NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islets (PIs) of β-cells through an as yet unknown mechanism. We found NADPH oxidase isoform 4 (NOX4) to be the main producer of cytosolic H2O2, which is essential for GSIS; an increase in ATP alone was insufficient for GSIS. The fast GSIS phase was absent from PIs from NOX4-null, β-cell–specific knockout mice (NOX4βKO) (though not from NOX2 knockout mice) and from NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H2O2 rescued GSIS in PIs from NOX4βKO mice. NOX4 silencing suppressed Ca2+ oscillations, and the patch-clamped KATP channel opened more frequently when glucose was high. Mitochondrial H2O2, decreasing upon GSIS, provided alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxides through electron-transfer flavoprotein:Q-oxidoreductase. Unlike GSIS, such insulin secretion was blocked with mitochondrial antioxidant SkQ1. Both NOX4 knockout and NOX4βKO mice exhibited impaired glucose tolerance and peripheral insulin resistance. Thus, the redox signaling previously suggested to cause β-cells to self-check hypothetically induces insulin resistance when it is absent. In conclusion, increases in ATP and H2O2 constitute an essential signal that switches on insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (it does so partially for fatty acids). Redox signaling could be impaired by cytosolic antioxidants; hence, those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage.

中文翻译：

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葡萄糖刺激的胰岛素分泌从根本上需要 NADPH 氧化酶 4 的 H2O2 信号传导

NADPH 通过一种未知的机制促进 β 细胞胰岛 (PI) 中葡萄糖刺激的胰岛素分泌 (GSIS)。我们发现 NADPH 氧化酶亚型 4 (NOX4) 是胞质 H2O2 的主要生产者，这对 GSIS 至关重要；GSIS 仅增加 ATP 是不够的。来自 NOX4 缺失、β 细胞特异性敲除小鼠（NOX4βKO）（尽管不是来自 NOX2 敲除小鼠）和 NOX4 沉默或过氧化氢酶过表达的 INS-1E 细胞的 PI 不存在快速 GSIS 阶段。慢病毒 NOX4 过表达或 H2O2 挽救了 NOX4βKO 小鼠 PI 中的 GSIS。NOX4 沉默抑制了 Ca2+ 振荡，并且当葡萄糖高时膜片钳 KATP 通道更频繁地打开。线粒体 H2O2，随 GSIS 减少，当 2-氧代异己酸或脂肪酸氧化通过电子转移黄素蛋白：Q-氧化还原酶形成超氧化物时，提供了替代氧化还原信号。与 GSIS 不同的是，这种胰岛素分泌被线粒体抗氧化剂 SkQ1 阻断。NOX4 敲除小鼠和 NOX4βKO 小鼠均表现出葡萄糖耐量受损和外周胰岛素抵抗。因此，先前提出的氧化还原信号导致 β 细胞进行自我检查，假设它不存在时会诱导胰岛素抵抗。总之，ATP 和 H2O2 的增加构成了开启胰岛素胞吐作用的基本信号，葡萄糖和支链含氧酸作为促泌剂（部分对脂肪酸起作用）。细胞溶质抗氧化剂可能会削弱氧化还原信号；因此，