Increased Number of Islet-Associated Macrophages in Type 2 Diabetes
Jan A. Ehses 1 ,
Aurel Perren 2 ,
Elisabeth Eppler 3 ,
Pascale Ribaux 4 ,
John A. Pospisilik 5 ,
Ranit Maor-Cahn 1 ,
Xavier Gueripel 2 ,
Helga Ellingsgaard 1 ,
Marten K.J. Schneider 6 ,
Gregoire Biollaz 7 ,
Adriano Fontana 7 ,
Manfred Reinecke 3 ,
Francoise Homo-Delarche 8 and
Marc Y. Donath 1
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
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.
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
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.
DIABETES...

Increased Number of Islet-Associated Macrophages in Type 2 Diabetes

10.2337/db06-1650