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      Islet Autoimmunity in Adults With Impaired Glucose Tolerance and Recently Diagnosed, Treatment Naïve Type 2 Diabetes in the Restoring Insulin SEcretion (RISE) Study

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          Abstract

          The presence of islet autoantibodies and islet reactive T cells (T+) in adults with established type 2 diabetes (T2D) have been shown to identify those patients with more severe β-cell dysfunction. However, at what stage in the progression toward clinical T2D does islet autoimmunity emerge as an important component influencing β-cell dysfunction? In this ancillary study to the Restoring Insulin SEcretion (RISE) Study, we investigated the prevalence of and association with β-cell dysfunction of T+ and autoantibodies to the 65 kDa glutamic acid decarboxylase antigen (GADA) in obese pre-diabetes adults with impaired glucose tolerance (IGT) and recently diagnosed treatment naïve (Ndx) T2D. We further investigated the effect of 12 months of RISE interventions (metformin or liraglutide plus metformin, or with 3 months of insulin glargine followed by 9 months of metformin or placebo) on islet autoimmune reactivity. We observed GADA(+) in 1.6% of NdxT2D and 4.6% of IGT at baseline, and in 1.6% of NdxT2D and 5.3% of IGT at 12 months, but no significant associations between GADA(+) and β-cell function. T(+) was observed in 50% of NdxT2D and 60.4% of IGT at baseline, and in 68.4% of NdxT2D and 83.9% of IGT at 12 months. T(+) NdxT2D were observed to have significantly higher fasting glucose ( p = 0.004), and 2 h glucose ( p = 0.0032), but significantly lower steady state C-peptide (sscpep, p = 0.007) compared to T(−) NdxT2D. T(+) IGT participants demonstrated lower but not significant ( p = 0.025) acute (first phase) C-peptide response to glucose (ACPRg) compared to T(−) IGT. With metformin treatment, T(+) participants were observed to have a significantly lower Hemoglobin A1c (HbA1c, p = 0.002) and fasting C-peptide ( p = 0.002) compared to T(−), whereas T(+) treated with liraglutide + metformin had significantly lower sscpep ( p = 0.010) compared to T(−) participants. In the placebo group, T(+) participants demonstrated significantly lower ACPRg ( p = 0.001) compared to T(−) participants. In summary, T(+) were found in a large percentage of obese pre-diabetes adults with IGT and in recently diagnosed T2D. Moreover, T(+) were significantly correlated with treatment effects and β-cell dysfunction. Our results demonstrate that T(+) are an important component in T2D.

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          Inflammatory mechanisms linking obesity and metabolic disease.

          There are currently over 1.9 billion people who are obese or overweight, leading to a rise in related health complications, including insulin resistance, type 2 diabetes, cardiovascular disease, liver disease, cancer, and neurodegeneration. The finding that obesity and metabolic disorder are accompanied by chronic low-grade inflammation has fundamentally changed our view of the underlying causes and progression of obesity and metabolic syndrome. We now know that an inflammatory program is activated early in adipose expansion and during chronic obesity, permanently skewing the immune system to a proinflammatory phenotype, and we are beginning to delineate the reciprocal influence of obesity and inflammation. Reviews in this series examine the activation of the innate and adaptive immune system in obesity; inflammation within diabetic islets, brain, liver, gut, and muscle; the role of inflammation in fibrosis and angiogenesis; the factors that contribute to the initiation of inflammation; and therapeutic approaches to modulate inflammation in the context of obesity and metabolic syndrome.
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            Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes

            Obesity is one of the major health burdens of the 21st century as it contributes to the growing prevalence of its related comorbidities, including insulin resistance and type 2 diabetes. Growing evidence suggests a critical role for overnutrition in the development of low-grade inflammation. Specifically, chronic inflammation in adipose tissue is considered a crucial risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. The triggers for adipose tissue inflammation are still poorly defined. However, obesity-induced adipose tissue expansion provides a plethora of intrinsic signals (e.g., adipocyte death, hypoxia, and mechanical stress) capable of initiating the inflammatory response. Immune dysregulation in adipose tissue of obese subjects results in a chronic low-grade inflammation characterized by increased infiltration and activation of innate and adaptive immune cells. Macrophages are the most abundant innate immune cells infiltrating and accumulating into adipose tissue of obese individuals; they constitute up to 40% of all adipose tissue cells in obesity. In obesity, adipose tissue macrophages are polarized into pro-inflammatory M1 macrophages and secrete many pro-inflammatory cytokines capable of impairing insulin signaling, therefore promoting the progression of insulin resistance. Besides macrophages, many other immune cells (e.g., dendritic cells, mast cells, neutrophils, B cells, and T cells) reside in adipose tissue during obesity, playing a key role in the development of adipose tissue inflammation and insulin resistance. The association of obesity, adipose tissue inflammation, and metabolic diseases makes inflammatory pathways an appealing target for the treatment of obesity-related metabolic complications. In this review, we summarize the molecular mechanisms responsible for the obesity-induced adipose tissue inflammation and progression toward obesity-associated comorbidities and highlight the current therapeutic strategies.
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              When worlds collide: Th17 and Treg cells in cancer and autoimmunity

              The balance between Th17 cells and regulatory T cells (Tregs) has emerged as a prominent factor in regulating autoimmunity and cancer. Th17 cells are vital for host defense against pathogens but have also been implicated in causing autoimmune disorders and cancer, though their role in carcinogenesis is less well understood. Tregs are required for self-tolerance and defense against autoimmunity and often correlate with cancer progression. This review addresses the importance of a functional homeostasis between these two subsets in health and the consequences of its disruption when these forces collide in disease. Importantly, we discuss the ability of Th17 cells to mediate cancer regression in immunotherapy, including adoptive transfer and checkpoint blockade therapy, and the therapeutic possibilities of purposefully offsetting the Th17/Treg balance to treat patients with cancer as well as those with autoimmune diseases.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                26 April 2021
                2021
                : 12
                : 640251
                Affiliations
                [1] 1Department of Medicine, University of Washington , Seattle, WA, United States
                [2] 2Veterans Affairs Puget Sound Health Care System , Seattle, WA, United States
                [3] 3Biostatistics Center, Milken School of Public Health, George Washington University Biostatistics Center , Rockville, MD, United States
                [4] 4Seattle Institute for Biochemical and Clinical Research , Seattle, WA, United States
                [5] 5Department of Medicine, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh , Pittsburgh, PA, United States
                [6] 6Indiana University School of Medicine, Richard L. Roudebush Veterans Affairs Medical Center , Indianapolis, IN, United States
                [7] 7University of Southern California Keck School of Medicine/Kaiser Permanente Southern California , Los Angeles, CA, United States
                [8] 8University of Colorado Anschutz Medical Campus/Children's Hospital Colorado , Aurora, CO, United States
                [9] 9University of Chicago Clinical Research Center and Jesse Brown Veterans Affairs Medical Center , Chicago, IL, United States
                Author notes

                Edited by: Myung-Shik Lee, Yonsei University Health System, South Korea

                Reviewed by: Paolo Pozzilli, Campus Bio-Medico University, Italy; Richard David Leslie, Queen Mary University of London, United Kingdom

                *Correspondence: Barbara M. Brooks-Worrell bbrooks_worrell@ 123456hotmail.com

                This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology

                †RISE Consortium are listed in the Appendix

                ‡Currently employed by Eli Lilly and Company

                Article
                10.3389/fimmu.2021.640251
                8108986
                33981301
                265afd0c-4ad6-4150-8755-c60770ea454d
                Copyright © 2021 Brooks-Worrell, Tjaden, Edelstein, Palomino, Utzschneider, Arslanian, Mather, Buchanan, Nadeau, Atkinson, Barengolts, Kahn, Palmer and the RISE Consortium.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 December 2020
                : 24 February 2021
                Page count
                Figures: 2, Tables: 5, Equations: 0, References: 48, Pages: 13, Words: 8928
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases 10.13039/100000062
                Categories
                Immunology
                Original Research

                Immunology
                islet reactive t-cells,islet autoantibodies,type 2 diabetes,islet autoimmunity,pre-diabetes,impaired glucose tolerance,beta cell function,gada

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