题名：Neprilysin deficiency protects against fat-induced insulin secretory dysfunction by maintaining calcium influx.
作者：ZRAIKA S; KOH DS; BARROW BM; LU B; KAHN SE; ANDRIKOPOULOS S;
来源：Diabetes. 2013 May;62(5):1593-601. doi: 10.2337/db11-1593. Epub 2013 Jan 17. [ IF= 8.29 ] ]
摘要：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 beta-cell function in obese humans with type 2 diabetes.