Pathophysiological Implications of Imbalances in Fibroblast Growth Factor 23 in the Development of Diabetes
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Donate-Correa, Javier
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Martín-Núñez, Ernesto
- González-Luis, Ainhoa
- Luis-Rodríguez, Desirée
- Tagua, Víctor G.
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Navarro-González, Juan F.
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Ferri, Carla M.
- Mora-Fernández, Carmen
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1
Universidad de La Laguna
info
ISSN: 2077-0383
Year of publication: 2021
Volume: 10
Issue: 12
Pages: 2583
Type: Article
More publications in: Journal of Clinical Medicine
Abstract
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 ß 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 αKlotho activates Ras/MAPK/ERK signaling. However, supraphysiological concentrations of FGF23 favor non-αKlotho-dependent binding of this molecule to other FGFRs, which could generate an undesired overactivation of the PLCγ/CN/NFAT pathway, as observed in cardiomyocytes and hepatocytes. Moreover, the decrease in αKlotho expression may constitute a contributing factor to the appearance of these effects by promoting the nonspecific activation of the PLCγ/CN/NFAT to the detriment of the αKlotho-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.
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