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 termed glucose toxicity and one that may play a secondary pathogenic role in type 2 diabetes. However, no mechanism of action has been definitively identified for glucose toxicity in 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 the antioxidants, 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), insulin content, and glucose-induced insulin secretion. These findings suggested that one mechanism of glucose toxicity in the beta cell may be chronic exposure to reactive oxygen species, i.e., chronic oxidative stress. To ascertain the effects of these drugs on diabetes, NAC or AG was given to Zucker diabetic fatty rats, a laboratory model of type 2 diabetes, from 6 through 12 weeks of age. Both drugs prevented a rise in blood oxidative stress markers (8-hydroxy-2'-deoxyguanosine and malondialdehyde + 4-hydroxy-2-nonenal), and partially prevented hyperglycemia, glucose intolerance, defective insulin secretion as well as decrements in beta cell insulin content, insulin gene 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.
Tanaka
Y
Y
The Pacific Northwest Research Institute and Departments of Pharmacology and Medicine, University of Washington, 720 Broadway, Seattle, WA 98122, USA.
Gleason
C E
CE
Tran
P O
PO
Harmon
J S
JS
Robertson
R P
RP
D000111:Acetylcysteine / Q000494:pharmacology*; D000367:Age Factors; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005947:Glucose / Q000633:toxicity*; D005951:Glucose Tolerance Test; D006146:Guanidines / Q000494:pharmacology*; D018398:Homeodomain Proteins; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D015534:Trans-Activators / Q000378:metabolism
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006146:Guanidines; D018398:Homeodomain Proteins; D007328:Insulin; D012333:RNA, Messenger; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose; C004479:pimagedine; D000111:Acetylcysteine