Sue Tsai, 1 Xavier Clemente-Casares, 1 Xavier S. Revelo, 1 Shawn Winer, 1 and Daniel A. Winer 1,2,3,4,5 Are Obesity-Related Insulin Resistance and Type 2 Diabetes Autoimmune Diseases? Diabetes 2015;64:1886–1897 | DOI: 10.2337/db14-1488 Obesity and associated insulin resistance predispose individuals to develop chronic metabolic diseases, such as type 2 diabetes and cardiovascular disease. Although these disorders affect a significant proportion of the global population, the underlying mechanisms of dis- ease remain poorly understood. The discovery of ele- vated tumor necrosis factor-a in adipose tissue as an inducer of obesity-associated insulin resistance marked a new era of understanding that a subclinical inflam- matory process underlies the insulin resistance and metabolic dysfunction that precedes type 2 diabetes. Advances in the field identified components of both the innate and adaptive immune response as key play- ers in regulating such inflammatory processes. As anti- gen specificity is a hallmark of an adaptive immune response, its role in modulating the chronic inflamma- tion that accompanies obesity and type 2 diabetes begs the question of whether insulin resistance and type 2 diabetes can have autoimmune components. In this Per- spective, we summarize current data that pertain to the activation and perpetuation of adaptive immune responses during obesity and discuss key missing links and potential mechanisms for obesity-related insulin re- sistance and type 2 diabetes to be considered as poten- tial autoimmune diseases. Traditional autoimmune diseases involve a wide spectrum of clinical pathology and include diseases such as systemic lupus erythematosus, multiple sclerosis, Sjögren’s syn- drome, rheumatoid arthritis, and type 1 diabetes. A dis- ease is considered autoimmune if its pathology is dictated by a self-antigen–specific adaptive immune response. Immunologists have adapted Koch’s postulates, originally conceived to establish a causative link between microbes and infectious diseases, to define key criteria that would qualify an autoimmune disease (1,2): 1) Evidence of disease-specific adaptive immune response in the affected target tissue or organ 2) Demonstration of the ability of autoreactive T and B cells and/or autoantibodies to transfer disease to healthy individuals or animals through adoptive transfer or autoantigen immunization 3) Elimination of the autoimmune response dampens disease progression Based on the above criteria, diseases with relatively well-established pathophysiology, such as type 1 diabetes and multiple sclerosis, are undisputedly classified as autoimmune. Key autoantigens have been identified and autoreactive specificities have been proven pathogenic through approaches such as adoptive transfer, autoan- tigen immunization, and transgenesis (3–6). Loss of tol- erance toward self is supported by ample evidence pointing toward defective immune regulation, manifested as a result of combined environmental and predisposing genetic factors (4,7). Furthermore, researchers have de- vised immunotherapeutic strategies based on these find- ings, many of which are being tested clinically as potential treatment for these autoimmune diseases (8). For many other chronic inflammatory conditions, however, the involvement of an autoimmune response 1 Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada 2 Department of Pathology, University Health Network, Toronto, Ontario, Canada 3 Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, Ontario, Canada 4 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada 5 Department of Immunology, University of Toronto, Toronto, Ontario, Canada Corresponding authors: Shawn Winer, shawn.winer@utoronto.ca, or Daniel A. Winer, dan.winer@uhn.ca. Received 29 September 2014 and accepted 25 January 2015. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. 1886 Diabetes Volume 64, June 2015 PERSPECTIVES IN DIABETES