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Research Article

TXNIP Regulates Peripheral Glucose Metabolism in Humans

  • Hemang Parikh,

    Affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden

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  • Emma Carlsson,

    Affiliations: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden, Steno Diabetes Center, Gentofte, Denmark

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  • William A Chutkow,

    Affiliation: Cardiovascular Division, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America

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  • Lovisa E Johansson,

    Affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden

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  • Heidi Storgaard,

    Affiliation: Steno Diabetes Center, Gentofte, Denmark

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  • Pernille Poulsen,

    Affiliation: Steno Diabetes Center, Gentofte, Denmark

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  • Richa Saxena,

    Affiliations: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America, Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America

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  • Christine Ladd,

    Affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America

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  • P. Christian Schulze,

    Affiliation: Cardiovascular Division, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America

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  • Michael J Mazzini,

    Affiliation: Cardiovascular Division, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America

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  • Christine Bjørn Jensen,

    Affiliation: Steno Diabetes Center, Gentofte, Denmark

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  • Anna Krook,

    Affiliation: Department of Physiology and Pharmacology, Section Integrative Physiology, Karolinska Institute, Stockholm, Sweden

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  • Marie Björnholm,

    Affiliation: Department of Molecular Medicine and Surgical Sciences, Section Integrative Physiology, Karolinska Institutet, Stockholm, Sweden

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  • Hans Tornqvist,

    Affiliation: Diabetes Biology, Novo Nordisk A/S, Maaloev, Denmark

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  • Juleen R Zierath,

    Affiliation: Department of Molecular Medicine and Surgical Sciences, Section Integrative Physiology, Karolinska Institutet, Stockholm, Sweden

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  • Martin Ridderstråle,

    Affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden

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  • David Altshuler,

    Affiliations: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America, Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America

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  • Richard T Lee,

    Affiliation: Cardiovascular Division, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America

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  • Allan Vaag,

    Affiliations: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden, Steno Diabetes Center, Gentofte, Denmark

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  • Leif C Groop mail,

    To whom correspondence should be addressed. E-mail: Leif.Groop@med.lu.se (LCG); vamsi@hms.harvard.edu (VKM)

    Affiliations: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden, Program in Molecular Medicine, Helsinki University, Helsinki, Finland

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  • Vamsi K Mootha mail

    To whom correspondence should be addressed. E-mail: Leif.Groop@med.lu.se (LCG); vamsi@hms.harvard.edu (VKM)

    Affiliations: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America

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  • Published: May 01, 2007
  • DOI: 10.1371/journal.pmed.0040158

Reader Comments (3)

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Genetic variation within the TXNIP locus is not associated with metabolic traits in Caucasian subjects at increased risk for type 2 diabetes

Posted by plosmedicine on 31 Mar 2009 at 00:17 GMT

Author: Karsten Müssig
Position: M.D.
Institution: Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany
E-mail: karsten.muessig@med.uni-tuebingen.de
Additional Authors: Harald Staiger, Fausto Machicao, Norbert Stefan, Andreas Fritsche, Hans-Ulrich Häring
Submitted Date: December 12, 2007
Published Date: December 12, 2007
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

The study by Parikh et al. [1] and previous studies indicate an important role of TXNIP in modulation of glucose metabolism in skeletal muscle and liver as well as in pancreatic beta-cell function [2, 3]. These data, together with its genetic localization within the diabetes susceptibility locus 1q21-1q23, support TXNIP as an attractive candidate that regulates prediabetes phenotypes. However, despite consistently elevated TXNIP expression in the muscle of prediabetics and diabetics, Parikh et al. [1] did not find an association of common genetic variation in TXNIP with type 2 diabetes (T2D). Nevertheless, the authors supposed an important role of TXNIP in the development of altered glucose homeostasis and T2D.

Due to the dynamic relationship between phenotype and genotype, longitudinal analyses play a central role in genome association testing [4]. Thus, we studied the correlations of common TXNIP SNPs with cross-sectional metabolic data as well as with changes in metabolic parameters after a lifestyle intervention.

We analysed 1430 non-diabetic subjects (male: 460, female: 970) at increased risk for T2D (age 38.4±0.3 yr, body mass index [BMI] 28.5±0.3 kg/m2, body fat 30.7±0.3 %, fasting glucose 5.09±0.01 mM). A subgroup of 312 subjects was metabolically reanalysed after a follow-up period of 9 months [259±56 (SD) days] in which they took part in a lifestyle intervention program, as previously described [5].

Using publically available HapMap data (release #22, April 2007), we identified three representative SNPs rs2236566, rs9245, and rs4636400 covering 100 % of the common genetic variation (MAF > 0.05) of the TXNIP locus with D2 = 1.0 and r2 over 0.8. All three SNPs were in Hardy-Weinberg equilibrium.

At baseline, SNPs rs2236566, rs9245, and rs4636400 were neither associated with parameters of insulin secretion or insulin sensitivity, including liver fat and intramyocellular lipid (IMCL) content in anterior tibialis muscle, nor with data on lipid metabolism (data not shown).

After a 9 months lifestyle intervention in 312 individuals (age: 46.4 plus or minus 0.6 yr) BMI (before: 30.1 plus or minus 0.3 kg/m2 vs. after: 29.2 plus or monus 0.3 kg/m2; p less than 0.0001), percent of body fat (before: 33.0±0.5 % vs. after: 31.9 plus or minus 0.5 %; p less than 0.0001), insulin sensitivity (before: 12.8 plus or minus 0.4 U vs. after: 14.6 plus or minus 0.4 U; p less than 0.0001), liver fat content (before: 5.8 plus or minus 0.4 % vs. after: 3.6±0.3 %; p less than 0.0001), and IMCL content (before: 4.01±0.12 AU vs. after: 3.69 plus or minus 0.12 AU; p less than 0.0001) were significantly improved. However, TXNIP SNPs rs2236566, rs9245, and rs4636400 were not associated with changes in parameters of insulin secretion or insulin sensitivity, or with changes in lipid metabolism (data not shown).

In conclusion, despite the convincing data on the important role of TXNIP in peripheral glucose metabolism and beta-cell function, our cross-sectional as well as longitudinal data do not support a major role of common genetic variation within the TXNIP gene in the development of prediabetic phenotypes, such as beta-cell dysfunction, insulin resistance, or dyslipidemia.

References

1. Parikh H, Carlsson E, Chutkow WA, Johansson LE, Storgaard H, et al. (2007) TXNIP regulates peripheral glucose metabolism in humans. PLoS Med 4: e158. doi:10.1371/journal.pmed.0040158

2. Chutkow WA, Patwari P, Yoshioka J, Lee RT (2007) Txnip is a critical regulator of hepatic glucose production. J Biol Chem [Epub ahead of print] doi/10.1074/jbc.M708169200.

3. Minn AH, Hafele C, Shalev A (2005) Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces beta-cell apoptosis. Endocrinology 146: 2397-2405.

4. Clark AG, Boerwinkle E, Hixson J, Sing CF. (2005) Determinants of the success of whole-genome association testing. Genome Res 15: 1463-1467.

5. Stefan N, Machicao F, Staiger H, Machann J, Schick F, et al. (2005) Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat. Diabetologia 48: 2282-2291.

No competing interests declared.