Table 1.

Studies investigating the relationship between FGF23-klotho, carbohydrate metabolism, and insulin resistance in animals

Author, Ref.	Aim	Study design	FGF23 assay	Outcome
Ellam et al.,58	-To investigate impact of dietary phosphate on IR	-Eight-week-old male apolipoprotein E−/− mice were randomly assigned to atherogenic diets with low (0.2%), standard (0.6%), or high (1.6%) phosphate content	-iFGF23	-Low-phosphate diet decreased FGF23 and increased HOMA-IR
Eller et al.,59	-To investigate metabolic of hyperphosphatemia	-Five-week-old, male, db/db leptin receptor-deficient mice (BKS.Cg-Dock7m / Leprdb/J) and male C57BL/6J control mice underwent uninephrectomy and were afterward fed with either a standard chow or a phosphorus-rich diet	-iFGF23	-db/db mice on phosphorus-rich diet had higher serum FGF23 and lower HOMA-IR and smaller visceral adipocytes
Hesse et al.,4	-To clarify role of vitamin D in FGF23 signaling	-Fgf23−/− and VDRΔ/Δ mice were generated by embryonic stem cell technology - Fgf23−/−/VDRΔ/Δ compound mutant mice were generated by mating Fgf23−/− and VDRΔ/Δ mice -All mouse were kept on a diet rich in calcium, phosphorus, and lactose (rescue diet) to prevent secondary hyperparathyroidism	-N/A	-Fgf23−/− mice had increased insulin sensitivity -Glucose tolerance and insulin secretion of Fgf23−/−/VDRΔ/Δ mice closely matched those of VDRΔ/Δ mice -Alterations in carbohydrate metabolism in Fgf23−/− mice were caused indirectly through vitamin D axis
Streicher et al.,22	-To investigate relationship between FGF23 and carbohydrate metabolism in mice with a nonfunctioning VDR	-9-month-old male WT mice, VDRΔ/Δ, and Fgf23−/−/VDRΔ/Δ mice were fed with a standard rodent chow, or a rescue diet enriched with calcium, phosphorus, and lactose	-N/A	-VDRΔ/Δ mice had improved insulin sensitivity and glucose tolerance compared to WT mice - FGF23 deficiency did not alter peripheral insulin sensitivity in VDRΔ/Δ mice -FGF23 regulation of carbohydrate metabolism in vitamin D-dependent
Ohnishi et al.,55	-To study role of klotho in obesity in vivo	-Heterozygous klotho mutants were crossbred with heterozygous obese [C57BL/6J lepob (+/−)] mutants to obtain ob/ob-klotho DKO mice in a C57BL6 background -The WT and klotho-knockout mice were fed either a normal fat (20%) diet or a high-fat (60%) diet, starting at 3 weeks and continuing for ≥9 weeks	-N/A	- Both leptin-deficient ob/ob mice and ob/ob-klotho DKO mice had significantly higher serum insulin levels -ob/ob mice higher blood glucose levels than WT, ob/ob-klotho DKO and klotho−/− mice -ob/ob-klotho DKO mice had similar fasting blood glucose levels to klotho−/− mice -Insulin resistant ob/ob mice became insulin sensitive when klotho activity was eliminated
Utsugi et al.,56	-To determine whether mutation of the klotho gene was associated with IR	-The mice homozygote (kl/kl) and heterozygote (kl/+) for klotho mutation were used	-N/A	-During OGTT, blood glucose of kl/kl mice was significantly lower than WT mice, and plasma insulin of kl/kl mice was undetectable -kl/kl mice had significantly lower pancreas insulin content than kl/+ and WT mice -During insulin tolerance test, kl/kl showed enhanced insulin sensitivity - GLUT4 mRNA was increased in skeletal muscle of kl/kl mice compared to kl/+ and WT mice

DKO, double-knockout; FGF23, fibroblast growth factor 23; GLUT4, glucose transporter type 4. HOMA-IR, homeostatic model assessment of insulin resistance; iFGF23, intact fibroblast growth factor 23; IR, insulin resistance; N/A, not applicable; OGTT, oral glucose tolerance test; VDR, vitamin D receptor; WT, wild-type.