Fibroblast Growth Factor 23, Glucose Homeostasis, and Incident Diabetes: Findings of 2 Cohort Studies

Abstract

Background The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood. This study investigates potential cross-talk between FGF23 and glucose homeostasis. Materials and Methods First, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (BMI 25-30 kg/m2) subjects using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI >30 kg/m2) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI. Results After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag=0.04). In the population-based cohort (N=5482; mean age 52 yrs, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (b 0.13[0.03-0.23], P=0.01), insulin (b 0.10[0.03-0.17], P<0.001), and proinsulin (b 0.06[0.02-0.10], P=0.01) at baseline. Upon longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events (4%); fully adjusted HR 1.66[95% CI 1.06-2.60], P=0.03) and development of obesity (241 events (6%); fully adjusted HR 1.84[1.34-2.50], P<0.001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. Conclusions Glucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels and obesity. These findings suggest cross-talk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.

Time-updated Fibroblast Growth Factor 23 Is Predictive for Posttransplant Diabetes Mellitus in Kidney Transplant Recipients

“…Furthermore, FGF23 is positively associated with markers of insulin resistance and adiposity [ 12-14 ]. Recently we found that a higher plasma FGF23 is associated with incident diabetes in the general population [ 15 ]. To our knowledge, the present study is the first to investigate the association between FGF23 and PTDM.…”

Non-Classical Effects of FGF23: Molecular and Clinical Features

“…On the other hand, FGF23 has been recognized as an important biomarker at the cardiovascular level [16,17]. In addition, it appears to be involved in iron metabolism [18], immune response [19], or glucose metabolism [20]. In this article, we will explore some of the recently discovered non-classical effects of FGF23.…”