Increased Number of Islet-Associated Macrophages in Type 2 Diabetes

  1. Jan A. Ehses1,
  2. Aurel Perren2,
  3. Elisabeth Eppler3,
  4. Pascale Ribaux4,
  5. John A. Pospisilik5,
  6. Ranit Maor-Cahn1,
  7. Xavier Gueripel2,
  8. Helga Ellingsgaard1,
  9. Marten K.J. Schneider6,
  10. Gregoire Biollaz7,
  11. Adriano Fontana7,
  12. Manfred Reinecke3,
  13. Francoise Homo-Delarche8 and
  14. Marc Y. Donath1
  1. 1Division of Endocrinology and Diabetes and Center for Integrated Human Physiology, University Hospital of Zürich, Zürich, Switzerland
  2. 2Department of Pathology, University Hospital of Zürich, Zürich, Switzerland
  3. 3Division of Neuroendocrinology, Institute of Anatomy, University of Zürich, Zürich, Switzerland
  4. 4Department of Genetic Medicine and Development, University Medical Center, Geneva, Switzerland
  5. 5Institute of Molecular Biotechnology, Austrian Academy of Science, Vienna, Austria
  6. 6Laboratory for Transplantation Immunology, University Hospital of Zürich, Zürich, Switzerland
  7. 7Division of Clinical Immunology, University Hospital of Zürich, Zürich, Switzerland
  8. 8Unité mixte de recherches 7059, National Center for Scientific Research, Paris 7 University/D. Diderot, Paris, France
  1. Address correspondence and reprint requests to Dr. Jan A. Ehses, Division of Endocrinology and Diabetes, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland. E-mail: jan.ehses{at}usz.ch. Or to Dr. Marc Y. Donath, Division of Endocrinology and Diabetes, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland. E-mail: marc.donath{at}usz.ch

Abstract

Activation of the innate immune system in obesity is a risk factor for the development of type 2 diabetes. The aim of the current study was to investigate the notion that increased numbers of macrophages exist in the islets of type 2 diabetes patients and that this may be explained by a dysregulation of islet-derived inflammatory factors. Increased islet-associated immune cells were observed in human type 2 diabetic patients, high-fat–fed C57BL/6J mice, the GK rat, and the db/db mouse. When cultured islets were exposed to a type 2 diabetic milieu or when islets were isolated from high-fat–fed mice, increased islet-derived inflammatory factors were produced and released, including interleukin (IL)-6, IL-8, chemokine KC, granulocyte colony-stimulating factor, and macrophage inflammatory protein 1α. The specificity of this response was investigated by direct comparison to nonislet pancreatic tissue and β-cell lines and was not mimicked by the induction of islet cell death. Further, this inflammatory response was found to be biologically functional, as conditioned medium from human islets exposed to a type 2 diabetic milieu could induce increased migration of monocytes and neutrophils. This migration was blocked by IL-8 neutralization, and IL-8 was localized to the human pancreatic α-cell. Therefore, islet-derived inflammatory factors are regulated by a type 2 diabetic milieu and may contribute to the macrophage infiltration of pancreatic islets that we observe in type 2 diabetes.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 19 June 2007. DOI: 10.2337/db06-1650.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted May 21, 2007.
    • Received November 26, 2006.
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  1. Diabetes vol. 56 no. 9 2356-2370
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