Plasma Growth Differentiation Factor-15 Research Articles

Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected locally advanced non-small cell lung cancer treated with chemoradiotherapy

IntroductionGrowth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard of care concurrent chemoradiotherapy (cCRT). OCOG-ALMERA was not able to demonstrate benefit in the metformin arm. Therefore, biomarker studies are needed to better define stratification parameters for future trials.MethodsPatients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60–66 Gy), with or without metformin (2000 mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes.ResultsBaseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p < 0.001), and the addition of metformin was associated with a further increase (week 6, p = 0.033). Baseline GDF15 levels correlated with the radiotherapy gross target volume (GTV, p < 0.01), while week 1 of radiotherapy levels correlated with radiotherapy planned target volume (PTV, p < 0.006). In multivariate analysis, baseline plasma GDF15 was prognostic for poor relapse-free (RFS) and overall survival (OS) (p = 0.005 and p = 0.002, respectively).ConclusionsGDF15 is a plasma marker that responds to the treatment of unresected LA-NSCLC with cCRT and metformin. GDF15 levels correspond with tumor volume and increased GDF15 levels predict for poor RFS and OS. These results require validation in larger clinical trial datasets.

Associations between prenatal distress, mitochondrial health, and gestational age: findings from two pregnancy studies in the USA and Turkey.

Pregnancy outcomes are influenced by maternal distress but the pathways underlying these effects are still unknown. Mitochondria, crucial for stress adaptation and energy production, may link psychosocial stress to its biological effects, especially during pregnancy when energy demands significantly increase. This study explores two mitochondrial markers-circulating cell-free mitochondrial DNA (cf-mtDNA) and Growth Differentiation Factor-15 (GDF15)-as potential mitochondrial health indicators linking maternal distress to pregnancy outcomes in two longitudinal studies from the USA and Turkey. We analyzed biological, demographic, and psychological data from women in two pregnancy studies: EPI (N=187, USA, Mean age=29.6(SD=6.2) and BABIP (N=198, Turkey, Mean age=32.4(SD=4.0)). Data were collected at multiple time points during the perinatal period, including late 2nd and 3rd trimester, with EPI also including additional data at early 2nd trimester and 4-14 months postpartum. Prenatal maternal psychological distress was measured as perceived stress, anxiety, and depressive symptoms. Plasma cf-mtDNA and GDF15 levels were assessed using qPCR and ELISA, respectively. Statistical analyses included Wilcoxon signed-rank tests, Spearman correlations, and Mann-Whitney tests. Plasma cf-mtDNA levels did not change significantly during pregnancy in either study. Plasma GDF15 levels increased from early to late pregnancy in both studies and significantly decreased postpartum in EPI. Perinatal maternal distress in the late 2 nd and 3 rd trimesters was not associated with cf-mtDNA or GDF15 in either study. Metabolic distress, measured as higher pre-pregnancy BMI, was negatively correlated with GDF15 in the late 2 nd trimester in EPI and showed a similar trend in BABIP. Similarly, higher maternal psychological distress in the early 2 nd trimester were associated with lower cf-mtDNA and a trend for lower GDF15 in EPI. Finally, higher pre-pregnancy BMI and maternal distress in late pregnancy were linked to a smaller decline in GDF15 from late pregnancy to postpartum in EPI, suggesting an interaction between metabolic stress, prenatal distress and post-pregnancy physiological recovery. This study identified distinct patterns of plasma cf-mtDNA and GDF15 levels during the perinatal period across studies from two countries, revealing unique associations between maternal characteristics, prenatal distress, and pregnancy outcomes, suggesting that maternal distress can interact with energy mobilization during pregnancy.

GDF-15 and mtDNA Deletions Are Useful Biomarkers of Mitochondrial Dysfunction in Insulin Resistance and PCOS.

There is no literature available about the growth differentiation factor-15 (GDF-15) biomarker in combination with mitochondrial DNA (mtDNA) deletions in insulin resistance (IR), and polycystic ovary syndrome (PCOS); however, it would be useful to achieve optimal metabolic status and improve pregnancy success. In this study, the role of GDF-15 and mtDNA deletions as biomarkers in the pathogenesis of IR and PCOS was investigated. In our study, 81 female patients who were treated for IR and/or PCOS and 41 healthy controls were included. GDF-15 levels in patients showed a marked increase compared to controls. Elevated GDF-15 levels were found in 12 patients; all of them had a BMI > 25 kg/m2, which is associated with reactive hyperinsulinemia. The presence of mitochondrial dysfunction was mainly observed in the IR-only subgroup. The increase in plasma levels of GDF-15 and the prevalence of mtDNA deletions is directly proportional to body mass index. The more marked metabolic abnormalities required more intensive drug therapy with a parallel increase in plasma GDF-15 levels. Elevated levels of GDF-15 and the presence of mitochondrial DNA deletions may be a consequence of carbohydrate metabolism disorders in patients and thus a predictor of the process of accelerated aging.

Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH

Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.

Growth differentiation factor 15 is not modified after weight loss induced by liraglutide in South Asians and Europids with type 2 diabetes mellitus.

Glucagon-like peptide-1 receptor (GLP-1R) agonists induce weight loss in patients with type 2 diabetes mellitus (T2DM), but the underlying mechanism is unclear. Recently, the mechanism by which metformin induces weight loss could be explained by an increase in growth differentiation factor 15 (GDF15), which suppresses appetite. Therefore, we aimed to investigate whether the GLP-1R agonist liraglutide modifies plasma GDF15 levels in patients with T2DM. GDF15 levels were measured in plasma samples obtained from Dutch Europids and Dutch South Asians with T2DM before and after 26weeks of treatment with daily liraglutide (n=44) or placebo (n=50) added to standard care. At baseline, circulating GDF15 levels did not differ between South Asians and Europids with T2DM. Treatment with liraglutide, compared to placebo, decreased body weight, but did not modify plasma GDF15 levels in all patients, or when data were split by ethnicity. Also, the change in plasma GDF15 levels after treatment with liraglutide did not correlate with changes in body weight or HbA1c levels. In addition, the dose of metformin used did not correlate with baseline plasma GDF15 levels. Compared to placebo, liraglutide treatment for 26weeks does not modify plasma GDF15 levels in Dutch Europid or South Asian patients with T2DM. Thus, the weight loss induced by liraglutide is likely explained by other mechanisms beyond the GDF15 pathway. HIGHLIGHTS: What is the central question of this study? Growth differentiation factor 15 (GDF15) suppresses appetite and is increased by metformin: does the GLP-1R agonist liraglutide modify plasma GDF15 levels in patients with type 2 diabetes mellitus (T2DM)? What is the main finding and its importance? Plasma GDF15 levels did not differ between South Asians and Europids with T2DM and were not modified by 26weeks of liraglutide in either ethnicity. Moreover, there was no correlation between the changes in plasma GDF15 levels and dosage of metformin administered, changes in body weight or HbA1c levels. The appetite-suppressing effect of liraglutide is likely exerted via pathways other than GDF15.

Growth Differentiation Factor 15 and Matrix Metalloproteinase 3 in Plasma as Biomarkers for Neuropathy and Nephropathy in Type 1 Diabetes.

Diabetic neuropathy and nephropathy are common complications of type 1 diabetes (T1D). The symptoms are often elusive in the early stages, and available diagnostic methods can be improved using biomarkers. Matrix metalloproteinase 3 (MMP-3) has been identified in the kidneys and is thought to be involved in diabetic nephropathy. Growth differentiation factor 15 (GDF-15) has been suggested to have positive effects in diabetes, but is otherwise associated with adverse effects such as cardiovascular risk, declined kidney function, and neurodegeneration. This study aims to investigate plasma MMP-3 and GDF-15 as systemic biomarkers for diabetic neuropathy and nephropathy in T1D. The study involves patients with childhood-onset T1D (n = 48, age 38 ± 4 years) and a healthy control group (n = 30, age 38 ± 5 years). Neurophysiology tests, evaluations of albuminuria, and measurements of routine biochemical markers were conducted. The neuropathy impairment assessment (NIA) scoring system, where factors such as loss of sensation and weakened reflexes are evaluated, was used to screen for symptoms of neuropathy. MMP-3 and GDF-15 concentrations were determined in heparinized plasma using ELISA kits. In total, 9 patients (19%) had albuminuria, and 25 (52%) had diabetic neuropathy. No significant differences were found in MMP-3 concentrations between the groups. GDF-15 levels were higher in T1D, with median and interquartile range (IQR) of 358 (242) pg/mL in T1D and 295 (59) in controls (p < 0.001). In the merged patient group, a positive correlation was found between MMP-3 and plasma creatinine, a negative correlation was found between MMP-3 and estimated glomerular filtration rate (eGFR; rho = -0.358, p = 0.012), and there was a positive correlation between GDF-15 and NIA (rho = 0.723, p < 0.001) and high-sensitive C-reactive protein (rho = 0.395, p = 0.005). MMP-3 was increased in macroalbuminuria and correlated positively with NIA only in the nine T1D patients with albuminuria (rho = 0.836, p = 0.005). The present study indicates that high MMP-3 is associated with low eGFR, high plasma creatinine, and macroalbuminuria, and that GDF-15 can be a biomarker for diabetic neuropathy in T1D. MMP-3 may be useful as biomarker for neuropathy in T1D with albuminuria.

GDF-15 is associated with sarcopenia and frailty in acutely admitted older medical patients.

Growth differentiation factor-15 (GDF-15) has been associated with senescence, lower muscle strength, and physical performance in healthy older people. Still, it is not clear whether GDF-15 can be utilized as a biomarker of sarcopenia and frailty in the early stages of hospitalization. We investigated the association of plasma GDF-15 with sarcopenia and frailty in older, acutely admitted medical patients. The present study is based on secondary analyses of cross-sectional data from the Copenhagen PROTECT study, a prospective cohort study including 1071 patients ≥65years of age admitted to the acute medical ward at Copenhagen University Hospital, Bispebjerg, Denmark. Muscle strength was assessed using handgrip strength, and lean mass was assessed using direct segmental multifrequency bioelectrical impedance analyses and used to clarify the potential presence of sarcopenia defined according to guidelines from the European Working Group on Sarcopenia in Older People. Frailty was evaluated using the Clinical Frailty Scale. Plasma GDF-15 was measured using electrochemiluminescence assays from Meso Scale Discovery (MSD, Rockville, MD, USA). We included 1036 patients with completed blood samples (mean age 78.9±7.8years, 53% female). The median concentration of GDF-15 was 2669.3pg/mL. Systemic GDF-15 was significantly higher in patients with either sarcopenia (P<0.01) or frailty (P<0.001) compared with patients without the conditions. Optimum cut-off points of GDF-15 relating to sarcopenia and frailty were 1541 and 2166pg/mL, respectively. Systemic GDF-15 was higher in acutely admitted older medical patients with sarcopenia and frailty compared with patients without. The present study defined the optimum cut-off for GDF-15, related to the presence of sarcopenia and frailty, respectively. When elevated above the derived cutoffs, GDF-15 was strongly associated with frailty and sarcopenia in both crude and fully adjusted models.

Growth differentiation factor 15 (GDF15) levels are associated with malnutrition in acutely admitted older adults

Background and aimsThe aging process is often accompanied by high risk of malnutrition and elevated levels of growth differentiation factor 15 (GDF15). GDF15 is an increasingly recognized biomarker for regulation of metabolism, but few studies have investigated the connection between GDF15 and malnutrition in older age and how it relates to other features of aging such as decreased appetite and physical function. Therefore, we investigated the associations between GDF15 levels and nutritional status, appetite, and physical function in acutely admitted older adults. MethodsPlasma GDF15 levels were measured using immunoassays in 302 older adults (≥65 years) admitted to the emergency department (ED). Nutritional status was evaluated with the Mini Nutritional Assessment Short-Form (MNA®-SF), appetite was evaluated with the Simplified Nutritional Appetite Questionnaire (SNAQ), and physical function was evaluated with handgrip strength (HGS), 30-second chair stand test (30s-RSS), and gait speed (GS). Associations between GDF15 and each outcome was determined by logistic regression adjusted for age, sex, and C-reactive protein (CRP). ResultsEach doubling in plasma GDF15 level was associated with an adjusted odds ratio (OR) (95% confidence interval) of 1.59 (1.10–2.29, P=0.01) for risk of malnutrition compared to normal nutrition and 1.19 (0.85–1.69, P=0.3)) for malnutrition compared to risk of malnutrition. Each doubling in GDF15 was associated with an adjusted OR of 1.63 (1.21–2.23)) for having poor appetite, 1.46 (1.07–1.99) for having low HGS, 1.74 (1.23–2.51) for having low 30s-RSS, and 1.99 (1.39–2.94) for having low GS. ConclusionAmong older adults admitted to the ED, higher GDF15 levels were significantly associated with malnutrition, poor appetite, and low physical function independent of age, sex, and CRP.

Growth/differentiation factor 15 (GDF15) expression in the heart after myocardial infarction and cardioprotective effect of pre-ischemic rGDF15 administration

Growth/differentiation factor-15 (GDF15) is considered an unfavourable prognostic biomarker for cardiovascular disease in clinical data, while experimental studies suggest it has cardioprotective potential. This study focuses on the direct cardiac effects of GDF15 during ischemia–reperfusion injury in Wistar male rats, employing concentrations relevant to patients at high cardiovascular risk. Initially, we examined circulating levels and heart tissue expression of GDF15 in rats subjected to ischemia–reperfusion and sham operations in vivo. We then evaluated the cardiac effects of GDF15 both in vivo and ex vivo, administering recombinant GDF15 either before 30 min of ischemia (preconditioning) or at the onset of reperfusion (postconditioning). We compared infarct size and cardiac contractile recovery between control and rGDF15-treated rats. Contrary to our expectations, ischemia–reperfusion did not increase GDF15 plasma levels compared to sham-operated rats. However, cardiac protein and mRNA expression increased in the infarcted zone of the ischemic heart after 24 h of reperfusion. Notably, preconditioning with rGDF15 had a cardioprotective effect, reducing infarct size both in vivo (65 ± 5% in control vs. 42 ± 6% in rGDF15 groups) and ex vivo (60 ± 4% in control vs. 45 ± 4% in rGDF15 groups), while enhancing cardiac contractile recovery ex vivo. However, postconditioning with rGDF15 did not alter infarct size or the recovery of contractile parameters in vivo or ex vivo. These novel findings reveal that the short-term exogenous administration of rGDF15 before ischemia, at physiologically relevant levels, protects the heart against ischemia–reperfusion injury in both in vivo and ex vivo settings. The ex vivo results indicate that rGDF15 operates independently of the inflammatory, endocrine and nervous systems, suggesting direct and potent cardioprotective properties against ischemia–reperfusion injury.

Correlation of plasma GDF15 with aging, organ disfunction, sarcopenia, and postoperative infectious complication in patients with esophageal cancer.

e16088 Background: The age of cancer incidence is increasing every year. Along with it, cancer patients getting has more comorbidity and decreasing muscle strength which may lead to increase postoperative complications. Especially, since esophageal cancer (EC) patients have heavy drinking and smoking history and high age of morbidity, they usually have multiple comorbidities and so that they particularly have high incidence of cachexia. A novel inflammatory marker known as growth differentiation factor 15 (GDF15) has been recently reported relation with cancer cachexia. This study conducted to evaluate correlation between clinical data which suggested cachexia of EC patients and plasma GDF15. Methods: Eighty-one esophageal cancer patients who first visited our outpatient ward from July 2021 to March 2023 were enrolled in this study. After obtaining consent for the study, plasma samples collected before starting any treatment for the cancer. The quantification of GDF15 was performed by ELISA. Clinical information was collected from clinical record including age, comorbidities, biochemical data, Controlling Nutritional Status (CONUT) score, and Skeletal Mass Index (SMI). GDF15 was then evaluated for clinical impact by comparison with postoperative results. Mann-Whitney U test, student-t test, ANOVA were used appropriately to analyze the relationship between the GDF-15 and patient characteristics and post operative complications. Multivariate analysis ware used logistic regression analysis. P-values &lt; 0.05 were considered statistically significant for all statistical analyses. Results: Mean age was 68.3-year-old and 80.3% of these were male. Malnutrition patients diagnosed by using CONUT were 24 (29.6%) and sarcopenia patients diagnosed by using SMI were 21 (25.9%). The median value of GDF15 was 1165 pg/mL with its range were from 298 to 9100 pg/mL. Plasma GDF15 was statistically correlated with age ( P&lt; 0.001), performance status ( P= 0.046), prevalence of hypertension ( P= 0.045) and/or diabetes ( P= 0.018), serum level of aspartate aminotransferase (AST) ( P&lt; 0.001)/ γ-glutamyltransferase (γ-GTP) ( P&lt; 0.001)/ creatinine ( P= 0.004)/ blood sugar ( P= 0.028), and SMI ( P= 0.003). Seventy-two patients underwent curative surgery, and no perioperative death was observed. The patients who occurred anastomotic leakage and infectious complication observed statistically higher GDF15 than those without (P = 0.030, P = 0.016). Optimal cut-off value was detected as 940 ng/mL for detecting infectious complication by ROC-curve with AUC value of 0.68. Conclusions: This study showed GDF15 is potentially suggesting deterioration of general condition, which came from aging, organ disfunction, and decreasing muscle mass, which may lead to cachexia in EC patients. In addition, higher GDF15 patients have risk of postoperative infectious complication.

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.

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.

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 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.