Skip to content
2000
Volume 21, Issue 3
  • ISSN: 1573-403X
  • E-ISSN: 1875-6557

Abstract

Cardiovascular-kidney-metabolic (CKM) syndrome is the association between obesity, diabetes, CKD (chronic kidney disease), and cardiovascular disease. GDF-15 mainly acts through the GFRAL (Glial cell line-derived neurotrophic factor Family Receptor Alpha-Like) receptor. GDF-15 and GDFRAL complex act mainly through RET co-receptors, further activating Ras and phosphatidylinositol-3-kinase (PI3K)/Akt pathways through downstream signaling. GDF-15 decreases cardiac dysfunction and hypertrophy by inducing HIF-α (hypoxia-inducible factor-1α). It causes increased fractional shortening and a significant decrease in ventricular dilation through the induction of the SMAD 2/3. GDF-15 prevents hyperglycemia-induced apoptosis in diabetes mellitus. GDF-15 causes anorexia by influencing the central systems regulating metabolism and appetite. Therefore, targeting GDF-15 can be useful for the treatment of anorexia caused by cancer as well as the prevention of resulting weight loss. GDF-15 has an important role in predicting mortality in acute kidney injury. Its high levels are related to eGFR decline and also have a prognostic role in CKD patients. Growth differentiation factor-15 (GDF-15) is a vital biomarker for diagnosis, treatment, and prognosis of CKM syndrome. Elevated GDF-15 levels can be utilised as a biomarker to determine the suitable metformin dosage. In light chain amyloidosis, a raised level of GDF-15 predicts early death in heart failure and renal disease patients. , studies using GDF-15 analogs and antibodies against GFRAL to affect metabolic parameters and ventricular dilatation have shown potential for GDF-15-based therapeutic interventions. This review aims to study the role of GDF-15 in CKM syndrome and establish it as a CKM biomarker.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ccr/10.2174/011573403X332671241121063641
2025-01-07
2025-10-03

  • From This Site

    /content/journals/ccr/10.2174/011573403X332671241121063641
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. NdumeleC.E. RangaswamiJ. ChowS.L. Cardiovascular-Kidney-metabolic health: A presidential advisory from the american heart association.Circulation2023148201606163510.1161/CIR.0000000000001184 37807924
     [Google Scholar]
  2. BaekS.J. KimK.S. NixonJ.B. WilsonL.C. ElingT.E. Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities.Mol. Pharmacol.200159490190810.1124/mol.59.4.901 11259636
     [Google Scholar]
  3. BaekS.J. HorowitzJ.M. ElingT.E. Molecular cloning and characterization of human nonsteroidal anti-inflammatory drug-activated gene promoter. Basal transcription is mediated by Sp1 and Sp3.J. Biol. Chem.200127636333843339210.1074/jbc.M101814200 11445565
     [Google Scholar]
  4. LawtonL.N. BonaldoM.F. JelencP.C. Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta.Gene19972031172610.1016/s0378‑1119(97)00485‑x 9426002
     [Google Scholar]
  5. HromasR. HuffordM. SuttonJ. XuD. LiY. LuL. PLAB, a novel placental bone morphogenetic protein.Biochim. Biophys. Acta Gene Struct. Expr.199713541404410.1016/S0167‑4781(97)00122‑X 9375789
     [Google Scholar]
  6. ParalkarV.M. VailA.L. GrasserW.A. Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family.J. Biol. Chem.199827322137601376710.1074/jbc.273.22.13760 9593718
     [Google Scholar]
  7. HarrisP. RalphP. Human leukemic models of myelomonocytic development: A review of the HL-60 and U937 cell lines.J. Leukoc. Biol.198537440742210.1002/jlb.37.4.407
     [Google Scholar]
  8. ValenzuelaS.M. MartinD.K. PorS.B. Molecular cloning and expression of a chloride ion channel of cell nuclei.J. Biol. Chem.199727219125751258210.1074/jbc.272.19.12575 9139710
     [Google Scholar]
  9. BauskinA.R. ZhangH.P. FairlieW.D. The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-β superfamily member, acts as a quality control determinant for correctly folded MIC-1.EMBO J.200019102212222010.1093/emboj/19.10.2212 10811612
     [Google Scholar]
  10. RochetteL. ZellerM. CottinY. VergelyC. Insights into mechanisms of GDF15 and receptor GFRAL: Therapeutic targets.Trends Endocrinol. Metab.2020311293995110.1016/j.tem.2020.10.004 33172749
     [Google Scholar]
  11. VaradiM. AnyangoS. DeshpandeM. AlphaFold protein structure database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models.Nucleic Acids Res.202250D1D439D44410.1093/nar/gkab1061 34791371
     [Google Scholar]
  12. JumperJ. EvansR. PritzelA. Highly accurate protein structure prediction with AlphaFold.Nature2021596787358358910.1038/s41586‑021‑03819‑2 34265844
     [Google Scholar]
  13. GrayA.M. MasonA.J. Requirement for activin A and transforming growth factor - Beta 1 pro-regions in homodimer assembly.Science199024749481328133010.1126/science.2315700 2315700
     [Google Scholar]
  14. DuboisC.M. LapriseM.H. BlanchetteF. GentryL.E. LeducR. Processing of transforming growth factor β 1 precursor by human furin convertase.J. Biol. Chem.199527018106181062410.1074/jbc.270.18.10618 7737999
     [Google Scholar]
  15. WangX. BaekS.J. ElingT.E. The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer.Biochem. Pharmacol.201385559760610.1016/j.bcp.2012.11.025 23220538
     [Google Scholar]
  16. BaekS.J. ElingT. Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases.Pharmacol. Ther.2019198465810.1016/j.pharmthera.2019.02.008 30790643
     [Google Scholar]
  17. HsuJ.Y. CrawleyS. ChenM. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15.Nature2017550767525525910.1038/nature24042 28953886
     [Google Scholar]
  18. LiuS. ChenX. WangH. Association of GDF‐15 and syntax score in patient with acute myocardial infarction.Cardiovasc. Ther.20192019982021010.1155/2019/9820210 31772623
     [Google Scholar]
  19. WollertK.C. KempfT. GiannitsisE. An automated assay for growth differentiation factor 15.J. Appl. Lab. Med.20171551052110.1373/jalm.2016.022376 33379802
     [Google Scholar]
  20. WelshP. KimenaiD.M. MarioniR.E. Reference ranges for GDF-15, and risk factors associated with GDF-15, in a large general population cohort.Clin. Chem. Lab. Med.202260111820182910.1515/cclm‑2022‑0135 35976089
     [Google Scholar]
  21. UhlénM. FagerbergL. HallströmB.M. Tissue-based map of the human proteome.Science20153476220126041910.1126/science.1260419 25613900
     [Google Scholar]
  22. The human protein atlas Available from: https://www.proteinatlas.org/ENSG00000130513-GDF15/tissue
  23. EmmersonP.J. DuffinK.L. ChintharlapalliS. WuX. GDF15 and growth control.Front Physiol201891712https://www.frontiersin.org/articles/10.3389/fphys.2018.0171210.3389/fphys.2018.01712 30542297
     [Google Scholar]
  24. KooB.K. UmS.H. SeoD.S. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease.Liver Int.201838469570510.1111/liv.13587 28898507
     [Google Scholar]
  25. YatsugaS. FujitaY. IshiiA. Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders.Ann. Neurol.201578581482310.1002/ana.24506 26463265
     [Google Scholar]
  26. KimK.H. KimS.H. HanD.H. JoY.S. LeeY. LeeM.S. Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice.Sci. Rep.201881678910.1038/s41598‑018‑25098‑0 29717162
     [Google Scholar]
  27. BaekS.J. KimJ.S. MooreS.M. LeeS.H. MartinezJ. ElingT.E. Cyclooxygenase inhibitors induce the expression of the tumor suppressor gene EGR-1, which results in the up-regulation of NAG-1, an antitumorigenic protein.Mol. Pharmacol.200567235636410.1124/mol.104.005108 15509713
     [Google Scholar]
  28. HanM. DaiD. YousafzaiN.A. CXXC4 activates apoptosis through up-regulating GDF15 in gastric cancer.Oncotarget201786110355710356710.18632/oncotarget.21581 29262584
     [Google Scholar]
  29. PatelS. Alvarez-GuaitaA. MelvinA. GDF15 provides an endocrine signal of nutritional stress in mice and humans.Cell Metab.2019293707718.e810.1016/j.cmet.2018.12.016 30639358
     [Google Scholar]
  30. ZhengH. WuY. GuoT. Hypoxia induces growth differentiation factor 15 to promote the metastasis of colorectal cancer via PERK-eIF2 α signaling.Biomed Res. Int.20202020595827210.1155/2020/5958272 32076610
     [Google Scholar]
  31. RochetteL. DogonG. ZellerM. CottinY. VergelyC. GDF15 and cardiac cells: Current concepts and new insights.Int. J. Mol. Sci.20212216888910.3390/ijms22168889 34445593
     [Google Scholar]
  32. AiraksinenM.S. HolmL. HätinenT. Evolution of the GDNF family ligands and receptors.Brain Behav. Evol.200668318119010.1159/000094087 16912471
     [Google Scholar]
  33. EmmersonP.J. WangF. DuY. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL.Nat. Med.201723101215121910.1038/nm.4393 28846098
     [Google Scholar]
  34. YangL. ChangC.C. SunZ. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand.Nat. Med.201723101158116610.1038/nm.4394 28846099
     [Google Scholar]
  35. IbáñezC.F. Structure and physiology of the RET receptor tyrosine kinase.Cold Spring Harb. Perspect. Biol.201352a00913410.1101/cshperspect.a009134 23378586
     [Google Scholar]
  36. DíezD. Sánchez-JiménezF. RaneaJ.A.G. Evolutionary expansion of the Ras switch regulatory module in eukaryotes.Nucleic Acids Res.201139135526553710.1093/nar/gkr154 21447561
     [Google Scholar]
  37. ChongH. VikisH.G. GuanK.L. Mechanisms of regulating the Raf kinase family.Cell. Signal.200315546346910.1016/S0898‑6568(02)00139‑0 12639709
     [Google Scholar]
  38. SmealT. BinetruyB. MercolaD.A. BirrerM. KarinM. Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73.Nature1991354635349449610.1038/354494a0 1749429
     [Google Scholar]
  39. BinétruyB. SmealT. KarinM. Ha-Ras augments c-Jun activity and stimulates phosphorylation of its activation domain.Nature1991351632212212710.1038/351122a0
     [Google Scholar]
  40. KolchW. Coordinating ERK/MAPK signalling through scaffolds and inhibitors.Nat. Rev. Mol. Cell Biol.200561182783710.1038/nrm1743 16227978
     [Google Scholar]
  41. LinC.G. LeuS.J. ChenN. CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family.J. Biol. Chem.200327826242002420810.1074/jbc.M302028200 12695522
     [Google Scholar]
  42. ChenN. LeuS.J. TodorovićV. LamS.C.T. LauL.F. Identification of a novel integrin alphavbeta3 binding site in CCN1 (CYR61) critical for pro-angiogenic activities in vascular endothelial cells.J. Biol. Chem.200427942441664417610.1074/jbc.M406813200 15308622
     [Google Scholar]
  43. WhitsonR.J. LuciaM.S. LambertJ.R. Growth differentiation factor‐15 (GDF‐15) suppresses in vitro angiogenesis through a novel interaction with connective tissue growth factor (CCN2).J. Cell. Biochem.201311461424143310.1002/jcb.24484 23280549
     [Google Scholar]
  44. KastritisE. PapassotiriouI. MerliniG. Growth differentiation factor-15 is a new biomarker for survival and renal outcomes in light chain amyloidosis.Blood2018131141568157510.1182/blood‑2017‑12‑819904 29386197
     [Google Scholar]
  45. Sánchez-DíazM. Nicolás-ÁvilaJ.Á. CorderoM.D. HidalgoA. Mitochondrial adaptations in the growing heart.Trends Endocrinol. Metab.202031430831910.1016/j.tem.2020.01.006 32035734
     [Google Scholar]
  46. SongH. YinD. LiuZ. GDF-15 promotes angiogenesis through modulating p53/HIF-1α signaling pathway in hypoxic human umbilical vein endothelial cells.Mol. Biol. Rep.20123944017402210.1007/s11033‑011‑1182‑7 21773947
     [Google Scholar]
  47. DongG. ZhengQ.D. MaM. Angiogenesis enhanced by treatment damage to hepatocellular carcinoma through the release of GDF 15.Cancer Med.20187382083010.1002/cam4.1330 29383859
     [Google Scholar]
  48. VaranitaT. SorianoM.E. RomanelloV. The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage.Cell Metab.201521683484410.1016/j.cmet.2015.05.007 26039448
     [Google Scholar]
  49. NanJ. ZhuW. RahmanM.S. Molecular regulation of mitochondrial dynamics in cardiac disease.Biochim. Biophys. Acta Mol. Cell Res.2017186471260127310.1016/j.bbamcr.2017.03.006 28342806
     [Google Scholar]
  50. OngS.B. SubrayanS. LimS.Y. YellonD.M. DavidsonS.M. HausenloyD.J. Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury.Circulation2010121182012202210.1161/CIRCULATIONAHA.109.906610 20421521
     [Google Scholar]
  51. KempfT. EdenM. StrelauJ. The transforming growth factor-β superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury.Circ. Res.200698335136010.1161/01.RES.0000202805.73038.48 16397141
     [Google Scholar]
  52. KempfT. ZarbockA. WideraC. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice.Nat. Med.201117558158810.1038/nm.2354 21516086
     [Google Scholar]
  53. HeymansS. LuttunA. NuyensD. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure.Nat. Med.5101135114210.1038/13459 10502816
     [Google Scholar]
  54. GalyavichA.S. SabirzyanovaA.A. BaleevaL.V. GaleevaZ.M. The role of growth differentiation factor-15 in assessing the prognosis of patients after uncomplicated myocardial infarction.Kardiologiia2023632404510.18087/cardio.2023.2.n2152 36880142
     [Google Scholar]
  55. WollertK.C. KempfT. LagerqvistB. Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non–ST-elevation acute coronary syndrome.Circulation2007116141540154810.1161/CIRCULATIONAHA.107.697714 17848615
     [Google Scholar]
  56. WideraC. PencinaM.J. BobadillaM. Incremental prognostic value of biomarkers beyond the GRACE (Global Registry of Acute Coronary Events) score and high-sensitivity cardiac troponin T in non-ST-elevation acute coronary syndrome.Clin. Chem.201359101497150510.1373/clinchem.2013.206185 23818444
     [Google Scholar]
  57. KatoE.T. MorrowD.A. GuoJ. Growth differentiation factor 15 and cardiovascular risk: individual patient meta-analysis.Eur. Heart J.202344429330010.1093/eurheartj/ehac577 36303404
     [Google Scholar]
  58. HuangH. ChenZ. LiY. GDF-15 suppresses atherosclerosis by inhibiting oxLDL-induced lipid accumulation and inflammation in macrophages.Evid. Based Complement. Alternat. Med.20212021649756810.1155/2021/6497568
     [Google Scholar]
  59. OtakiY. ShimizuM. WatanabeT. Growth differentiation factor 15 and clinical outcomes in Japanese patients with heart failure.Circ. J.20238781120112910.1253/circj.CJ‑23‑0088 36948614
     [Google Scholar]
  60. Mendez FernandezA.B. Ferrero-GregoriA. Garcia-OsunaA. Growth differentiation factor 15 as mortality predictor in heart failure patients with non‐reduced ejection fraction.ESC Heart Fail.2020752223222910.1002/ehf2.12621 32589369
     [Google Scholar]
  61. FluschnikN. OjedaF. ZellerT. Predictive value of long-term changes of growth differentiation factor-15 over a 27-year-period for heart failure and death due to coronary heart disease.PLoS One2018135e019749710.1371/journal.pone.0197497 29771963
     [Google Scholar]
  62. XuJ. KimballT.R. LorenzJ.N. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation.Circ. Res.200698334235010.1161/01.RES.0000202804.84885.d0 16397142
     [Google Scholar]
  63. HeldinC.H. MiyazonoK. ten DijkeP. TGF-β signalling from cell membrane to nucleus through SMAD proteins.Nature1997390665946547110.1038/37284 9393997
     [Google Scholar]
  64. YazawaH. FukudaT. KanedaH. Association of serum growth differentiation factor-15 with eGFR and hemoglobin in healthy older females.Int. J. Cardiol. Heart Vasc.20203110065110.1016/j.ijcha.2020.100651 33134478
     [Google Scholar]
  65. GarimellaP.S. KatzR. PatelK.V. Association of serum erythropoietin with cardiovascular events, kidney function decline, and mortality.Circ. Heart Fail.201691e00212410.1161/CIRCHEARTFAILURE.115.002124 26721912
     [Google Scholar]
  66. KimD. LeeG.Y. ChoiJ.O. Prognostic values of novel biomarkers in patients with AL amyloidosis.Sci. Rep.2019911220010.1038/s41598‑019‑48513‑6 31434944
     [Google Scholar]
  67. OkadaM. MisumiY. MasudaT. Plasma growth differentiation factor 15: A novel tool to detect early changes of hereditary transthyretin amyloidosis.ESC Heart Fail.2021821178118510.1002/ehf2.13176 33381924
     [Google Scholar]
  68. UnsickerK. SpittauB. KrieglsteinK. The multiple facets of the TGF-β family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1.Cytokine Growth Factor Rev.201324437338410.1016/j.cytogfr.2013.05.003 23787157
     [Google Scholar]
  69. LimJ.H. JeonY. AhnJ.S. GDF-15 predicts in-hospital mortality of critically ill patients with acute kidney injury requiring continuous renal replacement therapy: A multicenter prospective study.J. Clin. Med.20211016366010.3390/jcm10163660 34441955
     [Google Scholar]
  70. NairV. Robinson-CohenC. SmithM.R. Growth differentiation factor-15 and risk of CKD progression.J. Am. Soc. Nephrol.20172872233224010.1681/ASN.2016080919 28159780
     [Google Scholar]
  71. Perez-GomezM.V. Pizarro-SanchezS. Gracia-IguacelC. Urinary Growth Differentiation Factor-15 (GDF15) levels as a biomarker of adverse outcomes and biopsy findings in chronic kidney disease.J. Nephrol.20213461819183210.1007/s40620‑021‑01020‑2 33847920
     [Google Scholar]
  72. JaradatJ.H. NashwanA.J. Cardiovascular-kidney-metabolic syndrome: Understanding the interconnections and the need for holistic intervention.J Med Surg Public Health2023110002810.1016/j.glmedi.2023.100028
     [Google Scholar]
  73. Nogueira-MachadoJ.A. ChavesM.M. From hyperglycemia to AGE-RAGE interaction on the cell surface: A dangerous metabolic route for diabetic patients.Expert Opin. Ther. Targets200812787188210.1517/14728222.12.7.871 18554155
     [Google Scholar]
  74. LiJ. YangL. QinW. ZhangG. YuanJ. WangF. Adaptive induction of growth differentiation factor 15 attenuates endothelial cell apoptosis in response to high glucose stimulus.PLoS One201386e6554910.1371/journal.pone.0065549 23799024
     [Google Scholar]
  75. HiguchiK. MasakiT. GotohK. Apelin, an APJ receptor ligand, regulates body adiposity and favors the messenger ribonucleic acid expression of uncoupling proteins in mice.Endocrinology200714862690269710.1210/en.2006‑1270 17347313
     [Google Scholar]
  76. NakayasuE.S. SyedF. TerseyS.A. Comprehensive proteomics analysis of stressed human islets identifies GDF15 as a target for type 1 diabetes intervention.Cell Metab.2020312363374.e610.1016/j.cmet.2019.12.005 31928885
     [Google Scholar]
  77. EizirikD.L. PasqualiL. CnopM. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: Different pathways to failure.Nat. Rev. Endocrinol.202016734936210.1038/s41574‑020‑0355‑7 32398822
     [Google Scholar]
  78. Al-kuraishyH.M. Al-GareebA.I. AlexiouA. Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure.J. Diabetes2022141280681410.1111/1753‑0407.13334 36444166
     [Google Scholar]
  79. KadoglouN.P.E. TsanikidisH. KapelouzouA. Effects of rosiglitazone and metformin treatment on apelin, visfatin, and ghrelin levels in patients with type 2 diabetes mellitus.Metabolism201059337337910.1016/j.metabol.2009.08.005 19815243
     [Google Scholar]
  80. EddyA.C. TraskA.J. Growth differentiation factor-15 and its role in diabetes and cardiovascular disease.Cytokine Growth Factor Rev.202157111810.1016/j.cytogfr.2020.11.002 33317942
     [Google Scholar]
  81. JungS.B. ChoiM.J. RyuD. Reduced oxidative capacity in macrophages results in systemic insulin resistance.Nat. Commun.201891155110.1038/s41467‑018‑03998‑z 29674655
     [Google Scholar]
  82. GersteinH.C. PareG. HessS. Growth differentiation factor 15 as a novel biomarker for metformin.Diabetes Care201640228028310.2337/dc16‑1682 27974345
     [Google Scholar]
  83. MazagovaM. BuikemaH. van BuitenA. Genetic deletion of growth differentiation factor 15 augments renal damage in both type 1 and type 2 models of diabetes.Am. J. Physiol. Renal Physiol.20133059F1249F126410.1152/ajprenal.00387.2013 23986522
     [Google Scholar]
  84. JohnenH. LinS. KuffnerT. Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1.Nat. Med.200713111333134010.1038/nm1677 17982462
     [Google Scholar]
  85. SuribenR. ChenM. HigbeeJ. Antibody-mediated inhibition of GDF15–GFRAL activity reverses cancer cachexia in mice.Nat. Med.20202681264127010.1038/s41591‑020‑0945‑x 32661391
     [Google Scholar]
  86. BreitS.N. ManandharR. ZhangH.P. Lee-NgM. BrownD.A. TsaiV.W.W. GDF15 enhances body weight and adiposity reduction in obese mice by leveraging the leptin pathway.Cell Metab.202335813411355.e310.1016/j.cmet.2023.06.009 37433299
     [Google Scholar]
  87. WangJ. WeiL. YangX. ZhongJ. Roles of growth differentiation factor 15 in atherosclerosis and coronary artery disease.J. Am. Heart Assoc.2019817e01282610.1161/JAHA.119.012826 31432727
     [Google Scholar]
  88. MinaminoT. OrimoM. ShimizuI. A crucial role for adipose tissue p53 in the regulation of insulin resistance.Nat. Med.20091591082108710.1038/nm.2014 19718037
     [Google Scholar]
  89. KimY. Noren HootenN. EvansM.K. StimulatesC.R.P. CRP stimulates GDF15 expression in endothelial cells through p53.Mediators Inflamm.201820181910.1155/2018/8278039 29967567
     [Google Scholar]
  90. BenichouO. CoskunT. GonciarzM.D. Discovery, development, and clinical proof of mechanism of LY3463251, a long-acting GDF15 receptor agonist.Cell Metab.2023352274286.e1010.1016/j.cmet.2022.12.011 36630958
     [Google Scholar]
  91. XiongY. WalkerK. MinX. Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys.Sci. Transl. Med.20179412eaan873210.1126/scitranslmed.aan8732 29046435
     [Google Scholar]
  92. FungE. KangL. SapashnikD. Fc-GDF15 glyco-engineering and receptor binding affinity optimization for body weight regulation.Sci. Rep.2021111892110.1038/s41598‑021‑87959‑5 33903632
     [Google Scholar]
  93. LimS. KimD-H. YangJ. 235-LB: YH34160, a novel long-acting GDF15 fusion protein, exerts potent and sustained body weight loss in rodent obesity models.Diabetes202271Suppl. 1235-LB10.2337/db22‑235‑LB
     [Google Scholar]
  94. ZhangS.Y. BruceK. DanaeiZ. Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake and body weight.Cell Metab.2023355875886.e510.1016/j.cmet.2023.03.014 37060902
     [Google Scholar]
  95. KempfT. WollertK.C. Growth differentiation factor-15: A new biomarker in cardiovascular disease.Herz200934859459910.1007/s00059‑009‑3317‑3 20024638
     [Google Scholar]
  96. LindL. WallentinL. KempfT. Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: Results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study.Eur. Heart J.200930192346235310.1093/eurheartj/ehp261 19561023
     [Google Scholar]
  97. Dominguez-GonzalezC. BadosaC. Madruga-GarridoM. Growth differentiation factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy.Sci. Rep.20201011011110.1038/s41598‑020‑66940‑8 32572108
     [Google Scholar]
  98. HagströmE. JamesS.K. BertilssonM. Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: Results from the PLATO study.Eur. Heart J.201637161325133310.1093/eurheartj/ehv491 26417057
     [Google Scholar]
  99. LiuH. WangH. TaoL. Stress-induced growth-differentiation factor 15 plays an intriguing role in cardiovascular diseases.Chin. Med. J. (Engl.)201312671350135410.3760/cma.j.issn.0366‑6999.20121475 23557570
     [Google Scholar]
  100. WollertK.C. KempfT. Growth differentiation factor 15 in heart failure: An update.Curr. Heart Fail. Rep.20129433734510.1007/s11897‑012‑0113‑9 22961192
     [Google Scholar]
  101. Montoro-GarcíaS. Hernández-RomeroD. JoverE. Growth differentiation factor-15, a novel biomarker related with disease severity in patients with hypertrophic cardiomyopathy.Eur. J. Intern. Med.201223216917410.1016/j.ejim.2011.08.022 22284249
     [Google Scholar]
  102. KahliA. GuenanciaC. ZellerM. Growth differentiation factor-15 (GDF-15) levels are associated with cardiac and renal injury in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.PLoS One201498e10575910.1371/journal.pone.0105759 25171167
     [Google Scholar]
  103. EggersK.M. KempfT. LindL. Relations of growth-differentiation factor-15 to biomarkers reflecting vascular pathologies in a population-based sample of elderly subjects.Scand. J. Clin. Lab. Invest.2012721455110.3109/00365513.2011.626072 22023041
     [Google Scholar]
  104. AbdellahM.A. HassenH.A. Abdel-HafizA-R.M. FouadD.A. YoussefA.A. IdrissN.K. Growth differentiation factor 15 in patients with acute coronary syndrome and its relation to type 2 diabetes mellitus.Egypt. J. Hosp. Med.20208131546155110.21608/ejhm.2020.115620
     [Google Scholar]
  105. HeX. SuJ. MaX. The association between serum growth differentiation factor 15 levels and lower extremity atherosclerotic disease is independent of body mass index in type 2 diabetes.Cardiovasc. Diabetol.20201914010.1186/s12933‑020‑01020‑9 32222153
     [Google Scholar]
  106. CarlssonA.C. NowakC. LindL. Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: A proteomics approach.Ups. J. Med. Sci.20201251374310.1080/03009734.2019.1696430 31805809
     [Google Scholar]
  107. Frimodt-MøllerM. von ScholtenB.J. ReinhardH. Growth differentiation factor-15 and fibroblast growth factor-23 are associated with mortality in type 2 diabetes – An observational follow-up study.PLoS One2018134e019663410.1371/journal.pone.0196634 29698460
     [Google Scholar]
  108. NaK.R. KimY.H. ChungH.K. Growth differentiation factor 15 as a predictor of adverse renal outcomes in patients with immunoglobulin A nephropathy.Intern. Med. J.201747121393139910.1111/imj.13614 28869715
     [Google Scholar]
  109. HamY.R. SongC.H. BaeH.J. Growth differentiation factor-15 as a predictor of idiopathic membranous nephropathy progression: A retrospective study.Dis. Markers20182018146394010.1155/2018/1463940 29682097
     [Google Scholar]
  110. ThorsteinsdottirH. SalvadorC.L. MjøenG. Growth differentiation factor 15 in children with chronic kidney disease and after renal transplantation.Dis. Markers202020201810.1155/2020/6162892 32089755
     [Google Scholar]
  111. WangJ. HanL.N. AiD.S. Growth differentiation factor 15 predicts cardiovascular events in stable coronary artery disease.J. Geriatr. Cardiol.202320752753710.26599/1671‑5411.2023.07.007 37576485
     [Google Scholar]
  112. KopytsyaMP PetyuninaOV VyshnevskaIR TytarenkoNV HilovaYV The role of a new biomarker growth differentiation factor 15 in prognosis of patients with acute coronary syndrome and type 2 diabetes mellitus.Bull KhNU, Med201610.26565/2227‑6505‑2016‑32‑02
     [Google Scholar]
  113. BaoX. BornéY. MuhammadI.F. Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: The malmö diet and cancer–cardiovascular cohort.Diabetologia2019621788610.1007/s00125‑018‑4751‑7 30350239
     [Google Scholar]
  114. ShinM.Y. KimJ.M. KangY.E. Association between growth differentiation factor 15 (GDF15) and cardiovascular risk in patients with newly diagnosed type 2 diabetes mellitus.J. Korean Med. Sci.20163191413141810.3346/jkms.2016.31.9.1413 27510384
     [Google Scholar]
  115. KempfT. Guba-QuintA. TorgersonJ. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: Results from the XENDOS trial.Eur. J. Endocrinol.2012167567167810.1530/EJE‑12‑0466 22918303
     [Google Scholar]
/content/journals/ccr/10.2174/011573403X332671241121063641
Loading
Molecular and Functional Significance of Growth Differentiation Factor-15: A Review on Cardiovascular-Kidney-Metabolic Biomarker
Curr. Cardiol. Rev. 21, E1573403X332671 (2025); https://doi.org/10.2174/011573403X332671241121063641
/content/journals/ccr/10.2174/011573403X332671241121063641
/content/journals/ccr/10.2174/011573403X332671241121063641
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): cardiovascular-kidney-metabolic syndrome; cellular functions; diagnostic marker; GDF-15; molecular functions; prognostic marker; therapeutic target

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test