TXNIP regulates peripheral glucose metabolism in humans

Hemang Parikh, Emma Carlsson, William A. Chutkow, Lovisa E. Johansson, Heidi Storgaard, Pernille Poulsen, Richa Saxena, Christine Ladd, P. Christian Schulze, Michael J. Mazzini, Christine Bjørn Jensen, Anna Krook, Marie Björnholm, Hans Tornqvist, Juleen R. Zierath, Martin Ridderstråle, David Altshuler, Richard T. Lee, Allan Vaag, Leif C. GroopVamsi K. Mootha

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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 β-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.

Original languageEnglish (US)
Pages (from-to)868-879
Number of pages12
JournalPLoS medicine
Volume4
Issue number5
DOIs
StatePublished - May 1 2007

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Parikh, H., Carlsson, E., Chutkow, W. A., Johansson, L. E., Storgaard, H., Poulsen, P., Saxena, R., Ladd, C., Schulze, P. C., Mazzini, M. J., Jensen, C. B., Krook, A., Björnholm, M., Tornqvist, H., Zierath, J. R., Ridderstråle, M., Altshuler, D., Lee, R. T., Vaag, A., ... Mootha, V. K. (2007). TXNIP regulates peripheral glucose metabolism in humans. PLoS medicine, 4(5), 868-879. https://doi.org/10.1371/journal.pmed.0040158