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Original Research

Link Between GIP and Osteopontin in Adipose Tissue and Insulin Resistance

  1. Emma Ahlqvist1,
  2. Peter Osmark1,
  3. Tiina Kuulasmaa2,
  4. Kasper Pilgaard3,
  5. Bilal Omar4,
  6. Charlotte Brøns3,
  7. Olga Kotova5,
  8. Anna V. Zetterqvist5,
  9. Alena Stančáková6,
  10. Anna Jonsson1,
  11. Ola Hansson1,
  12. Johanna Kuusisto6,
  13. Timothy J. Kieffer7,8,
  14. Tiinamaija Tuomi9,10,
  15. Bo Isomaa9,11,
  16. Sten Madsbad12,
  17. Maria F. Gomez5,
  18. Pernille Poulsen3,
  19. Markku Laakso6,
  20. Eva Degerman4,
  21. Jussi Pihlajamäki2,6,
  22. Nils Wierup13,
  23. Allan Vaag3,14,
  24. Leif Groop1,15 and
  25. Valeriya Lyssenko1⇑
  1. 1Department of Clinical Sciences, Diabetes, and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden
  2. 2Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
  3. 3Steno Diabetes Center, Gentofte, Denmark
  4. 4Department of Experimental Medical Sciences, Lund University, Lund, Sweden
  5. 5Vascular ET-Coupling, Department of Clinical Sciences, University Hospital Malmö, Lund University, Malmö, Sweden
  6. 6Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
  7. 7Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
  8. 8Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
  9. 9Folkhalsan Research Centre, Helsinki, Finland
  10. 10Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland
  11. 11Department of Social Services and Health Care, Jakobstad, Finland
  12. 12Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
  13. 13Unit of Neuroendocrine Cell Biology, Department of Clinical Sciences, Lund University, Malmö, Sweden
  14. 14Department of Endocrinology, Rigshospitalet and Copenhagen University, Copenhagen, Denmark
  15. 15Finnish Institute of Molecular Medicine, Helsinki University, Helsinki, Finland
  1. Corresponding author: Valeriya Lyssenko, valeriya.lyssenko{at}med.lu.se.
Diabetes 2013 Jun; 62(6): 2088-2094. https://doi.org/10.2337/db12-0976
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Abstract

Low-grade inflammation in obesity is associated with accumulation of the macrophage-derived cytokine osteopontin (OPN) in adipose tissue and induction of local as well as systemic insulin resistance. Since glucose-dependent insulinotropic polypeptide (GIP) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate OPN expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13 ± 0.04 vs. 0.04 ± 0.01, P < 0.05) and correlated inversely with measures of insulin sensitivity (r = −0.24, P = 0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with a lower amount of the exon 9–containing isoform required for transmembrane activity. Carriers of the A allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of the GIPR rs10423928 A allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0976/-/DC1.

  • Received July 20, 2012.
  • Accepted January 7, 2013.
  • © 2013 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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Link Between GIP and Osteopontin in Adipose Tissue and Insulin Resistance
Emma Ahlqvist, Peter Osmark, Tiina Kuulasmaa, Kasper Pilgaard, Bilal Omar, Charlotte Brøns, Olga Kotova, Anna V. Zetterqvist, Alena Stančáková, Anna Jonsson, Ola Hansson, Johanna Kuusisto, Timothy J. Kieffer, Tiinamaija Tuomi, Bo Isomaa, Sten Madsbad, Maria F. Gomez, Pernille Poulsen, Markku Laakso, Eva Degerman, Jussi Pihlajamäki, Nils Wierup, Allan Vaag, Leif Groop, Valeriya Lyssenko
Diabetes Jun 2013, 62 (6) 2088-2094; DOI: 10.2337/db12-0976

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Link Between GIP and Osteopontin in Adipose Tissue and Insulin Resistance
Emma Ahlqvist, Peter Osmark, Tiina Kuulasmaa, Kasper Pilgaard, Bilal Omar, Charlotte Brøns, Olga Kotova, Anna V. Zetterqvist, Alena Stančáková, Anna Jonsson, Ola Hansson, Johanna Kuusisto, Timothy J. Kieffer, Tiinamaija Tuomi, Bo Isomaa, Sten Madsbad, Maria F. Gomez, Pernille Poulsen, Markku Laakso, Eva Degerman, Jussi Pihlajamäki, Nils Wierup, Allan Vaag, Leif Groop, Valeriya Lyssenko
Diabetes Jun 2013, 62 (6) 2088-2094; DOI: 10.2337/db12-0976
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