Roos M D, Xie W, Su K, Clark J A, Yang X, Chin E, Paterson A J, Kudlow J E
Department of Medicine/Endocrinology, University of Alabama at Birmingham, 35294, USA.
Proc Assoc Am Physicians. 1998 Sep-Oct;110(5):422-32.
Streptozotocin (STZ), an analog of N-acetylglucosamine (GlcNAc), is a specific toxin for the pancreatic beta cell. We found that treatment of rats with STZ results in an early beta-cell-specific increase in the level of intracellular protein modification by O-linked GlcNAc (O-GlcNAc). Using a model O-GlcNAc peptide based on the transcription factor Sp1, we show that treatment of cultured cells with STZ during peptide biosynthesis results in hyperglycosylation of the peptide as a result of the ability of STZ to specifically inhibit the activity of O-GlcNAc-selective N-acetyl-beta-D-glucosaminidase. Although this inhibitory activity of STZ probably can occur in all cells, we found, using in situ hybridization, that beta cells express very high levels of the mRNA encoding the enzyme responsible for cytoplasmic protein O-glycosylation, O-GlcNAc transferase (OGT). These findings suggest that the pancreatic beta cell is particularly sensitive to the toxicity of STZ because it expresses such high levels of OGT. When STZ blocks O-GlcNAc removal from intracellular proteins, the cell with the most rapid on-rate for O-GlcNAc, the beta cell, will experience the most rapid accumulation of this protein modification. Because we also show that the on-rate of O-GlcNAc is substrate driven in several cell types, we speculate that the beta cell, with its high level of OGT, may also respond to elevations of blood sugar with increased protein modification by O-GlcNAc. Thus, this proposed mechanism of STZ toxicity on the beta cell may result from an exaggeration of a heretofore unrecognized physiological response to glucose mediated through the high level of OGT in these cells.
链脲佐菌素（STZ）是N-乙酰葡糖胺（GlcNAc）的类似物，是一种对胰腺β细胞具有特异性的毒素。我们发现，用STZ处理大鼠会导致早期β细胞特异性的O-连接的N-乙酰葡糖胺（O-GlcNAc）介导的细胞内蛋白质修饰水平升高。使用基于转录因子Sp1的模型O-GlcNAc肽，我们发现，在肽生物合成过程中用STZ处理培养细胞会导致肽的高糖基化，这是因为STZ能够特异性抑制O-GlcNAc选择性N-乙酰-β-D-葡糖胺酶的活性。尽管STZ的这种抑制活性可能在所有细胞中都能发生，但我们通过原位杂交发现，β细胞中负责细胞质蛋白质O-糖基化的酶——O-GlcNAc转移酶（OGT）的mRNA表达水平非常高。这些发现表明，胰腺β细胞对STZ的毒性特别敏感，因为它表达了如此高水平的OGT。当STZ阻止从细胞内蛋白质上去除O-GlcNAc时，O-GlcNAc结合速率最快的细胞，即β细胞，将经历这种蛋白质修饰的最快积累。因为我们还表明，在几种细胞类型中，O-GlcNAc的结合速率是由底物驱动的，所以我们推测，具有高水平OGT的β细胞也可能对血糖升高作出反应，使O-GlcNAc介导的蛋白质修饰增加。因此，这种提出的STZ对β细胞毒性的机制可能是由于这些细胞中高水平的OGT介导的对葡萄糖的一种迄今未被认识的生理反应被放大所致。
