Neprilysin Deficiency Is Associated With Expansion of Islet β-Cell Mass in High Fat-Fed Mice

Abstract

Neprilysin (NEP) is an endopeptidase known to modulate nervous, cardiovascular, and immune systems via inactivation of regulatory peptides. In addition, it may also contribute to impaired glucose homeostasis as observed in type 2 diabetes (T2D). Specifically, we and others have shown that NEP is upregulated under conditions associated with T2D, whereas NEP deficiency and/or inhibition improves glucose homeostasis via enhanced glucose tolerance, insulin sensitivity, and pancreatic β-cell function. Whether increased β-cell mass also occurs with lack of NEP activity is unknown. We sought to determine whether NEP deficiency confers beneficial effects on β- and α-cell mass in a mouse model of impaired glucose homeostasis. Wild-type and NEP mice were fed low- or high-fat diet for 16 weeks, after which pancreatic β- and α-cell mass were assessed by immunostaining for insulin and glucagon, respectively. Following low-fat feeding, NEP mice exhibited lower β- and α-cell mass compared with wild-type controls. A high-fat diet had no effect on these parameters in wild-type mice, but in NEP mice, it resulted in the expansion of β-cell mass. Our findings support a role for NEP in modulating β-cell mass, making it an attractive T2D drug target that acts via multiple mechanisms to affect glucose homeostasis.

Neprilysin expression and functions in development, ageing and disease

“…This effect of green tea was not observed in obese NEP-knockout mice. NEP deficient mice are also characterised by increased islet β-cell mass when fed on a high fat diet which suggests a role for NEP in modulating metabolism of this type of cells ( Parilla et al, 2018 ). Elevated NEP activity was also observed in the vitreous of patients with diabetic retinopathy which inversely correlated with Aβ levels ( Hara et al, 2006 ).…”

Neprilysin inhibition: a new therapeutic option for type 2 diabetes?

“…Also, islets from neprilysin-deficient mice were protected against palmitate-induced insulin secretory dysfunction in vitro [24]. In vivo, we have shown that high-fat-fed neprilysin-deficient mice display improvements in insulin sensitivity, beta cell function and glucose tolerance, as well as beta cell mass expansion [12,25]. Furthermore, acute inhibition of neprilysin with subcutaneous or intravenous administration of a pharmacological inhibitor increased insulin secretion and sensitivity in a time-and/or dose-dependent manner in pigs, as well as in lean or obese insulin-resistant rats [3,[18][19][20] (Table 1).…”

Modeling Diet‐Induced Metabolic Syndrome in Rodents

“…All data presented herein were obtained from refs. [44,54,55,70,72,74,75,78,88,95,96,98,102–111,116,119–121,124–130,132,134–137,140–144,147–156,158,159,161,163–171,173–176...…”