The potential mechanism of the diabetogenic action of streptozotocin: inhibition of pancreatic beta-cell O-GlcNAc-selective N-acetyl-beta-D-glucosaminidase

Streptozotocin (STZ), an analogue of GlcNAc, inhibits purified rat spleen O -GlcNAc-seiective N-acetyl-beta -D-glucosaminidase (O-GlcNAcase), the enzym e that removes O-GlcNAc from protein. We have shown previously that STZ inc reases pancreatic islet O-linked protein glycosylation. In light of these d ata, we investigated the possibility further that STZ causes beta -cell dea th by inhibiting O-GlcNAcase. In isolated islets, the time course and dose curve of STZ-induced O-glycosylation correlated with beta -cell toxicity. S TZ inhibition of rat islet O-GlcNAcase activity also paralleled that of its beta -cell toxicity, with significant inhibition occurring at a concentrat ion of 1 mM. In contrast, STZ inhibition of rat brain O-GlcNAcase and beta -TC3 insulinoma cell O-GlcNAcase was significantly right-shifted compared w ith islets, with STZ only significantly inhibiting activity at a concentrat ion of 5 mM, the same concentration required for beta -TC3 cell toxicity. I n 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-G lcNAcase compared with O-GlcNAcase from other tissues or an insulinoma cell line suggests why actual islet beta -cells are particularly sensitive to S TZ. Confirming this idea, STZ-induced islet beta -cell toxicity was complet ely blocked by GlcNAc, which also prevented STZ-induced O-GlcNAcase inhibit ion, but was not even partially blocked by glucose, glucosamine or GalNAc. Together, these data demonstrate that STZ's inhibition of beta -cell O-GlcN Acase is the mechanism that accounts for its diabetogenic toxicity.