Inadequate β-cell mass is essential for the pathogenesis of type 2 diabetes (T2D). Previous report showed that an immunomodulator FTY720, a sphingosine 1-phosphate (S1P) receptor modulator sustainably normalized hyperglycemia by stimulating β-cell in vivo regeneration in db/db mice. To further evaluate the therapeutic potential, we examined the effects of FTY720 on glucose homeostasis in a translational nonhuman primate (NHP) model of spontaneous diabetes. Daily administration of FTY720 (5

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... ) effectively lowered HbA1c, blood concentrations of fasting glucose (FBG) and insulin, hence, decreased homeostatic model assessment of insulin resistance (HOMA-IR); ameliorated glucose intolerance and restored glucose-stimulated insulin release, which was largely diminished in the vehicle-treated diabetic NHPs. Importantly, after discontinuation of FTY720, FBG and HbA1c remained at the reduced levels in washout period for 8 weeks. Accompanied by the glucose lowering effects, echocardiography revealed that FTY720 significantly improved cardiac left ventricular systolic function measured by increase in ejection fraction and fractional shortening, which was compromised in the diabetic NHPs. Finally, flow cytometry analysis detected that FTY720 significantly reduced CD4+ and increased DC cells. These data strongly suggest that immunomodulator FTY720 may be a novel immunotherapy to reverse T2D progression via rejuvenation of β-cell function with benefit to improve the cardiac function.