The potential mechanism of the diabetogenic action of streptozotocin:: inhibition of pancreatic β-cell O-GlcNAc-selective N-acetyl-β-D-glucosaminidase
The potential mechanism of the diabetogenic action of streptozotocin:: inhibition of pancreatic β-cell O-GlcNAc-selective N-acetyl-β-D-glucosaminidase
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DOI：
10.1042/0264-6021:3560031
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发表时间：
2001-05-15
影响因子：
4.1
通讯作者：
Kudlow, JE
中科院分区：
文献类型：
--
作者：
Konrad, RJ;Mikolaenko, I;Kudlow, JE
链脲佐菌素（STZ）是GlcNAc的类似物，可抑制纯化的大鼠脾脏O-GlcNAc-选择性N-乙酰-β-D-氨基葡萄糖苷酶（O-GlcNAc酶），该酶可从蛋白质中除去O-GlcNAc。我们以前已经表明，STZ增加胰岛O-连接蛋白糖基化。根据这些数据，我们进一步研究了STZ通过抑制O-GlcNAc酶引起β细胞死亡的可能性。在分离的胰岛中，STZ诱导的O-糖基化的时间过程和剂量曲线与β细胞毒性相关。STZ对大鼠胰岛O-GlcNAcase活性的抑制也与其β细胞毒性的抑制相同，在1 mM的浓度下发生显著抑制。相反，STZ对大鼠脑O-GlcNAcase和β-TC 3胰岛素瘤细胞O-GlcNAcase的抑制与胰岛相比显著右移，STZ仅在5 mM的浓度下显著抑制活性，与β-TC 3细胞毒性所需的浓度相同。相比之下。N-甲基-N-亚硝基脲（STZ的一氧化氮供体部分）不引起胰岛O-糖基化增加、β细胞毒性或β细胞O-GlcNAcase的抑制。与来自其它组织或胰岛素瘤细胞系的O-GlcNAcase相比，胰岛O-GlcNAcase的STZ敏感性增强，这表明为什么实际的胰岛β细胞对STZ特别敏感。证实了这一想法，STZ诱导的胰岛β细胞毒性被GlcNAc完全阻断，GlcNAc也阻止了STZ诱导的O-GlcNAc酶抑制，但甚至没有被葡萄糖、葡糖胺或GalNAc部分阻断。总之，这些数据表明STZ对β细胞O-GlcNAc酶的抑制是导致其致糖尿病毒性的机制。
Streptozotocin (STZ), an analogue of GlcNAc, inhibits purified rat spleen O-GlcNAc-seiective N-acetyl-beta -D-glucosaminidase (O-GlcNAcase), the enzyme that removes O-GlcNAc from protein. We have shown previously that STZ increases pancreatic islet O-linked protein glycosylation. In light of these data, we investigated the possibility further that STZ causes beta -cell death by inhibiting O-GlcNAcase. In isolated islets, the time course and dose curve of STZ-induced O-glycosylation correlated with beta -cell toxicity. STZ inhibition of rat islet O-GlcNAcase activity also paralleled that of its beta -cell toxicity, with significant inhibition occurring at a concentration of 1 mM. In contrast, STZ inhibition of rat brain O-GlcNAcase and beta -TC3 insulinoma cell O-GlcNAcase was significantly right-shifted compared with islets, with STZ only significantly inhibiting activity at a concentration of 5 mM, the same concentration required for beta -TC3 cell toxicity. In comparison. N-methyl-N-nitrosourea, the nitric oxide-donating portion of STZ, did not cause increased islet O-glycosylation, beta -cell toxicity or inhibition of beta -cell O-GlcNAcase, Enhanced STZ sensitivity of islet O-GlcNAcase compared with O-GlcNAcase from other tissues or an insulinoma cell line suggests why actual islet beta -cells are particularly sensitive to STZ. Confirming this idea, STZ-induced islet beta -cell toxicity was completely blocked by GlcNAc, which also prevented STZ-induced O-GlcNAcase inhibition, but was not even partially blocked by glucose, glucosamine or GalNAc. Together, these data demonstrate that STZ's inhibition of beta -cell O-GlcNAcase is the mechanism that accounts for its diabetogenic toxicity.