Thioredoxin-interacting protein: a critical link between glucose toxicity and beta-cell apoptosis.
OBJECTIVE
In diabetes, glucose toxicity affects different organ systems, including pancreatic islets where it leads to beta-cell apoptosis, but the mechanisms are not fully understood. Recently, we identified thioredoxin-interacting protein (TXNIP) as a proapoptotic beta-cell factor that is induced by glucose, raising the possibility that TXNIP may play a role in beta-cell glucose toxicity.


METHODS
To assess the effects of glucose on TXNIP expression and apoptosis and define the role of TXNIP, we used INS-1 beta-cells; primary mouse islets; obese, diabetic BTBR.ob mice; and a unique mouse model of TXNIP deficiency (HcB-19) that harbors a natural nonsense mutation in the TXNIP gene.


RESULTS
Incubation of INS-1 cells at 25 mmol/l glucose for 24 h led to an 18-fold increase in TXNIP protein, as assessed by immunoblotting. This was accompanied by increased apoptosis, as demonstrated by a 12-fold induction of cleaved caspase-3. Overexpression of TXNIP revealed that TXNIP induces the intrinsic mitochondrial pathway of apoptosis. Islets of diabetic BTBR.ob mice also demonstrated increased TXNIP and apoptosis as did isolated wild-type islets incubated at high glucose. In contrast, TXNIP-deficient HcB-19 islets were protected against glucose-induced apoptosis as measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and caspase-3, indicating that TXNIP is a required causal link between glucose toxicity and beta-cell death.


CONCLUSIONS
These findings shed new light onto the molecular mechanisms of beta-cell glucose toxicity and apoptosis, demonstrate that TXNIP induction plays a critical role in this vicious cycle, and suggest that inhibition of TXNIP may represent a novel approach to reduce glucotoxic beta-cell loss.
Chen
Junqin
J
Department of Medicine, University of Wisconsin-Madison, WI 53792, USA.
Saxena
Geetu
G
Mungrue
Imran N
IN
Lusis
Aldons J
AJ
Shalev
Anath
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018929:Cell Culture Techniques; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology / Q000633:toxicity*; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D007515:Islets of Langerhans / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013879:Thioredoxins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D002352:Carrier Proteins; D007328:Insulin; C445672:Txnip protein, mouse; D013879:Thioredoxins; D004253:DNA Nucleotidylexotransferase; D005947:Glucose