Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants

Chronic exposure of pancreatic islets to supraphysiologic concentrations of glucose causes adverse alterations in beta cell function, a phenomenon ter med glucose toxicity and one that may play a secondary pathogenic role in t ype 2 diabetes. However, no mechanism of action has been definitively ident ified for glucose toxicity in beta cells. To ascertain whether chronic oxid ative stress might play a role, we chronically cultured the beta cell line, HIT-T15, in medium containing 11.1 mM glucose with and without the antioxi dants, N-acetyl-L-cysteine (NAC) or aminoguanidine (AG). Addition of NAC or AG to the culture medium at least partially prevented decreases in insulin mRNA, insulin gene promoter activity, DNA binding of two important insulin promoter transcription factors (PDX-1/STF-1 and RIPE-3b1 activator), insul in content, and glucose-induced insulin secretion. These findings suggested that one mechanism of glucose toxicity in the beta cell may be chronic exp osure to reactive oxygen species, i.e., chronic oxidative stress. To ascert ain the effects of these drugs on diabetes, NAC or AG was given to Zucker d iabetic fatty rats, a laboratory model of type 2 diabetes, from 6 through 1 2 weeks of age. Both drugs prevented a rise in blood oxidative stress marke rs (8-hydroxy-2'-deoxyguanosine and malondialdehyde + 4-hydroxy-2-nonenal), and partially prevented hyperglycemia, glucose intolerance, defective insu lin secretion as well as decrements in beta cell insulin content, insulin g ene expression, and PDX-1 (STF-1) binding to the insulin gene promoter. We conclude that chronic oxidative stress may play a role in glucose toxicity, which in turn may worsen the severity of type 2 diabetes.