title: Mice lacking thioredoxin-interacting protein provide evidence linking cellular redox state to appropriate response to nutritional signals.
abstract: 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.
authors.affiliation: Mammalian Cell and Molecular Biology Laboratory, Department of Biology, Molecular Biology Institute and Heart Institute, San Diego State University, San Diego, California 92182, USA.
authors.forename: To Yuen
authors.initials: TY
authors.lastname: Hui
authors.forename: Sonal S
authors.initials: SS
authors.lastname: Sheth
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Diffley
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Potter
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.forename: Roger A
authors.initials: RA
authors.lastname: Davis
mesh_terms: 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
chemical_list: 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