1662-P: The Bidirectional Relationship of Fibroblast Growth Factor 23 and Glucose Homeostasis Free

Objective: To investigate potential cross-talk between the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) and glucose homeostasis.

Research Design and Methods: First, we investigated the effect of glucose loading on plasma FGF23 and its temporal relationship with changes in plasma phosphate (0-15-30-45-60-75-90-120-150-180-240-300-360-420-480 minutes) in 45 overweight (BMI 25-30) subjects using time-lag analyses. Second, we studied cross-sectional associations of plasma FGF23 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 (P_time-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 (est. β 0.13[0.03-0.23], P=0.01), insulin (est. β 0.10[0.03-0.17], P<0.001), and proinsulin (est. β 0.06[0.02-0.10], P=0.01) at baseline. Upon longitudinal analyses, a higher baseline FGF23 was independently associated with the 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; vice versa, FGF23 is associated with glucose, insulin, proinsulin levels and obesity. These findings suggest deleterious cross-talk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.