Exenatide inhibits beta-cell apoptosis by decreasing thioredoxin-interacting protein.
Exenatide (Ex-4) is a novel anti-diabetic drug that stimulates insulin secretion and enhances beta-cell mass, but the mechanisms involved are not fully understood. We found that Ex-4 protects INS-1 beta-cells against oxidative stress-induced apoptosis (TUNEL) and also reduces expression (mRNA and protein) of thioredoxin-interacting protein (TXNIP), a pro-apoptotic factor involved in beta-cell glucose toxicity and oxidative stress. This reduction was observed in INS-1 cells, mouse, and human islets as well as in wild-type mice receiving Ex-4 and was accompanied by decreased expression of the apoptotic factors caspase-3 and Bax. To determine whether Ex-4-mediated TXNIP reduction is critical for this inhibition of apoptosis, we stably overexpressed TXNIP in INS-1 cells, which completely blunted the anti-apoptotic Ex-4 effects. Thus, Ex-4 inhibits apoptosis by reducing TXNIP expression and early initiation of Ex-4 treatment may help preserve endogenous beta-cell mass, protect against oxidative stress, and delay type 2 diabetes progression.
Chen
Junqin
J
Department of Medicine, University of Wisconsin, Madison, WI 53792, USA.
Couto
Francesca M
FM
Minn
Alexandra H
AH
Shalev
Anath
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D000077270:Exenatide; D005786:Gene Expression Regulation; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D013879:Thioredoxins / Q000378:metabolism*; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D010455:Peptides; C486715:TXNIP protein, human; C493796:TXNIP protein, rat; C445672:Txnip protein, mouse; D014688:Venoms; D013879:Thioredoxins; D000077270:Exenatide