Immunomodulator FTY720 improves glucose homeostasis and diabetic complications by rejuvenation of β‐cell function in nonhuman primate model of diabetes

Abstract

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. We further examined the effects of FTY720 on glucose homeostasis and diabetic complications in a translational nonhuman primate (NHP) model of spontaneously developed diabetes. The male diabetic cynomolgus macaques of 18-19 year old were randomly divided into Vehicle (Purified water, n = 5) and FTY720 (5 mg/kg, n = 7) groups with oral gavage once daily for 10 weeks followed by 10 weeks drug free period. Compared with the Vehicle group, FTY720 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, indicating rejuvenation of β-cell function in diabetic NHPs. Importantly, after withdrawal of FTY720, FBG, and HbA1c remained at low level in the drug free period. Echocardiography revealed that FTY720 significantly reduced proteinuria and improved cardiac left ventricular systolic function measured by increased ejection fraction and fractional shortening in the diabetic NHPs. Finally, flow cytometry analysis (FACS) detected that FTY720 significantly reduced CD4 + and CD8 + T lymphocytes as well as increased DC cells in

A spontaneous hyperglycaemic cynomolgus monkey presents cognitive deficits, neurological dysfunction and cataract

“…Meanwhile, our data showed that the fasting insulin and concomitant C‐peptide in the HGM monkey were still within common level. Some reports also showed no difference with the insulin and C‐peptide between spontaneously diabetic and non‐diabetic monkeys, 16,27 but some reports are contradictory 15,23,28‐30 . The primary reason is likely that the insulin maintains normal at early stage of T2DM, whereas it increases to compensate the insulin resistance later and ultimately decreases or does not express because of β‐cells dysfunctions 29 .…”

FTY720-P, a Biased S1PR Ligand, Increases Mitochondrial Function through STAT3 Activation in Cardiac Cells

“…FTY720 improves glucose homeostasis in non-obese diabetic (NOD) mice, in db/db mice, and a in non-human primate model of spontaneous diabetes (NHP) [ 8 , 9 , 10 ]. Moreover, this compound promotes lipolysis activation and prevents obesity in a high-fat diet (HFD) mouse model [ 11 ].…”

“…Supporting these findings, the administration of FTY720 also improved cardiac dysfunction and decreased fibrosis in recent independent studies using animal models of genetically induced hypertrophic cardiomyopathy and in myocardial ischemic/reperfusion [ 5 , 6 , 7 ]. The administration of FTY720 favorably influences glucose sensitivity in non-obese diabetic mice (NOD), in db/db mice, and in a non-human primate model [ 8 , 9 , 10 ]. Moreover, it promotes lipolysis upon consumption of a high-fat diet (HFD) [ 11 ].…”

Therapeutic Potential of Fingolimod in Diabetes Mellitus and Its Chronic Complications

“…This may be due to FTY720 significantly reducing CD4+ T and CD8+ T lymphocytes and increasing dendritic cells, thereby preventing islet β cells from being destroyed by autoimmune cells and improving glucose homeostasis. 29 …”

“…This may be due to FTY720 significantly reducing CD4+ T and CD8+ T lymphocytes and increasing dendritic cells, thereby preventing islet β cells from being destroyed by autoimmune cells and improving glucose homeostasis. 29 In addition to protecting islet β cells function, FTY720 also improved glucose tolerance and insulin sensitivity in obese and insulin-resistant rodent models. In diet-induced obesity mice, FTY720 treatment can prevent weight gain, improve insulin sensitivity, and reduce lymphocytes and macrophages in adipose tissue.…”