Pharmacological Neprilysin Inhibition Improves Glucose Homeostasis in a Mouse Model of Type 2 Diabetes

Abstract

Neprilysin (NEP) is a ubiquitous peptidase whose plasma activity in humans and rodents increases in conditions associated with type 2 diabetes (T2D). In high fat-fed mice, increased plasma NEP activity correlates with insulin resistance and impaired beta-cell function, and we’ve shown genetic ablation of NEP ameliorates these deleterious effects, thereby decreasing glucose levels. Thus, we sought to determine whether clinically relevant, pharmacological inhibition of NEP also confers beneficial effects on glycemic status in a mouse model of T2D. Five-week old C57BL/6 mice were fed high fat diet for 3 weeks, followed by injection of low-dose beta-cell toxin streptozotocin (30 mg/kg i.p. once daily for 3 consecutive days; STZ) to induce diabetes, or vehicle (VEH) as a control. Mice were continued on high fat diet alone (CON) or supplemented with the NEP inhibitor sacubitril (48 mg/kg/day; SAC) for 8 weeks. Body weight did not differ among the 3 groups of mice at baseline (Table), and increased to a similar extent in all groups after 8 weeks of treatment. Further, both fasting and fed glucose levels were higher in STZ-CON vs VEH-CON mice after 8 weeks, but significantly lower in STZ-SAC vs STZ-CON mice. Together, these data show that pharmacological NEP inhibition improves both fasting and fed glucose levels in a mouse model of T2D, and thus may be a useful treatment strategy in human T2D.VEH-CON (n=3)STZ-CON (n=5)STZ-SAC (n=7)Body weight (g)Baseline19.9±0.220.9±0.418.6±0.5Post-Treatment35.1±3.532.1±1.331.0±1.9Plasma glucose levels post-treatment (mg/dl)fasting145±5*314±38184±21*fed292±6*459±41317±29**p<0.vs STZ-CON Disclosure J.H. Parilla: None. S. Mongovin: None. B. Barrow: None. N. Esser: None. S. Zraika: None.