Pathophysiological Implications of Imbalances in Fibroblast Growth Factor 23 in the Development of Diabetes

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 alpha Klotho activates Ras/MAPK/ERK signaling. However, supraphysiological concentrations of FGF23 favor non-alpha Klotho-dependent binding of this molecule to other FGFRs, which could generate an undesired overactivation of the PLC gamma/CN/NFAT pathway, as observed in cardiomyocytes and hepatocytes. Moreover, the decrease in alpha Klotho expression may constitute a contributing factor to the appearance of these effects by promoting the nonspecific activation of the PLC gamma/CN/NFAT to the detriment of the alpha Klotho-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.

Automated summary

Observational studies have linked the increase in FGF23 levels with the onset of diabetes, suggesting the existence of potential diabetogenic mechanisms originating from chronic supraphysiological levels of FGF23 in CKD and ESRD patients. These mechanisms could involve direct and indirect effects on pancreatic ss cells, as well as the stimulation of pro-inflammatory factors synthesis, potentially mediated by the binding of FGF23 to noncanonical receptor complexes.