Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL signaling and pancreatic beta-cell mass and protects against diabetes.
Pancreatic beta-cell loss through apoptosis represents a key factor in the pathogenesis of diabetes; however, no effective approaches to block this process and preserve endogenous beta-cell mass are currently available. To study the role of thioredoxin-interacting protein (TXNIP), a proapoptotic beta-cell factor we recently identified, we used HcB-19 (TXNIP nonsense mutation) and beta-cell-specific TXNIP knockout (bTKO) mice. Interestingly, HcB-19 mice demonstrate increased adiposity, but have lower blood glucose levels and increased pancreatic beta-cell mass (as assessed by morphometry). Moreover, HcB-19 mice are resistant to streptozotocin-induced diabetes. When intercrossed with obese, insulin-resistant, and diabetic mice, double-mutant BTBRlep(ob/ob)txnip(hcb/hcb) are even more obese, but are protected against diabetes and beta-cell apoptosis, resulting in a 3-fold increase in beta-cell mass. Beta-cell-specific TXNIP deletion also enhanced beta-cell mass (P<0.005) and protected against diabetes, and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) revealed a approximately 50-fold reduction in beta-cell apoptosis in streptozotocin-treated bTKO mice. We further discovered that TXNIP deficiency induces Akt/Bcl-xL signaling and inhibits mitochondrial beta-cell death, suggesting that these mechanisms may mediate the beta-cell protective effects of TXNIP deficiency. These results suggest that lowering beta-cell TXNIP expression could serve as a novel strategy for the treatment of type 1 and type 2 diabetes by promoting endogenous beta-cell survival.
Department of Medicine, University of Wisconsin, Madison, Wisconsin 53792, USA.
Junqin
J
Chen
Simon T
ST
Hui
Francesca M
FM
Couto
Imran N
IN
Mungrue
Dawn B
DB
Davis
Alan D
AD
Attie
Aldons J
AJ
Lusis
Roger A
RA
Davis
Anath
A
Shalev
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002452:Cell Count; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D007003:Hypoglycemia; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013879:Thioredoxins / Q000235:genetics*; D051020:bcl-X Protein / Q000378:metabolism*
D002352:Carrier Proteins; C445672:Txnip protein, mouse; D051020:bcl-X Protein; D013879:Thioredoxins; D051057:Proto-Oncogene Proteins c-akt