Mice lacking thioredoxin-interacting protein provide evidence linking cellular redox state to appropriate response to nutritional signals

J Biol Chem. 2004 Jun 4;279(23):24387-93. doi: 10.1074/jbc.M401280200. Epub 2004 Mar 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • C-Peptide / chemistry
  • Carrier Proteins / genetics*
  • Carrier Proteins / physiology*
  • DNA-Binding Proteins
  • Disulfides
  • Down-Regulation
  • Galactose / metabolism
  • Glucose / metabolism
  • Glucose-6-Phosphate / metabolism
  • Glutathione / metabolism
  • Hypoglycemia
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / metabolism
  • Ketones / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred C3H
  • Models, Biological
  • Oxidation-Reduction
  • Protein Binding
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Streptozocin / pharmacology
  • Sulfhydryl Compounds
  • Thioredoxins / genetics*
  • Thioredoxins / metabolism
  • Time Factors
  • Transcription Factors
  • Up-Regulation

Substances

  • C-Peptide
  • Carrier Proteins
  • DNA-Binding Proteins
  • Disulfides
  • Insulin
  • Ketones
  • RNA, Messenger
  • Sulfhydryl Compounds
  • Transcription Factors
  • Txnip protein, mouse
  • Thioredoxins
  • Glucose-6-Phosphate
  • Streptozocin
  • Glutathione
  • Glucose
  • Galactose