levels, food intake, and body weight in rodents and humans, but the mechanistic site(s) of action remain elusive. Metformin increases plasma growth/differentiation factor 15 (GDF15) levels to regulate energy balance, while GDF15 administration activates GDNF family receptor α-like (GFRAL) that is highly expressed in the area postrema (AP) and the nucleus of the solitary tract (NTS) of the hindbrain to lower food intake and body weight. However, the tissue-specific contribution of plasma GDF15 levels after metformin treatment is still under debate. Here, we found that metformin increased plasma GDF15 levels in high-fat (HF) fed male rats through the upregulation of GDF15 synthesis in the kidney. Importantly, the kidney-specific knockdown of GDF15 expression as well as the AP-specific knockdown of GFRAL expression negated the ability of metformin to lower food intake and body weight gain. Taken together, we unveil the kidney as a target of metformin to regulate energy homeostasis through a kidney GDF15-dependent AP axis.

The role of growth differentiation factor-15 in assessing the prognosis of patients after uncomplicated myocardial infarction

Aim To study the role of growth differentiation factor 15 (GDF-15) in the long-term prognosis for patients after uncomplicated myocardial infarction (MI).Material and methods This study included 118 MI patients aged &lt;70 years with and without ST-segment elevation on electrocardiogram (ECG). All patients underwent an examination that included ECG, echocardiography, Holter ECG monitoring, routine laboratory tests, and tests for plasma N-terminal pro-brain natriuretic peptide (NT-proBNT) and GDF-15. GDF-15 was measured by ELISA. The dynamics of patients was evaluated by interviews at 1, 3, 6, and 12 months. The endpoints were cardiovascular death and hospitalization for recurrent MI and/or unstable angina.Results Median concentration of GDF-15 in MI patients was 2.07 (1.55; 2.73) ng/ml. No significant dependence was found between GDF-15 concentration and age and gender, MI localization, smoking, body weight index, total cholesterol, and low-density lipoprotein cholesterol. During 12-month follow-up, 22.8 % of patients were hospitalized for unstable angina or recurrent MI. In 89.6 % of all cases of recurrent events, GDF-15 was ≥2.07 ng/ml. For patients with GDF-15 in the upper quartile, the time dependence of recurrent MI was logarithmic. High concentrations of NT-proBNP in MI patients were also associated with increased risk of cardiovascular death and recurrent cardiovascular events [RR, 3.3 (95 % CI, 1.87-5.96), р=0.046].Conclusion A combination of GDF-15 and NT-proBNP at high concentrations significantly reflects an adverse prognosis for patients with uncomplicated MI within 12 months [RR, 5.4 (95 % CI, 3.4-8.5), р=0.004].