Mice lacking thioredoxin-interacting protein provide evidence linking cellular redox state to appropriate response to nutritional signals.
Thioredoxin-interacting protein (Txnip) is a ubiquitous protein that binds with high affinity to thioredoxin and inhibits its ability to reduce sulfhydryl groups via NADPH oxidation. HcB-19 mice contain a nonsense mutation in Txnip that eliminates its expression. Unlike normal animals, HcB-19 mice have approximately 3-fold increase in insulin levels when fasted. The C-peptide/insulin ratio is normal, suggesting that the hyperinsulinemia is due to increased insulin secretion. Fasted HcB-19 mice are hypoglycemic, hypertriglyceridemic, and have higher than normal levels of ketone bodies. Ablation of pancreatic beta-cells with streptozotocin completely blocks the fasting-induced hypoglycemia/hypertriglyceridemia, suggesting that these abnormalities are due to excess insulin secretion. This is supported by increased hepatic mRNA levels of the insulin-inducible, lipogenic transcription factor sterol-responsive element-binding protein-1c and two of its targets, acetyl-CoA carboxylase and fatty acid synthase. During a prolonged fast, the hyperinsulinemia up-regulates lipogenesis but fails to down-regulate hepatic phosphoenolpyruvate carboxykinase mRNA expression. Hepatic ratios of reduced:oxidized glutathione, established regulators of gluconeogenic/glycolytic/lipogenic enzymes, were elevated 30% in HcB-19 mice, suggesting a loss of Txnip-enhanced sulfhydryl reduction. The altered hepatic enzymatic profiles of HcB-19 mice divert phosphoenolpyruvate to glyceroneogenesis and lipogenesis rather than gluconeogenesis. Our findings implicate Txnip-modulated sulfhydryl redox as a central regulator of insulin secretion in beta-cells and regulation of many of the branch-points of gluconeogenesis/glycolysis/lipogenesis.
Hui
To Yuen
TY
Mammalian Cell and Molecular Biology Laboratory, Department of Biology, Molecular Biology Institute and Heart Institute, San Diego State University, San Diego, California 92182, USA.
Sheth
Sonal S
SS
Diffley
J Matthew
JM
Potter
Douglas W
DW
Lusis
Aldons J
AJ
Attie
Alan D
AD
Davis
Roger A
RA
D000818:Animals; D002096:C-Peptide / Q000737:chemistry; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D004268:DNA-Binding Proteins; D004220:Disulfides; D015536:Down-Regulation; D005690:Galactose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007003:Hypoglycemia; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D007659:Ketones / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008954:Models, Biological; D010084:Oxidation-Reduction; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin / Q000494:pharmacology; D013438:Sulfhydryl Compounds; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors; D015854:Up-Regulation
D002096:C-Peptide; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004220:Disulfides; D007328:Insulin; D007659:Ketones; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; C445672:Txnip protein, mouse; D013879:Thioredoxins; D019298:Glucose-6-Phosphate; D013311:Streptozocin; D005978:Glutathione; D005947:Glucose; D005690:Galactose