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Increased Number of Islet-Associated Macrophages in Type 2 Diabetes

¹ Division of Endocrinology and Diabetes and Center for Integrated Human Physiology, University Hospital of Zürich, Zürich, Switzerland
² Department of Pathology, University Hospital of Zürich, Zürich, Switzerland
³ Division of Neuroendocrinology, Institute of Anatomy, University of Zürich, Zürich, Switzerland
⁴ Department of Genetic Medicine and Development, University Medical Center, Geneva, Switzerland
⁵ Institute of Molecular Biotechnology, Austrian Academy of Science, Vienna, Austria
⁶ Laboratory for Transplantation Immunology, University Hospital of Zürich, Zürich, Switzerland
⁷ Division of Clinical Immunology, University Hospital of Zürich, Zürich, Switzerland
⁸ Unité mixte de recherches 7059, National Center for Scientific Research, Paris 7 University/D. Diderot, Paris, France

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

Abbreviations: AEC, 3-amino-9-ethylcarbazole; ECM, extracellular matrix; FITC, fluorescein isothiocyanate; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; IP-10, interferon-inducible protein 10; MHC, major histocompatibility complex; MIP, macrophage inflammatory protein

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 1. The specificity of this response was investigated by direct comparison to nonislet pancreatic tissue and ß-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 -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.

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