Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington, USA.
Diabetes. 2013 May;62(5):1593-601. doi: 10.2337/db11-1593. Epub 2013 Jan 17.
Neprilysin contributes to free fatty acid (FFA)-induced cellular dysfunction in nonislet tissues in type 2 diabetes. Here, we show for the first time that with prolonged FFA exposure, islet neprilysin is upregulated and this is associated with reduced insulin pre-mRNA and ATP levels, oxidative/nitrative stress, impaired potassium and calcium channel activities, and decreased glucose-stimulated insulin secretion (GSIS). Genetic ablation of neprilysin specifically protects against FFA-induced impairment of calcium influx and GSIS in vitro and in vivo but does not ameliorate other FFA-induced defects. Importantly, adenoviral overexpression of neprilysin in islets cultured without FFA reproduces the defects in both calcium influx and GSIS, suggesting that upregulation of neprilysin per se mediates insulin secretory dysfunction and that the mechanism for protection conferred by neprilysin deletion involves prevention of reduced calcium influx. Our findings highlight the critical nature of calcium signaling for normal insulin secretion and suggest that interventions to inhibit neprilysin may improve β-cell function in obese humans with type 2 diabetes.
Neprilysin 有助于 2 型糖尿病中非胰岛组织中游离脂肪酸 (FFA) 诱导的细胞功能障碍。在这里，我们首次表明，随着 FFA 暴露时间的延长，胰岛 Neprilysin 上调，这与胰岛素前体 mRNA 和 ATP 水平降低、氧化/硝化应激、钾和钙通道活性受损以及葡萄糖刺激的胰岛素分泌 (GSIS) 减少有关。Neprilysin 的基因缺失特异性地防止了体外和体内 FFA 诱导的钙内流和 GSIS 损伤，但不能改善其他 FFA 诱导的缺陷。重要的是，在没有 FFA 的情况下培养胰岛时，腺病毒过表达 Neprilysin 会重现钙内流和 GSIS 的缺陷，这表明 Neprilysin 的上调本身介导了胰岛素分泌功能障碍，而 Neprilysin 缺失赋予的保护机制涉及防止钙内流减少。我们的研究结果强调了钙信号对于正常胰岛素分泌的关键性质，并表明抑制 Neprilysin 的干预措施可能会改善肥胖 2 型糖尿病患者的β细胞功能。
