Diastolic Dysfunction and Impaired Cardiac Output Reserve in Dysmetabolic Nonhuman Primate With Proteinuria

Abstract

Background Cardiorenal complications are common in patients with dysmetabolism and diabetes. The present study aimed to examine if a nonhuman primate (NHP) model with spontaneously developed metabolic disorder and diabetes develops similar complications to humans, such as proteinuria and cardiac dysfunction at resting condition or diminished cardiac functional reserve following dobutamine stress echocardiography (DSE).Methods and Results A total of 66 dysmetabolic and diabetic cynomolgus (Macaca fascicularis) NHPs were enrolled to select 19 NHPs (MetS) with marked metabolic disorders and diabetes (fasting blood glucose: 178+18 vs. 61+3 mg/dL) accompanied by proteinuria (ACR: 134+34 vs. 1.5+0.4 mg/mmol) compared to 8 normal NHPs (CTRL). Under resting condition, MetS NHPs showed mild left ventricular (LV) diastolic dysfunction (E/A: 1+0.06 vs. 1.5+0.13), but with preserved ejection fraction (EF: 65+2 vs. 71+3%) compared to CTRL. DSE with an intravenous infusion of dobutamine at ascending doses (5, 10, 20, 30 and 40 μg/kg/min, 7 min for each dose) resulted in a dose-dependent increase in cardiac function, however, with a significantly diminished magnitude at the highest dose of dobutamine infusion (40 μg/kg/min) in both diastole (E/A: -12+3 vs. -38+5%) and systole (EF: 25+3 vs. 33+5%) as well as ~42% reduced cardiac output reserve (COR: 63+8 vs. 105+18%, p<0.02) in the MetS compared to CTRL NHPs.Conclusion These data demonstrate that MetS NHPs with cardiorenal complications: proteinuria, LV diastolic dysfunction and preserved LV systolic function under resting conditions displayed compromised cardiac functional reserve under dobutamine stress. Based on these phenotypes, this NHP model of diabetes with cardiorenal complications can be used as a highly translational model mimic human disease for pharmaceutical research.

Immunomodulator FTY720 Rejuvenates β-cell and Ameliorates Cardiorenal Complications in Nonhuman Primate Model of Diabetes

“…This observation is consistent with the previous nding in db/db mice that FTY720 led to sustained normalization of hyperglycemia, which was also remained for life even after withdrawal of FTY20 11 . The animal model used in the present study is well-characterized naturally occurred diabetic NHPs with all the T2D characteristics in human patients at different stages of the disease progression and is by far the most predictive translational animal model for human metabolic syndrome, including diabetes [19][20][21][22][23][24][25] . To our knowledge, FTY720 is the only compound with a sustained anti-glycemic effect even after cease of the treatment in both the diabetic mice and NHPs.…”

“…Previous reports showed that the diabetic NHPs had the compromised cardiac functions, particularly, the LV systolic functions measured by reduced ejection fraction (EF) and fractional shortening (FS) 20,27 . In the present study, the standard echocardiography was performed in the anesthetized diabetic NHPs before (baseline) and 9 weeks after (post-dose) administration of vehicle or FTY720 (5 mg/kg, PO, QD).…”

“…The present study aimed to evaluate the therapeutic bene ts of FTY720 in the treatment of T2D using a nonhuman primate (NHP) model with spontaneously developed diabetes, which has been shown to have all the characteristics of T2D in human patients at different stages of the progressive disease, and is widely used in academia and pharmaceutical industry as by far the most predictive animal model for both the basic and preclinical research in testing novel therapeutics for human metabolic disease, including diabetes [19][20][21][22][23][24][25] .…”

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

“…The echocardiography revealed that the ejection fraction (EF) is significantly reduced from 68% in the T A B L E 1 General characteristics of the diabetic NHPs following once daily oral administration of vehicle (purified water, 1 ml/kg) or FTY720 ( normal NHPs to 62% in the diabetic NHPs and fractional shortening (FS) from 43% to 30% [17,21]. In the present study, the echocardiography was performed in the anesthetized diabetic NHPs before (baseline) and 8 weeks after administration of the vehicle or FTY720.…”

“…With the limitations of the rodent models of diabetes, from which the experiment results often are unable to translate to human diseases, the present study aimed to further explore the therapeutic potential of FTY720 in the treatment of T2D using a nonhuman primate (NHP) model with spontaneously developed diabetes, which has been proved to be highly resemble all the characteristics of T2D in human patients at different stages of the disease progression, and is widely used in academia and pharmaceutical industry as by far the most predictive animal model for both the basic and preclinical research in testing novel therapeutics for human metabolic diseases, including diabetes [17][18][19][20][21][22]. Interestingly, the spontaneous diabetes NHPs clearly showed β-cell failure in response to glucose stimulation [20], thus, the findings in this well-characterized naturally occurred diabetic model can provide significant insight information for development of FTY720 as a therapeutic drug for the treatment of T2D in human patients.…”