title: TXNIP regulates peripheral glucose metabolism in humans.
abstract: BACKGROUND
  Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure.
  
  
  RESULTS
  We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM.
  
  
  CONCLUSIONS
  TXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic beta-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden.
authors.forename: Hemang
authors.initials: H
authors.lastname: Parikh
authors.forename: Emma
authors.initials: E
authors.lastname: Carlsson
authors.forename: William A
authors.initials: WA
authors.lastname: Chutkow
authors.forename: Lovisa E
authors.initials: LE
authors.lastname: Johansson
authors.forename: Heidi
authors.initials: H
authors.lastname: Storgaard
authors.forename: Pernille
authors.initials: P
authors.lastname: Poulsen
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.forename: Christine
authors.initials: C
authors.lastname: Ladd
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mazzini
authors.forename: Christine Bjørn
authors.initials: CB
authors.lastname: Jensen
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
authors.forename: Marie
authors.initials: M
authors.lastname: Björnholm
authors.forename: Hans
authors.initials: H
authors.lastname: Tornqvist
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
authors.forename: Martin
authors.initials: M
authors.lastname: Ridderstråle
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.forename: Leif C
authors.initials: LC
authors.lastname: Groop
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000235:genetics; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D015810:Linkage Disequilibrium; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000502:physiology; D040081:Protein Array Analysis; D051560:Proto-Oncogene Proteins c-bcl-6; D050766:Qb-SNARE Proteins / Q000235:genetics
chemical_list: C084103:BCL6 protein, human; D001786:Blood Glucose; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D051560:Proto-Oncogene Proteins c-bcl-6; D050766:Qb-SNARE Proteins; C486715:TXNIP protein, human