FTY720 Treatment Rejuvenates ß-Cell Function and Improves Cardiac Function in Diabetic Nonhuman Primates (NHPs)

Abstract

Pancreatic β-cell regeneration is considered as a possible therapy for cure of type 2 diabetes (T2D). It has been reported that administration of FTY720, a sphingosine 1-phosphate (S1P) receptor modulator, to db/db mice led to sustained normalization of hyperglycemia by stimulating β-cell in vivo regeneration through PI3K-dependent regulation of cyclin D3 and p57KIP2. To further evaluate the therapeutic potential of FTY720 in the treatment of T2D, we examined the effects of FTY720 on glucose homeostasis in spontaneous diabetic NHP model. NHPs with mean fasting glucose (FG) level of 249 mg/dL were randomly divided into the control (vehicle) and the FTY720-treatment group. FTY720 was orally administered at 5 mg/kg to diabetic NHPs once per day and the FG and HbA1c levels were measured biweekly. Here we show that FTY720 treatment of diabetic NHPs significantly lowered their FG and HbA1c in two weeks. After 10 weeks of treatment, their FG and HbA1c levels remained low and their glucose tolerance was significantly improved. To determine the effect of FTY720 on β-cell function, IVGTT was performed. Following glucose injection, the insulin levels in the control NHPs barely changed. In contrast, the FTY720-treated NHPs secreted large amount of insulin in response to glucose stimulation, consistent with β-cell in vivo regeneration observed in mice. We also evaluated the cardiac function in these NHPs by echocardiography, from which ejection fraction (EF) and fractional shortening (FS) are found abnormally lower in diabetic NHPs (EF=60% and FS=30%) than that in normal NHPs (EF=68% and FS=43%). After 10 weeks of treatment, however, EF in the treatment group was significantly increased from 60% to 70% and FS from 30% to 38% while these values remained abnormally low in the control group. Our data strongly suggest that FTY720 has a great therapeutic promise for the treatment of T2D with benefit to improve the cardiac function in the patients. Disclosure Y. Wang: None. Y. Liu: None. Q. Wei: Employee; Self; Crownbio.Inc.. X. Wang: None. G. Sun: None. Y. Xiao: None. G. Yu: None. Z.A. Ma: None.