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

Abstract

Streptozotocin (STZ), an analogue of GlcNAc, inhibits purified rat spleen O-GlcNAc-selective 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.

• Authors: R J Konrad, I Mikolaenko, J F Tolar, K Liu, J E Kudlow
• Journal: The Biochemical journal (Biochem J) Vol. 356 Issue Pt 1 Pg. 31-41 (May 15 2001) ISSN: 0264-6021 [Print] England
• PMID: 11336633 (Publication Type: Journal Article)

Chemical References

• Streptozocin
• Acetylglucosaminidase
• Acetylglucosamine

Topics

• Acetylglucosamine (analogs & derivatives)
• Acetylglucosaminidase (antagonists & inhibitors)
• Animals
• Brain (enzymology)
• Diabetes Mellitus, Experimental (etiology)
• Dose-Response Relationship, Drug
• Glycosylation (drug effects)
• Islets of Langerhans (drug effects, enzymology)
• Rats
• Rats, Sprague-Dawley
• Streptozocin (toxicity)