Prevention of glucose toxicity in HIT-T15 cells and ZDF rats by an antioxidant, N-acetyl-L-cysteine

Y. Tanaka, C. E. Gleason, E. A. Oseid, K. K. Hunter-Berger, P. O.T. Tran, J. S. Harmon, R. P. Robertson

Research output: Contribution to journalArticlepeer-review


Exposure of pancreatic islets to a supraphysiologic concentration of glucose causes adverse alterations in beta cell function. Manifestations of such glucose toxicity include loss of insulin gene expression and glucose-induced insulin secretion. However, no mechanism has been established for the glucose toxic effects on beta cells. To ascertain whether chronic oxidative stress might play a role, we chronically cultured the beta cell line HIT-T15 in medium containing 11.1 mM glucose with and without various concentrations (0.1-5 mM) of the antioxidant, N-acetyl-L-cysteine (NAC) for 35 weeks. The supraphysiologic glucose concentration caused loss of insulin mRNA (15 % control), diminution of insulin gene promoter activity (34 % control), decreased DNA binding of two important transcription factors [STF-1/PDX-1 (61 % control) and RIPE-3b1 activator (29 % control)], reduced insulin content (8 % control), and defective glucose-induced insulin secretion (5 % control). Inclusion of NAC in the culture medium at least partially, but significantly, prevented all of these adverse changes in insulin gene expression and insulin secretion. We treated Zucker diabetic fatty (ZDF) rats with NAC to ascertain whether these in vitro beneficial effects could be reproduced in vivo. After a 6 week period, non-treated ZDF rats had obvious hyperglycemia caused by insufficient insulin secretion. NAC treatment prevented the development of hyperglycemia in these rats. Levels of the markers of oxidative stress, MDA, 4HNE and 8OHdG, were elevated in non-treated ZDF rats, but these levels were reduced by MAC treatments. We conclude that one mechanism of glucose toxicity in the beta cell may be chronic exposure to reactive oxygen species, i.e., chronic oxidative stress.

Original languageEnglish (US)
Pages (from-to)29A
JournalInvestigative Ophthalmology and Visual Science
Issue number3
StatePublished - Feb 15 1996
Externally publishedYes


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