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

CONTEXT: The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood. OBJECTIVE: This study investigates potential crosstalk between FGF23 and glucose homeostasis. 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 (body mass index [BMI] 25-30) individuals 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) 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) = .04). In the population-based cohort (N = 5482; mean age 52 years, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (β (=) .13 [.03-.23]; P = .01), insulin (β (=) .10 [.03-.17]; P < .001), and proinsulin (β (=) .06 [0.02-0.10]; P = .01) at baseline. On longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events [4%]; fully adjusted hazard ratio [HR] 1.66 [95% CI, 1.06-2.60]; P = .03) and development of obesity (241 events [6%]; fully adjusted HR 1.84 [95% CI, 1.34-2.50]; P < .001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. CONCLUSION: 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 crosstalk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.