Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces beta-cell apoptosis.
Recently, we identified thioredoxin-interacting protein (TXNIP) as the most dramatically glucose-induced gene in our human islet microarray study. TXNIP is a regulator of the cellular redox state, but its role in pancreatic beta-cells and the mechanism of its regulation by glucose remain unknown. We therefore generated a stable transfected beta-cell line (INS-1) overexpressing human TXNIP and found that TXNIP overexpression induced apoptosis as assessed by Bax, Bcl2, caspase-3, and cleaved caspase-9 as well as Hoechst staining. Interestingly, islets of insulin-resistant/diabetic mice (AZIP-F1, BTBRob/ob) demonstrated elevated TXNIP expression, suggesting that TXNIP may play a role in glucotoxicity and the beta-cell loss observed under these conditions. Furthermore, we found that glucose-induced TXNIP transcription is not dependent on glucose metabolism and is mediated by a distinct carbohydrate response element (ChoRE) in the human TXNIP promoter consisting of a perfect nonpalindromic repeat of two E-boxes. Transfection studies demonstrated that this ChoRE was necessary and sufficient to confer glucose responsiveness. Thus, TXNIP is a novel proapoptotic beta-cell gene elevated in insulin resistance/diabetes and up-regulated by glucose through a unique ChoRE and may link glucotoxicity and beta-cell apoptosis.
Minn
Alexandra H
AH
Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA. ahm@medicine.wisc.edu
Hafele
Christian
C
Shalev
Anath
A
D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D007515:Islets of Langerhans / Q000187:drug effects*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012091:Repetitive Sequences, Nucleic Acid; D020218:Response Elements / Q000187:drug effects / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013879:Thioredoxins / Q000235:genetics*; D014162:Transfection; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C486715:TXNIP protein, human; D051028:bcl-2-Associated X Protein; D013879:Thioredoxins; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D005947:Glucose