The potential mechanism of the diabetogenic action of streptozotocin: inhibition of pancreatic beta-cell O-GlcNAc-selective N-acetyl-beta-D-glucosaminidase
Rj. Konrad et al., The potential mechanism of the diabetogenic action of streptozotocin: inhibition of pancreatic beta-cell O-GlcNAc-selective N-acetyl-beta-D-glucosaminidase, BIOCHEM J, 356, 2001, pp. 31-41
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.