Donath MY, Shoelson SEType 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2): 98-107

Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland.
Nature Reviews Immunology (Impact Factor: 34.99). 02/2011; 11(2):98-107. DOI: 10.1038/nri2925
Source: PubMed


Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease.

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    • "Additionally, IL-1b is a primary cytokine during the acute phase of infection [50] [51] and requires stringent regulation to avoid inflammation related pathogenesis, as may be the case with C. pneumoniae infected mast cells in this study. However, obesity and inflammation may promote production of additional inflammatory cytokines, including TNF-a, and IL-6 [2] [5]. Also, additional cell types, such as macrophages, may contribute to IL-1b production [41] [50] [51]. "
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    ABSTRACT: The human pathogen Chlamydia pneumoniae has been implicated in chronic inflammatory diseases including type 2 diabetes. Therefore, we designed a study to evaluate pancreatic beta cells and mast cells during chlamydial infection. Our study revealed that C. pneumoniae infected mast cells significantly (p<0.005) decreased beta cell ATP and insulin production, in contrast to uninfected mast cells co-cultured with beta cells. Infected mast cells exhibited pyknotic nuclei and active caspase-3 and caspase-1 expression. Additionally, ex vivo analyses of tissues collected from C. pneumoniae infected mice showed increased interleukin-1β production in splenocytes and pancreatic tissues as was observed with in vitro mast cell-beta cell co-cultures during C. pneumoniae infection. Notably, infected mast cells promoted beta cell destruction. Our findings reveal the negative effect of C. pneumoniae on mast cells, and the consequential impact on pancreatic beta cell function and viability. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Cellular Immunology
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    • "As a consequence, insulin signaling is impaired, which leads to overall insulin resistance [3]. Activation of the innate immune system coupled with adipose tissue inflammation, as well as increased IL-1b signaling in islets; both contribute to the pathogenesis of T2D [1] [4] [5]. "
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    ABSTRACT: CD55 is a glycosylphosphatidylinositol-anchored protein, which inhibits complement activation by acting on the complement C3 convertases. CD55 is widely localized in the cholesterol rich regions of the cell plasma membrane termed membrane rafts. CD55 is attached to these specialized regions via a GPI link on the outer leaflet of the plasma membrane. Membrane rafts anchor many important signaling proteins, which control several cellular functions within the cell. For example, we recently demonstrated that the membrane raft protein and complement inhibitor CD59 also controls insulin secretion by an intracellular mechanism. Therefore, we have in this study aimed at addressing the expression and function of CD55 in pancreatic beta cells. To this end, we observe that CD55 is highly expressed in INS1 832/13 beta cells as well as human pancreatic islets. Diabetic human islets show a tendency for increased expression of CD55 when compared to the healthy controls. Importantly, silencing of CD55 in INS1 832/13 cells does not affect their insulin secretory capacity. On the other hand, silencing of CD55 diminished the intensity of membrane rafts as determined by Atto-SM staining. We hence conclude that CD55 expression is affected by glycemic status in human islets and plays a critical role in maintaining the conserved structure of rafts in pancreatic islets, which is similar to that of the related complement inhibitor CD59. However CD55 does not interfere with insulin secretion in beta cells, which is in sharp contrast to the action of the complement inhibitor CD59. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Biochemical and Biophysical Research Communications
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    • "Emerging evidence suggests inflammation to play essential roles in the pathogenesis of T2D and diabetic complications including DN [6] [7] [8] [9] [10] [11] [12] [13]. Infiltrating macrophages have been found in both diabetic kidneys from experimental animal models and human DN renal biopsies [12] [13] [14]. "
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    ABSTRACT: Diabetic nephropathy (DN) is a serious complication of longstanding diabetes affecting up to 30% of all diabetes patients and is the main cause of end-stage kidney disease globally. Current standard treatment e.g. ACE-inhibitors like enalapril merely offers a delay in the progression leading to DN. Herein, we describe in two preclinical models evidence to local effects on the inflammatory signatures after intervention treatment with enalapril which provides enhanced understanding of the mechanism of ACE inhibitors.
    Full-text · Article · Jan 2015 · International Immunopharmacology
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