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Increased number of islet associated macrophages in type 2 diabetes

¹Division of Endocrinology and Diabetes, and the Center for Integrated Human Physiology, University Hospital of Zürich, 8045 Zürich, Switzerland
²Department of Pathology, University Hospital of Zürich, 8045 Zürich, Switzerland
³Laboratory for Transplantation Immunology, University Hospital of Zürich, 8045 Zürich, Switzerland
⁴Division of Clinical Immunology, University Hospital of Zürich, 8045 Zürich, Switzerland
⁵Division of Neuroendocrinology, Institute of Anatomy, University of Zurich, CH 8057, Zürich, Switzerland
⁶Department of Medicine Genetic and Development, University Medical Center, Geneva, Switzerland
⁷Institute of Molecular Biotechnology of the Austrian Academy of Science, Dr. Bohrgasse 3, 1030 Vienna, Austria
⁸Unité mixte de recherches (UMR) 7059, National Center for Scientific Research (CNRS), Paris 7 University/D. Diderot, Paris, France

Correspondence: jan.ehses{at}usz.ch

Correspondence: marc.donath{at}usz.ch

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 (HF) fed C57BL/6 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 HF fed mice, increased islet-derived inflammatory factors were produced and released, including IL-6, IL-8, chemokine KC, G-CSF, and MIP-1. The specificity of this response was investigated by direct comparison to non-islet 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, since 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 we observe in type 2 diabetes.

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