Neprilysin, a widely expressed peptidase upregulated in type 2 diabetes, is capable of cleaving and inactivating the insulinotropic glucagon-like peptide-1 (GLP-1). Like dipeptidyl peptidase-4 (DPP-4), inhibition of neprilysin activity under diabetic conditions is associated with increased active GLP-1 levels and improved glycemic control. While neprilysin expression has been demonstrated in islets, its local contribution to GLP-1-mediated insulin secretion remains unknown. We investigated in vitro whether islet neprilysin inhibition enhances insulin secretion in response to glucose and/or exogenous GLP-1, and whether these effects are mediated by GLP-1 receptor (GLP-1R). Further, we compared the effect of neprilysin versus DPP-4 inhibition on insulin secretion. Isolated islets from wild-type (Glp1r^+/+) and GLP-1 receptor knockout (Glp1r^−/−) mice were incubated with or without the neprilysin inhibitor thiorphan and/or the DPP-4 inhibitor sitagliptin for 2.5 hours. During the last hour, insulin secretion was assessed in response to 2.8 mmol/l or 20 mmol/l glucose alone or plus exogenous active GLP-1. In Glp1r^+/+ islets, neprilysin inhibition enhanced 2.8 mmol/l and 20 mmol/l glucose- and GLP-1-mediated insulin secretion to the same extent as DPP-4 inhibition. These effects were blunted in Glp1r^−/− islets. In conclusion, inhibition of islet neprilysin in vitro increases glucose-mediated insulin secretion in a GLP-1R-dependent manner and enhances the insulinotropic effect of exogenous active GLP-1. Thus, neprilysin inhibitors may have therapeutic potential in type 2 diabetes by preserving islet-derived and circulating active GLP-1 levels.

脑啡肽酶是在2型糖尿病中广泛表达的肽酶，能够裂解和失活促胰岛素的胰高血糖素样肽1（GLP-1）。像二肽基肽酶-4（DPP-4）一样，在糖尿病条件下抑制中性溶酶的活性与活性GLP-1水平的提高和血糖控制的改善有关。尽管在胰岛中已经证明了脑啡肽酶的表达，但其对GLP-1介导的胰岛素分泌的局部作用仍然未知。我们在体外调查了胰岛中性溶酶的抑制是否响应于葡萄糖和/或外源性GLP-1来增强胰岛素分泌，以及这些作用是否由GLP-1受体（GLP-1R）介导。此外，我们比较了中枢溶酶和DPP-4抑制对胰岛素分泌的影响。从野生型分离的胰岛将Glp1r ^{+ / +}和GLP-1受体基因敲除（Glp1r ^-/-）小鼠与或不与中性溶酶抑制剂噻菌灵和/或DPP-4抑制剂西他列汀温育2.5小时。在最后一个小时内，评估了胰岛素对单独的2.8 mmol / l或20 mmol / l葡萄糖或外源性活性GLP-1的响应。在Glp1r ^{+ / +}胰岛中，中性溶酶抑制作用增强了2.8 mmol / l和20 mmol / l葡萄糖和GLP-1介导的胰岛素分泌，其抑制作用与DPP-4抑制作用相同。这些作用在Glp1r ^-/-胰岛中减弱了。综上所述，胰岛中性溶酶的体外抑制作用以GLP-1R依赖性方式增加葡萄糖介导的胰岛素分泌，并增强外源活性GLP-1的促胰岛素作用。因此，中性溶酶抑制剂通过保持胰岛来源和循环的活性GLP-1水平，可能在2型糖尿病中具有治疗潜力。