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

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.