TXNIP regulates peripheral glucose metabolism in humans.
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.
Parikh
Hemang
H
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden.
Carlsson
Emma
E
Chutkow
William A
WA
Johansson
Lovisa E
LE
Storgaard
Heidi
H
Poulsen
Pernille
P
Saxena
Richa
R
Ladd
Christine
C
Schulze
P Christian
PC
Mazzini
Michael J
MJ
Jensen
Christine Bjørn
CB
Krook
Anna
A
Björnholm
Marie
M
Tornqvist
Hans
H
Zierath
Juleen R
JR
Ridderstråle
Martin
M
Altshuler
David
D
Lee
Richard T
RT
Vaag
Allan
A
Groop
Leif C
LC
Mootha
Vamsi K
VK
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
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