{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:35:12Z","timestamp":1792805712161,"version":"4.5.0"},"reference-count":99,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T00:00:00Z","timestamp":1623369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III","award":["PI07\/0870, PI15\/00298, PI16\/02057, PI16\/00024, ISCIII\u2010RETIC REDinREN RD16\/0009"],"award-info":[{"award-number":["PI07\/0870, PI15\/00298, PI16\/02057, PI16\/00024, ISCIII\u2010RETIC REDinREN RD16\/0009"]}],"id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Instituto de Salud Carlos III","award":["CP20\/00122"],"award-info":[{"award-number":["CP20\/00122"]}],"id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Instituto de Salud Carlos III","award":["FI14\/00033"],"award-info":[{"award-number":["FI14\/00033"]}],"id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Agencia Canaria de Investigaci\u00f3n, Innovaci\u00f3n y Sociedad de la Informaci\u00f3n\u2010","award":["TESIS2018010110"],"award-info":[{"award-number":["TESIS2018010110"]}],"id":[{"id":"https:\/\/ror.org\/01eeqch44","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Observational studies have associated the increase in fibroblast growth factor (FGF) 23 levels, the main regulator of phosphate levels, with the onset of diabetes. These studies open the debate on the plausible existence of undescribed diabetogenic mechanisms derived from chronic supraphysiological levels of FGF23, a prevalent condition in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. These maladaptive and diabetogenic responses to FGF23 may occur at different levels, including a direct effect on the pancreatic \u00df cells, and an indirect effect derived from the stimulation of the synthesis of pro-inflammatory factors. Both mechanisms could be mediated by the binding of FGF23 to noncanonical receptor complexes with the subsequent overactivation of signaling pathways that leads to harmful effects. The canonical binding of FGF23 to the receptor complex formed by the receptor FGFR1c and the coreceptor \u03b1Klotho activates Ras\/MAPK\/ERK signaling. However, supraphysiological concentrations of FGF23 favor non-\u03b1Klotho-dependent binding of this molecule to other FGFRs, which could generate an undesired overactivation of the PLC\u03b3\/CN\/NFAT pathway, as observed in cardiomyocytes and hepatocytes. Moreover, the decrease in \u03b1Klotho expression may constitute a contributing factor to the appearance of these effects by promoting the nonspecific activation of the PLC\u03b3\/CN\/NFAT to the detriment of the \u03b1Klotho-dependent Ras\/MAPK\/ERK pathway. The description of these mechanisms would allow the development of new therapeutic targets susceptible to be modified by dietary changes or by pharmacological intervention.<\/jats:p>","DOI":"10.3390\/jcm10122583","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T12:44:37Z","timestamp":1623415477000},"page":"2583","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Pathophysiological Implications of Imbalances in Fibroblast Growth Factor 23 in the Development of Diabetes"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7389-7347","authenticated-orcid":false,"given":"Javier","family":"Donate-Correa","sequence":"first","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital Universitario Nuestra Se\u00f1ora de Candelaria, 38010 Santa Cruz de Tenerife, Spain"},{"name":"GEENDIAB (Grupo Espa\u00f1ol para el Estudio de la Nefropat\u00eda Diab\u00e9tica), Sociedad Espa\u00f1ola de Nefrolog\u00eda, 39008 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0341-0956","authenticated-orcid":false,"given":"Ernesto","family":"Mart\u00edn-N\u00fa\u00f1ez","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital Universitario Nuestra Se\u00f1ora de Candelaria, 38010 Santa Cruz de Tenerife, Spain"},{"name":"GEENDIAB (Grupo Espa\u00f1ol para el Estudio de la Nefropat\u00eda Diab\u00e9tica), Sociedad Espa\u00f1ola de Nefrolog\u00eda, 39008 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainhoa","family":"Gonz\u00e1lez-Luis","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital Universitario Nuestra Se\u00f1ora de Candelaria, 38010 Santa Cruz de Tenerife, Spain"},{"name":"Escuela de Doctorado y Estudios de Posgrado, Universidad de La Laguna, 38200 San Crist\u00f3bal de La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2711-3836","authenticated-orcid":false,"given":"Carla M.","family":"Ferri","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital Universitario Nuestra Se\u00f1ora de Candelaria, 38010 Santa Cruz de Tenerife, Spain"},{"name":"Escuela de Doctorado y Estudios de Posgrado, Universidad de La Laguna, 38200 San Crist\u00f3bal de La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desir\u00e9e","family":"Luis-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Servicio de Nefrolog\u00eda, Hospital Universitario Nuestra Se\u00f1ora de Candelaria, 38010 Santa Cruz de Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00edctor G.","family":"Tagua","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital Universitario Nuestra Se\u00f1ora de Candelaria, 38010 Santa Cruz de Tenerife, Spain"},{"name":"Instituto de Tecnolog\u00edas Biom\u00e9dicas, Universidad de La Laguna, 38010 San Crist\u00f3bal de La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1570-6332","authenticated-orcid":false,"given":"Carmen","family":"Mora-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital Universitario Nuestra Se\u00f1ora de Candelaria, 38010 Santa Cruz de Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5015-7474","authenticated-orcid":false,"given":"Juan F.","family":"Navarro-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital Universitario Nuestra Se\u00f1ora de Candelaria, 38010 Santa Cruz de Tenerife, Spain"},{"name":"GEENDIAB (Grupo Espa\u00f1ol para el Estudio de la Nefropat\u00eda Diab\u00e9tica), Sociedad Espa\u00f1ola de Nefrolog\u00eda, 39008 Santander, Spain"},{"name":"Servicio de Nefrolog\u00eda, Hospital Universitario Nuestra Se\u00f1ora de Candelaria, 38010 Santa Cruz de Tenerife, Spain"},{"name":"Instituto de Tecnolog\u00edas Biom\u00e9dicas, Universidad de La Laguna, 38010 San Crist\u00f3bal de La Laguna, Spain"},{"name":"REDINREN (Red de Investigaci\u00f3n Renal-RD16\/0009\/0022), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,11]]},"reference":[{"key":"ref_1","unstructured":"IDF (2019). Diabetes Atlas, International Diabetes Federation. [9th ed.]. Available online: https:\/\/idf.org\/e-library\/epidemiology-research\/diabetes-atlas.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1007\/s00125-014-3241-9","article-title":"Calcium and Phosphate Concentrations and Future Development of Type 2 Diabetes: The Insulin Resistance Atherosclerosis Study","volume":"57","author":"Lorenzo","year":"2014","journal-title":"Diabetologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1258\/ebm.2011.011252","article-title":"Insulin Resistance Induces Medial Artery Calcification in Fructose-Fed Rats","volume":"237","author":"Zhou","year":"2012","journal-title":"Exp. Biol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.2215\/CJN.02420409","article-title":"Mineral metabolism and inflammation in chronic kidney disease patients: A cross-sectional study","volume":"4","author":"Muros","year":"2009","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1046\/j.1464-5491.2003.01030.x","article-title":"Type 2 diabetes mellitus: A disease of the innate immune system? An update","volume":"21","author":"Crook","year":"2004","journal-title":"Diabet. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1161\/01.CIR.102.1.42","article-title":"Chronic subclinical inflammation as part of the insulin resistance syndrome: The Insulin Resistance Atherosclerosis Study","volume":"102","author":"Festa","year":"2000","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.mad.2010.02.008","article-title":"A Potential Link Between Phosphate and Aging\u2014Lessons from Klotho-deficient Mice","volume":"131","author":"Kuro","year":"2010","journal-title":"Mech. Ageing Dev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"640","DOI":"10.7326\/0003-4819-152-10-201005180-00004","article-title":"The Associations of FGF23 and Uncarboxylated Matrix Gla Protein with Mortality in Coronary Artery Disease: The Heart and Soul Study","volume":"152","author":"Parker","year":"2010","journal-title":"Ann. Intern. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/sj.ki.5002009","article-title":"Prevalence of Abnormal Serum Vitamin D, PTH, Calcium, and Phosphorus in Patients with Chronic Kidney Disease: Results of the Study to Evaluate Early Kidney Disease","volume":"71","author":"Levin","year":"2007","journal-title":"Kidney Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cytogfr.2012.01.004","article-title":"FGF23\/Klotho Axis: Phosphorus, Mineral Metabolism and Beyond","volume":"23","year":"2012","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.bone.2016.11.013","article-title":"FGF23-Klotho as a Paradigm for a Kidney-Bone Network","volume":"100","author":"Moe","year":"2017","journal-title":"Bone"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1172\/JCI200419081","article-title":"Targeted Ablation of Fgf23 Demonstrates Essential Physiological Role of FGF23 in Phosphate & Vitamin D Metabolism","volume":"113","author":"Shimada","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6500","DOI":"10.1073\/pnas.101545198","article-title":"Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia","volume":"98","author":"Shimada","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1210\/jc.2004-1039","article-title":"Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men","volume":"90","author":"Ferrari","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5358","DOI":"10.1210\/en.2005-0777","article-title":"Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1, 25-dihydroxyvitamin D metabolism in mice","volume":"146","author":"Perwad","year":"2005","journal-title":"Endocrinology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1007\/s00774-015-0651-9","article-title":"Phosphate enhances Fgf23 expression through reactive oxygen species in UMR-106 cells","volume":"34","author":"Hori","year":"2016","journal-title":"J. Bone Miner. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11418","DOI":"10.1073\/pnas.1815166116","article-title":"Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation","volume":"116","author":"Takashi","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4393","DOI":"10.1172\/JCI46122","article-title":"FGF23 induces left ventricular hypertrophy","volume":"121","author":"Faul","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1001\/jama.2011.826","article-title":"Chronic Renal Insufficiency Cohort (CRIC) Study Group. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease","volume":"305","author":"Isakova","year":"2011","journal-title":"JAMA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1681\/ASN.2013050465","article-title":"Chronic Renal Insufficiency Cohort (CRIC) Study Investigators. Fibroblast growth factor-23 and cardiovascular events in CKD","volume":"25","author":"Scialla","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1161\/ATVBAHA.110.214619","article-title":"Circulating Fibroblast Growth factor-23 Is Associated with Fat Mass and Dyslipidemia in Two Independent Cohorts of Elderly Individuals","volume":"31","author":"Mirza","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1111\/j.1365-2265.2011.04299.x","article-title":"FGF23 Contributes to Insulin Sensitivity in Obese Adolescents -Preliminary Results","volume":"77","author":"Wojcik","year":"2012","journal-title":"Clin. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1515\/jpem-2012-0064","article-title":"The Association of FGF23 Levels in Obese Adolescents with Insulin Sensitivity","volume":"25","author":"Wojcik","year":"2012","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jdiacomp.2013.09.004","article-title":"Insulin Resistance Is Associated with Fibroblast Growth Factor-23 in Stage 3\u20135 Chronic Kidney Disease Patients","volume":"28","author":"Garland","year":"2014","journal-title":"J. Diabetes Complicat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.2215\/CJN.13281211","article-title":"Chronic Renal Insufficiency Cohort. Fibroblast Growth Factor 23 and Inflammation in CKD","volume":"7","author":"Isakova","year":"2012","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hanks, L.J., Casazza, K., Judd, S.E., Jenny, N.S., and Guti\u00e9rrez, O.M. (2015). Associations of Fibroblast Growth factor-23 With Markers of Inflammation, Insulin Resistance and Obesity in Adults. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122885"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Vervloet, M.G., van Zuilen, A.D., Heijboer, A.C., Ter Wee, P.M., Bots, M.L., Blankestijn, P.J., Wetzels, J.F.M., and MASTERPLAN Group Study (2012). Fibroblast growth factor 23 is associated with proteinuria and smoking in chronic kidney disease: An analysis of the MASTERPLAN cohort. BMC Nephrol., 13.","DOI":"10.1186\/1471-2369-13-20"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E575","DOI":"10.1210\/jc.2011-2836","article-title":"Serum level of the phosphaturic factor FGF23 is associated with abdominal aortic calcification in men: The STRAMBO study","volume":"97","author":"Schoppet","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"34696","DOI":"10.1038\/srep34696","article-title":"Elevation in Fibroblast Growth Factor 23 and Its Value for Identifying Subclinical Atherosclerosis in First-Degree Relatives of Patients with Diabetes","volume":"6","author":"Hu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"994","DOI":"10.2337\/dc11-2235","article-title":"Chronic Renal Insufficiency Cohort Study Group. Earlier Onset and Greater Severity of Disordered Mineral Metabolism in Diabetic Patients with Chronic Kidney Disease","volume":"35","author":"Wahl","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7899","DOI":"10.18632\/aging.102297","article-title":"Fibroblast growth factor 23 expression in human calcified vascular tissues","volume":"11","author":"Ferri","year":"2019","journal-title":"Aging"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lee, J.E., Gohda, T., Walker, W.H., Skupien, J., Smiles, A.M., Holak, R.R., Jeong, J., McDonnell, K.P., Krolewski, A.S., and Niewczas, M.A. (2013). Risk of ESRD and all-cause Mortality in Type 2 Diabetes According to Circulating Levels of FGF-23 and TNFR1. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058007"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1055\/a-0813-3164","article-title":"Prediabetes Is Characterized by Higher FGF23 Levels and Higher Prevalence of Vitamin D Deficiency Compared to Normal Glucose Tolerance Subjects","volume":"51","author":"Gateva","year":"2019","journal-title":"Horm. Metab. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3109\/00365513.2011.640407","article-title":"Acute hyperinsulinemia is followed by increased serum concentrations of fibroblast growth factor 23 in type 2 diabetes patients","volume":"72","author":"Winther","year":"2012","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e89","DOI":"10.2337\/dc13-2235","article-title":"FGF23 in type 2 diabetic patients: Relationship with bone metabolism and vascular disease","volume":"37","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1373\/clinchem.2013.206649","article-title":"Pathophysiological implications of fibroblast growth factor-23 and Klotho and their potential role as clinical biomarkers","volume":"60","year":"2014","journal-title":"Clin. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Real, J.M., Puig, J., Serrano, M., Sabater, M., Rubi\u00f3, A., Moreno-Navarrete, J.M., Fontan, M., Casamitjana, R., Xifra, G., and Ortega, F.J. (2013). Iron and obesity status-associated insulin resistance influence circulating fibroblast-growth factor-23 concentrations. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058961"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.2215\/CJN.02740311","article-title":"Fibroblast growth factor 23, cardiovascular disease risk factors, and phosphorus intake in the health professionals follow-up study","volume":"6","author":"Wolf","year":"2011","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5804","DOI":"10.1073\/pnas.1800160115","article-title":"Insulin Suppresses the Production of Fibroblast Growth Factor 23 (FGF23)","volume":"115","author":"Bar","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/jb\/mvq121","article-title":"Fibroblast growth factors: From molecular evolution to roles in development, metabolism and disease","volume":"149","author":"Itoh","year":"2011","journal-title":"J. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1248\/bpb.30.1819","article-title":"The Fgf families in humans, mice, and zebrafish: Their evolutional processes and roles in development, metabolism, and disease","volume":"30","author":"Itoh","year":"2007","journal-title":"Biol. Pharm. Bull."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1210\/endo.143.5.8850","article-title":"Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity","volume":"143","author":"Tomlinson","year":"2002","journal-title":"Endocrinology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2594","DOI":"10.1210\/en.2003-1671","article-title":"Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes","volume":"145","author":"Fu","year":"2004","journal-title":"Endocrinology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1172\/JCI23606","article-title":"FGF-21 as a novel metabolic regulator","volume":"115","author":"Kharitonenkov","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6018","DOI":"10.1210\/en.2008-0816","article-title":"Fibroblast growth factor 21 corrects obesity in mice","volume":"149","author":"Coskun","year":"2008","journal-title":"Endocrinology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"250","DOI":"10.2337\/db08-0392","article-title":"Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in dietinduced obese mice","volume":"58","author":"Xu","year":"2009","journal-title":"Diabetes"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s00467-009-1260-4","article-title":"Overview of the FGF23\u2013Klotho axis","volume":"25","author":"Kuro","year":"2010","journal-title":"Pediatr. Nephrol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.cytogfr.2005.01.008","article-title":"Structural basis for fibroblast growth factor receptor activation","volume":"16","author":"Mohammadi","year":"2005","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/nature05315","article-title":"Klotho converts canonical FGF receptor into a specific receptor for FGF23","volume":"444","author":"Urakawa","year":"2006","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"17218","DOI":"10.1074\/jbc.RA118.003036","article-title":"Fibroblast growth factor receptor 5 (FGFR5) is a co-receptor for FGFR1 that is up-regulated in beta-cells by cytokine-induced inflammation","volume":"293","author":"Regeenes","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/wdev.176","article-title":"The fibroblast growth factor signaling pathway","volume":"4","author":"Ornitz","year":"2015","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nature25451","article-title":"\u03b1-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling","volume":"553","author":"Chen","year":"2018","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/36285","article-title":"Mutation of the mouse Klotho gene leads to a syndrome resembling ageing","volume":"390","author":"Kuro","year":"1997","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ijcard.2011.08.850","article-title":"Expression of FGF23\/KLOTHO System in Human Vascular Tissue","volume":"165","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1097\/TP.0000000000001339","article-title":"Effect of Paricalcitol on FGF-23 and Klotho in Kidney Transplant Recipients","volume":"100","year":"2016","journal-title":"Transplantation"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"27890","DOI":"10.1074\/jbc.M115.655431","article-title":"Klotho Reduction in Alveolar Macrophages Contributes to Cigarette Smoke Extract-induced Inflammation in Chronic Obstructive Pulmonary Disease","volume":"290","author":"Li","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_57","first-page":"771","article-title":"Klotho-\u03b1 common link in physiological and rheumatoid arthritis-related aging of human CD4+ lymphocytes","volume":"178","author":"Witkowski","year":"2007","journal-title":"Immunol"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.jns.2017.09.012","article-title":"Klotho gene expression decreases in peripheral blood mononuclear cells (PBMCs) of patients with relapsing-remitting multiple sclerosis","volume":"381","author":"Karami","year":"2017","journal-title":"J. Neurol. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.2337\/db14-0632","article-title":"In Vivo Pancreatic-Cell-Specific Expression of Antiaging Gene Klotho. A Novel Approach for Preserving b-Cells in T2 Diabetes","volume":"64","author":"Lin","year":"2015","journal-title":"Diabetes"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1359\/JBMR.0301264","article-title":"FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis","volume":"19","author":"Shimada","year":"2004","journal-title":"J. Bone Miner. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"F1088","DOI":"10.1152\/ajprenal.00474.2004","article-title":"Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism","volume":"289","author":"Shimada","year":"2005","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/nrm3528","article-title":"Exploring mechanisms of FGF signalling through the lens of structural biology","volume":"14","author":"Goetz","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3005.1","DOI":"10.1186\/gb-2001-2-3-reviews3005","article-title":"Fibroblast growth factors","volume":"2","author":"Ornitz","year":"2001","journal-title":"Genome Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.kint.2016.05.019","article-title":"Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease","volume":"90","author":"Singh","year":"2016","journal-title":"Kidney Int."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/j.cmet.2015.09.002","article-title":"Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy","volume":"22","author":"Grabner","year":"2015","journal-title":"Cell Metab."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1172\/JCI83470","article-title":"FGF23 signaling impairs neutrophil recruitment and host defense during CKD","volume":"126","author":"Rossaint","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Olauson, H., Lindberg, K., Amin, R., Sato, T., Jia, T., Goetz, R., Mohammadi, M., Andersson, G., Lanske, B., and Larsson, T.E. (2013). Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003975"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"40534","DOI":"10.1038\/srep40534","article-title":"Persistent FGF23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease","volume":"7","author":"Kawakami","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1210\/me.2007-0241","article-title":"Fibroblast growth factor receptor-1 signaling in pancreatic islet beta-cells is modulated by the extracellular matrix","volume":"22","author":"Kilkenny","year":"2008","journal-title":"Mol. Endocrinol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1016\/j.bpj.2012.10.028","article-title":"Autofluorescence imaging of living pancreatic islets reveals fibroblast growth factor-21 (FGF21)-induced metabolism","volume":"103","author":"Sun","year":"2012","journal-title":"Biophys. J."},{"key":"ref_71","first-page":"114","article-title":"Nerve and fibroblast growth factors as modulators of pancreatic beta cell plasticity and insulin secretion","volume":"3","author":"Hiriart","year":"2001","journal-title":"Isr. Med. Assoc. J."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"939","DOI":"10.3727\/000000006783981323","article-title":"Amelioration of diabetes in mice after single-donor islet transplantation using the controlled release of gelatinized FGF-2","volume":"15","author":"Okitsu","year":"2006","journal-title":"Cell Transplant."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/35048589","article-title":"Attenuation of FGF signalling in mouse beta-cells leads to diabetes","volume":"408","author":"Hart","year":"2000","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/S0167-4781(00)00282-7","article-title":"A novel fibroblast growth factor receptor-5 preferentially expressed in the pancreas","volume":"1518","author":"Kim","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6062","DOI":"10.1073\/pnas.0400782101","article-title":"A gene atlas of the mouse and human protein-encoding transcriptomes","volume":"101","author":"Su","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"17859","DOI":"10.1074\/jbc.M112.440677","article-title":"Fibroblast growth factor receptor like-1 (FGFRL1) interacts with SHP-1 phosphatase at insulin secretory granules and induces beta-cell ERK1\/2 protein activation","volume":"288","author":"Silva","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1210\/mend.15.10.0702","article-title":"Regulation of insulin gene transcription by a Ca2+-responsive pathway involving calcineurin and NFAT","volume":"15","author":"Lawrence","year":"2001","journal-title":"Mol. Endocrinol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Bernal-Mizrachi, E., Cras-M\u00e9neur, C., Ye, B.R., Johnson, J.D., and Permutt, M.A. (2010). Transgenic Overexpression of Active Calcineurin in \u03b2-Cells Results in Decreased \u03b2-Cell Mass and Hyperglycemia. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011969"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1053\/meta.2000.8606","article-title":"Decreased insulin production and increased insulin sensitivity in the klotho mutant mouse, a novel animal model for human aging","volume":"49","author":"Utsugi","year":"2000","journal-title":"Metabolism"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1210\/en.2012-1091","article-title":"Antiaging gene Klotho enhances glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 in MIN6 b-cells","volume":"153","author":"Lin","year":"2012","journal-title":"Endocrinology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1007\/s001250051058","article-title":"Is Type II diabetes mellitus a disease of the innate immune system?","volume":"41","author":"Pickup","year":"1998","journal-title":"Diabetologia"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"813","DOI":"10.2337\/diacare.27.3.813","article-title":"Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes","volume":"27","author":"Pickup","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1016\/S0140-6736(99)01046-6","article-title":"Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): A cohort study","volume":"353","author":"Schmidt","year":"1999","journal-title":"Lancet"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1001\/jama.286.3.327","article-title":"C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus","volume":"286","author":"Pradhan","year":"2001","journal-title":"JAMA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"812","DOI":"10.2337\/diabetes.52.3.812","article-title":"Inflammatory cytokines and the risk to develop type 2 diabetes: Results of the prospective population based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study","volume":"52","author":"Spranger","year":"2003","journal-title":"Diabetes"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.kint.2019.04.009","article-title":"Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and non-renal inflammation","volume":"96","author":"Glaudemans","year":"2019","journal-title":"Kidney Int."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/ki.2015.290","article-title":"Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production","volume":"89","author":"David","year":"2016","journal-title":"Kidney Int."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.mce.2014.10.007","article-title":"Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli","volume":"399","author":"Ito","year":"2015","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1359\/jbmr.070107","article-title":"FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets","volume":"22","author":"Imel","year":"2007","journal-title":"J. Bone Miner. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/jbmr.1740","article-title":"Fibroblast growth factor 23 inhibits extrarenal synthesis of 1, 25-Dihydroxyvitamin D in human monocytes","volume":"28","author":"Bacchetta","year":"2013","journal-title":"J. Bone Miner. Res."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Dai, B., David, V., Martin, A., Huang, J., Li, H., Jiao, Y., Gu, W., and Quarles, L.D. (2012). A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044161"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Zhang, X.M., Guo, K., Xia, F., Zhao, X., Huang, Z., and Niu, J. (2018). FGF23 (C-tail) improves diabetic nephropathy by attenuating renal fibrosis and inflammation. BMC Biotechnol., 18.","DOI":"10.1186\/s12896-018-0449-7"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/1873-3468.12040","article-title":"Counter-regulatory paracrine actions of FGF-23 and 1,25(OH)2D in macrophages","volume":"590","author":"Han","year":"2016","journal-title":"FEBS Lett."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.cca.2011.02.034","article-title":"Association of exonic variants of Klotho with metabolic syndrome in Asian Indians","volume":"412","author":"Majumdar","year":"2011","journal-title":"Clin. Chim. Acta"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Luo, L., Hao, Q., Dong, B., and Yang, M. (2016). The Klotho gene G-395A polymorphism and metabolic syndrome in very elderly people. BMC Geriatr., 16.","DOI":"10.1186\/s12877-016-0221-6"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1126\/science.1112766","article-title":"Suppression of aging in mice by the hormone Klotho","volume":"309","author":"Kurosu","year":"2005","journal-title":"Science"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1007\/s11255-017-1646-3","article-title":"Klotho levels: Association with insulin resistance and albumin-to-creatinine ratio in type 2 diabetic patients","volume":"49","author":"Silva","year":"2017","journal-title":"Int. Urol. Nephrol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s00424-009-0735-2","article-title":"Evidence against a direct role of klotho in insulin resistance","volume":"459","author":"Lorenzi","year":"2010","journal-title":"Pflug. Arch."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13023-019-1014-8","article-title":"FGF23 and its role in X-linked hypophosphatemia-related morbidity","volume":"14","author":"Mughal","year":"2019","journal-title":"Orphanet J. Rare Dis."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/12\/2583\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:13:19Z","timestamp":1760163199000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/12\/2583"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,11]]},"references-count":99,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["jcm10122583"],"URL":"https:\/\/doi.org\/10.3390\/jcm10122583","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,11]]}}}