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TXNIP regulates peripheral glucose metabolism in humans

Parikh, Hemang LU ; Nilsson, Emma A LU ; Chutkow, William A.; Johansson, Lovisa LU ; Storgaard, Heidi; Poulsen, Pernille; Saxena, Richa; Ladd, Christine; Schulze, P. Christian and Mazzini, Michael J., et al. (2007) In PLoS Medicine 4(5). p.868-879
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. Methods and Findings 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... (More)
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. Methods and Findings 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. (Less)
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Contribution to journal
publication status
published
subject
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PLoS Medicine
volume
4
issue
5
pages
868 - 879
publisher
Public Library of Science
external identifiers
  • wos:000246889700016
  • scopus:34249660144
ISSN
1549-1676
DOI
10.1371/journal.pmed.0040158
language
English
LU publication?
yes
id
63ce9d43-6a11-449b-ad18-7f2c4e4d0330 (old id 649066)
date added to LUP
2007-12-14 15:39:01
date last changed
2017-11-19 03:38:17
@article{63ce9d43-6a11-449b-ad18-7f2c4e4d0330,
  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. Methods and Findings 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.},
  author       = {Parikh, Hemang and Nilsson, Emma A and Chutkow, William A. and Johansson, Lovisa and Storgaard, Heidi and Poulsen, Pernille and Saxena, Richa and Ladd, Christine and Schulze, P. Christian and Mazzini, Michael J. and Jensen, Christine Bjorn and Krook, Anna and Bjornholm, Marie and Tornqvist, Hans and Zierath, Juleen R. and Ridderstråle, Martin and Altshuler, David and Lee, Richard T. and Vaag, Allan and Groop, Leif and Mootha, Vamsi K.},
  issn         = {1549-1676},
  language     = {eng},
  number       = {5},
  pages        = {868--879},
  publisher    = {Public Library of Science},
  series       = {PLoS Medicine},
  title        = {TXNIP regulates peripheral glucose metabolism in humans},
  url          = {http://dx.doi.org/10.1371/journal.pmed.0040158},
  volume       = {4},
  year         = {2007},
}