Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets.
OBJECTIVE
In type 2 diabetes, glucose toxicity leads to beta cell apoptosis with decreased beta cell mass as a consequence. Thioredoxin-interacting protein (TXNIP) is a critical mediator of glucose-induced beta cell apoptosis. Since hyperglycaemia leads to elevated serum insulin, we hypothesised that insulin is involved in the regulation of TXNIP protein levels in beta cells.


METHODS
We studied the production of TXNIP in INS-1E beta cells and in islets of Psammomys obesus, an animal model of type 2 diabetes, in response to glucose and different modulators of insulin secretion.


RESULTS
TXNIP production was markedly augmented in islets from diabetic P. obesus and in beta cells exposed to high glucose concentration. In contrast, adding insulin to the culture medium or stimulating insulin secretion with different secretagogues suppressed TXNIP. Inhibition of glucose and fatty acid-stimulated insulin secretion with diazoxide increased TXNIP production in beta cells. Nitric oxide (NO), a repressor of TXNIP, enhanced insulin signal transduction, whereas inhibition of NO synthase abolished its activation, suggesting that TXNIP inhibition by NO is mediated by stimulation of insulin signalling. Treatment of beta cells chronically exposed to high glucose with insulin reduced beta cell apoptosis. Txnip knockdown mimicking the effect of insulin prevented glucose-induced beta cell apoptosis.


CONCLUSIONS
Insulin is a potent repressor of TXNIP, operating a negative feedback loop that restrains the stimulation of TXNIP by chronic hyperglycaemia. Repression of TXNIP by insulin is probably an important compensatory mechanism protecting beta cells from oxidative damage and apoptosis in type 2 diabetes.
Shaked
M
M
Endocrinology and Metabolism Service, Department of Medicine, Hadassah, Hebrew University Medical Center, P.O. Box 12000, Jerusalem, 91120, Israel.
Ketzinel-Gilad
M
M
Ariav
Y
Y
Cerasi
E
E
Kaiser
N
N
Leibowitz
G
G
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005849:Gerbillinae; D005947:Glucose / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000502:physiology; D014162:Transfection
D002352:Carrier Proteins; D007328:Insulin; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C486715:TXNIP protein, human; D013879:Thioredoxins; D005947:Glucose