Fibroblast growth factor 23 in relation to phosphate and classical cardiovascular risk factors in patients with diabetes mellitus type 1 compared to controls

Fibroblast growth factor 23 (FGF23) is primarily synthesized in bone and its main target organs are the kidneys and parathyroid glands. FGF23 has a role in phosphate metabolism, cardiovascular risk in chronic kidney disease and possibly in glucose metabolism.
FGF23 plays an important role in phosphate homeostasis and vitamin D metabolism. When dietary phosphate intake is high, FGF23 stimulates renal phosphate excretion by inhibiting phosphate reabsorption in the proximal tubules and decreases gastrointestinal phosphate absorption by inhibiting 1 ? hydroxylase, the enzyme that converts 25-hydroxyvitamin D3 to active vitamin D (1,25-dihydroxyvitamin D3). When dietary phosphate intake is low, FGF23 levels are reduced to maintain normal serum phosphate levels.[1] Preventing hyperphosphatemia is important since it is associated with cardiovascular disease and mortality.  
In the parathyroid glands, FGF23 inhibits the secretion of PTH.[2]
FGF23 may have an important role in aging-related disorders including atherosclerosis, left ventricular hypertrophy, diabetes mellitus type 2, cancer and chronic kidney disease (CKD). [3,4]. In patients with CKD, higher levels of FGF23 are associated with progression of kidney disease and mortality independent of other risk factors such as phosphate itself. [5,6] Previous studies have found that elevated FGF23 levels are associated with adverse cardiovascular outcomes in patients with and without established cardiovascular disease. [7] 
A third possible role of FGF23 is in the glucose metabolism. Previous studies showed a positive correlation between insulin resistance and FGF23 levels in patients with CKD[8,9]. It is known that in patients with CKD, insulin resistance increases as renal function decreases. 
Only few studies focused on the relation between insulin resistance and FGF23 in individuals without CKD and results are conflicting. Fernández-Real et al showed a significant positive correlation between FGF23 and insulin resistance.[10] Accordingly, the study of Hanks et al performed in a large cohort of community dwelling individuals, showed that FGF23 was positively associated with HOMA-IR in individuals without CKD, but not among individuals with CKD.[11] In contrast to these studies, Wojcik et al showed a significant inverse correlation between FGF23 levels and HOMA-IR in 36 obese insulin-resistant adolescents.[12]
Ursem et al examined the effect of a change in serum glucose and insulin on FGF23 levels. They showed that an oral glucose load in vitamin D deficient patients decreased FGF23 and phosphate levels and this was attributed to the increase in plasma glucose rather than a change in insulin since they did not found a decrease in FGF23 levels after a 2-step hyperinsulinemic-euglycemic clamp. This may indicate that bone decreases FGF23 secretion rapidly after glucose loading.[13]
Cardiovascular disease is the major cause of death in patient with diabetes mellitus type 1. Very little is known about FGF23 levels in patients with diabetes type 1.In a previous study in 68 patients with diabetes type 1 without previous cardiovascular events, higher FGF23 levels were positively associated with arterial stiffness measured as aortic pulse wave velocity, also after correction for bone mineral parameters (Ca, PTH, 25OHD), estimated glomerular filtration rate (eGFR) and classical cardiovascular risk factors .[14]
Only few general population studies were performed and the following factors were associated with higher FGF23 levels: female sex, smoking, PTH, creatinine, C-reactive protein, a higher calcium and energy intake and a lower iron intake[15], adiposity [16,17] and dyslipidemia [17].