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Liang W, Qi Y, Yi H, Mao C, Meng Q, Wang H, Zheng C. The Roles of Adipose Tissue Macrophages in Human Disease. Front Immunol 2022; 13:908749. [PMID: 35757707 PMCID: PMC9222901 DOI: 10.3389/fimmu.2022.908749] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/12/2022] [Indexed: 01/02/2023] Open
Abstract
Macrophages are a population of immune cells functioning in antigen presentation and inflammatory response. Research has demonstrated that macrophages belong to a cell lineage with strong plasticity and heterogeneity and can be polarized into different phenotypes under different microenvironments or stimuli. Many macrophages can be recruited by various cytokines secreted by adipose tissue. The recruited macrophages further secrete various inflammatory factors to act on adipocytes, and the interaction between the two leads to chronic inflammation. Previous studies have indicated that adipose tissue macrophages (ATMs) are closely related to metabolic diseases like obesity and diabetes. Here, we will not only conclude the current progress of factors affecting the polarization of adipose tissue macrophages but also elucidate the relationship between ATMs and human diseases. Furthermore, we will highlight its potential in preventing and treating metabolic diseases as immunotherapy targets.
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Affiliation(s)
- Weizheng Liang
- Central Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China.,Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yanxu Qi
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Hongyang Yi
- National Clinical Research Centre for Infectious Diseases, The Third People's Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Chenyu Mao
- School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, United States
| | - Qingxue Meng
- Central Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
| | - Hao Wang
- Shenzhen Key Laboratory, Shenzhen University General Hospital, Shenzhen, China.,Department of Obstetrics and Gynecology, Shenzhen University General Hospital, Shenzhen, China
| | - Chunfu Zheng
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada
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Cai Z, Huang Y, He B. New Insights into Adipose Tissue Macrophages in Obesity and Insulin Resistance. Cells 2022; 11:1424. [PMID: 35563728 PMCID: PMC9104938 DOI: 10.3390/cells11091424] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 04/15/2022] [Accepted: 04/20/2022] [Indexed: 02/04/2023] Open
Abstract
Obesity has become a worldwide epidemic that poses a severe threat to human health. Evidence suggests that many obesity comorbidities, such as type 2 diabetes mellitus, steatohepatitis, and cardiovascular diseases, are related to obesity-induced chronic low-grade inflammation. Macrophages are the primary immune cells involved in obesity-associated inflammation in both mice and humans. Intensive research over the past few years has yielded tremendous progress in our understanding of the additional roles of adipose tissue macrophages (ATMs) beyond classical M1/M2 polarization in obesity and related comorbidities. In this review, we first characterize the diverse subpopulations of ATMs in the context of obesity. Furthermore, we review the recent advance on the role of the extensive crosstalk between adipocytes and ATMs in obesity. Finally, we focus on the extended crosstalk within adipose tissue between perivascular mesenchymal cells and ATMs. Understanding the pathological mechanisms that underlie obesity will be critical for the development of new intervention strategies to prevent or treat this disease and its associated co-morbidities.
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Affiliation(s)
| | | | - Ben He
- Heart Center, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 Huaihai West Road, Shanghai 200030, China; (Z.C.); (Y.H.)
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3
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Adipocyte Phenotype Flexibility and Lipid Dysregulation. Cells 2022; 11:cells11050882. [PMID: 35269504 PMCID: PMC8909878 DOI: 10.3390/cells11050882] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/22/2022] [Accepted: 03/01/2022] [Indexed: 12/04/2022] Open
Abstract
The prevalence of obesity and associated cardiometabolic diseases continues to rise, despite efforts to improve global health. The adipose tissue is now regarded as an endocrine organ since its multitude of secretions, lipids chief among them, regulate systemic functions. The loss of normal adipose tissue phenotypic flexibility, especially related to lipid homeostasis, appears to trigger cardiometabolic pathogenesis. The goal of this manuscript is to review lipid balance maintenance by the lean adipose tissue’s propensity for phenotype switching, obese adipose tissue’s narrower range of phenotype flexibility, and what initial factors account for the waning lipid regulatory capacity. Metabolic, hypoxic, and inflammatory factors contribute to the adipose tissue phenotype being made rigid. A better grasp of normal adipose tissue function provides the necessary context for recognizing the extent of obese adipose tissue dysfunction and gaining insight into how pathogenesis evolves.
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Lahav R, Haim Y, Bhandarkar NS, Levin L, Chalifa-Caspi V, Sarver D, Sahagun A, Maixner N, Kovesh B, Wong GW, Rudich A. CTRP6 rapidly responds to acute nutritional changes, regulating adipose tissue expansion and inflammation in mice. Am J Physiol Endocrinol Metab 2021; 321:E702-E713. [PMID: 34632797 PMCID: PMC8799396 DOI: 10.1152/ajpendo.00299.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In chronic obesity, activated adipose tissue proinflammatory cascades are tightly linked to metabolic dysfunction. Yet, close temporal analyses of the responses to obesogenic environment such as high-fat feeding (HFF) in susceptible mouse strains question the causal relationship between inflammation and metabolic dysfunction, and/or raises the possibility that certain inflammatory cascades play adaptive/homeostatic, rather than pathogenic roles. Here, we hypothesized that CTRP6, a C1QTNF family member, may constitute an early responder to acute nutritional changes in adipose tissue, with potential physiological roles. Both 3-days high-fat feeding (3dHFF) and acute obesity reversal [2-wk switch to low-fat diet after 8-wk HFF (8wHFF)] already induced marked changes in whole body fuel utilization. Although adipose tissue expression of classical proinflammatory cytokines (Tnf-α, Ccl2, and Il1b) exhibited no, or only minor, change, C1qtnf6 uniquely increased, and decreased, in response to 3dHFF and acute obesity reversal, respectively. CTRP6 knockout (KO) mouse embryonic fibroblasts (MEFs) exhibited increased adipogenic gene expression (Pparg, Fabp4, and Adipoq) and markedly reduced inflammatory genes (Tnf-α, Ccl2, and Il6) compared with wild-type MEFs, and recombinant CTRP6 induced the opposite gene expression signature, as assessed by RNA sequencing. Consistently, 3dHFF of CTRP6-KO mice induced a greater whole body and adipose tissue weight gain compared with wild-type littermates. Collectively, we propose CTRP6 as a gene that rapidly responds to acute changes in caloric intake, acting in acute overnutrition to induce a "physiological inflammatory response" that limits adipose tissue expansion.NEW & NOTEWORTHY CTRP6 (C1qTNF6), a member of adiponectin gene family, regulates inflammation and metabolism in established obesity. Here, short-term high-fat feeding in mice is shown to increase adipose tissue expression of CTRP6 before changes in the expression of classical inflammatory genes occur. Conversely, CTRP6 expression in adipose tissue decreases early in the course of obesity reversal. Gain- and loss-of-function models suggest CTRP6 as a positive regulator of inflammatory cascades, and a negative regulator of adipogenesis and adipose tissue expansion.
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Affiliation(s)
- Rotem Lahav
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Yulia Haim
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Nikhil S Bhandarkar
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Liron Levin
- Bioinformatics Core Facility, National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Vered Chalifa-Caspi
- Bioinformatics Core Facility, National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Dylan Sarver
- Department of Physiology and Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ageline Sahagun
- Department of Physiology and Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nitzan Maixner
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Barr Kovesh
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - G William Wong
- Department of Physiology and Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Assaf Rudich
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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Velikova TV, Kabakchieva PP, Assyov YS, Georgiev TА. Targeting Inflammatory Cytokines to Improve Type 2 Diabetes Control. BIOMED RESEARCH INTERNATIONAL 2021; 2021:7297419. [PMID: 34557550 PMCID: PMC8455209 DOI: 10.1155/2021/7297419] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes (T2D) is one of the most common chronic metabolic disorders in adulthood worldwide, whose pathophysiology includes an abnormal immune response accompanied by cytokine dysregulation and inflammation. As the T2D-related inflammation and its progression were associated with the balance between pro and anti-inflammatory cytokines, anticytokine treatments might represent an additional therapeutic option for T2D patients. This review focuses on existing evidence for antihyperglycemic properties of disease-modifying antirheumatic drugs (DMARDs) and anticytokine agents (anti-TNF-α, anti-interleukin-(IL-) 6, -IL-1, -IL-17, -IL-23, etc.). Emphasis is placed on their molecular mechanisms and on the biological rationale for clinical use. Finally, we briefly summarize the results from experimental model studies and promising clinical trials about the potential of anticytokine therapies in T2D, discussing the effects of these drugs on systemic and islet inflammation, beta-cell function, insulin secretion, and insulin sensitivity.
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Affiliation(s)
- Tsvetelina V. Velikova
- Department of Clinical Immunology, University Hospital “Lozenetz”, Sofia University “St. Kliment Ohridski”, Sofia 1407, Bulgaria
| | - Plamena P. Kabakchieva
- Clinic of Endocrinology, University Hospital “Alexandrovska, ” Department of Internal Medicine, Medical Faculty, Medical University of Sofia, Sofia 1431, Bulgaria
- Clinic of Internal Medicine, Naval Hospital-Varna, Military Medical Academy, Varna 9010, Bulgaria
| | - Yavor S. Assyov
- Clinic of Endocrinology, University Hospital “Alexandrovska, ” Department of Internal Medicine, Medical Faculty, Medical University of Sofia, Sofia 1431, Bulgaria
| | - Tsvetoslav А. Georgiev
- Clinic of Rheumatology, University Hospital “St. Marina, ” First Department of Internal Medicine, Medical Faculty, Medical University-Varna, Varna 9010, Bulgaria
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Abstract
In this review, Lee and Olefsky discuss the characteristics of chronic inflammation in the major metabolic tissues and how obesity triggers these events, including a focus on the role of adipose tissue hypoxia and macrophage-derived exosomes. Obesity is the most common cause of insulin resistance, and the current obesity epidemic is driving a parallel rise in the incidence of T2DM. It is now widely recognized that chronic, subacute tissue inflammation is a major etiologic component of the pathogenesis of insulin resistance and metabolic dysfunction in obesity. Here, we summarize recent advances in our understanding of immunometabolism. We discuss the characteristics of chronic inflammation in the major metabolic tissues and how obesity triggers these events, including a focus on the role of adipose tissue hypoxia and macrophage-derived exosomes. Last, we also review current and potential new therapeutic strategies based on immunomodulation.
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Affiliation(s)
- Yun Sok Lee
- Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA
| | - Jerrold Olefsky
- Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA
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Ruiz HH, Nguyen A, Wang C, He L, Li H, Hallowell P, McNamara C, Schmidt AM. AGE/RAGE/DIAPH1 axis is associated with immunometabolic markers and risk of insulin resistance in subcutaneous but not omental adipose tissue in human obesity. Int J Obes (Lond) 2021; 45:2083-2094. [PMID: 34103691 PMCID: PMC8380543 DOI: 10.1038/s41366-021-00878-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 05/19/2021] [Accepted: 05/27/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND/OBJECTIVES The incidence of obesity continues to increase worldwide and while the underlying pathogenesis remains largely unknown, nutrient excess, manifested by "Westernization" of the diet and reduced physical activity have been proposed as key contributing factors. Western-style diets, in addition to higher caloric load, are characterized by excess of advanced glycation end products (AGEs), which have been linked to the pathophysiology of obesity and related cardiometabolic disorders. AGEs can be "trapped" in adipose tissue, even in the absence of diabetes, in part due to higher expression of the receptor for AGEs (RAGE) and/or decreased detoxification by the endogenous glyoxalase (GLO) system, where they may promote insulin resistance. It is unknown whether the expression levels of genes linked to the RAGE axis, including AGER (the gene encoding RAGE), Diaphanous 1 (DIAPH1), the cytoplasmic domain binding partner of RAGE that contributes to RAGE signaling, and GLO1 are differentially regulated by the degree of obesity and/or how these relate to inflammatory and adipocyte markers and their metabolic consequences. SUBJECTS/METHODS We sought to answer this question by analyzing gene expression patterns of markers of the AGE/RAGE/DIAPH1 signaling axis in abdominal subcutaneous (SAT) and omental (OAT) adipose tissue from obese and morbidly obese subjects. RESULTS In SAT, but not OAT, expression of AGER was significantly correlated with that of DIAPH1 (n = 16; [Formula: see text], [0.260, 1.177]; q = 0.008) and GLO1 (n = 16; [Formula: see text], [0.364, 1.182]; q = 0.004). Furthermore, in SAT, but not OAT, regression analyses revealed that the expression pattern of genes in the AGE/RAGE/DIAPH1 axis is strongly and positively associated with that of inflammatory and adipogenic markers. Remarkably, particularly in SAT, not OAT, the expression of AGER positively and significantly correlated with HOMA-IR (n = 14; [Formula: see text], [0.338, 1.249]; q = 0.018). CONCLUSIONS These observations suggest associations of the AGE/RAGE/DIAPH1 axis in the immunometabolic pathophysiology of obesity and insulin resistance, driven, at least in part, through expression and activity of this axis in SAT.
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Affiliation(s)
- Henry H Ruiz
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA.
| | - Anh Nguyen
- Cardiovascular Division, Department of Medicine and Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
| | - Chan Wang
- Division of Biostatistics, Department of Population Health, New York University Grossman School of Medicine, New York, NY, USA
| | - Linchen He
- Division of Biostatistics, Department of Population Health, New York University Grossman School of Medicine, New York, NY, USA
| | - Huilin Li
- Division of Biostatistics, Department of Population Health, New York University Grossman School of Medicine, New York, NY, USA
| | - Peter Hallowell
- General Surgery Division, Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Coleen McNamara
- Cardiovascular Division, Department of Medicine and Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
| | - Ann Marie Schmidt
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
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8
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Chang TT, Lin LY, Chen JW. A Novel Resolution of Diabetes: C-C Chemokine Motif Ligand 4 Is a Common Target in Different Types of Diabetes by Protecting Pancreatic Islet Cell and Modulating Inflammation. Front Immunol 2021; 12:650626. [PMID: 33968046 PMCID: PMC8102776 DOI: 10.3389/fimmu.2021.650626] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 04/09/2021] [Indexed: 01/07/2023] Open
Abstract
Systemic inflammation is related to hyperglycemia in diabetes mellitus (DM). C-C chemokine motif ligand (CCL) 4 is upregulated in type 1 & type 2 DM patients. This study aimed to investigate if CCL4 could be a potential target to improve blood sugar control in different experimental DM models. Streptozotocin-induced diabetic mice, Leprdb /JNarl diabetic mice, and C57BL/6 mice fed a high fat diet were used as the type 1 DM, type 2 DM, and metabolic syndrome model individually. Mice were randomly assigned to receive an anti-CCL4 neutralizing monoclonal antibody. The pancreatic β-cells were treated with streptozotocin for in vitro experiments. In streptozotocin-induced diabetic mice, inhibition of CCL4 controlled blood sugar, increased serum insulin levels, increased islet cell proliferation and decreased pancreatic interleukin (IL)-6 expression. In the type 2 diabetes and metabolic syndrome models, CCL4 inhibition retarded the progression of hyperglycemia, reduced serum tumor necrosis factor (TNF)-α and IL-6 levels, and improved insulin resistance via reducing the phosphorylation of insulin receptor substrate-1 in skeletal muscle and liver tissues. CCL4 inhibition directly protected pancreatic β-cells from streptozotocin stimulation. Furthermore, CCL4-induced IL-6 and TNF-α expressions could be abolished by siRNA of CCR2/CCR5. In summary, direct inhibition of CCL4 protected pancreatic islet cells, improved insulin resistance and retarded the progression of hyperglycemia in different experimental models, suggesting the critical role of CCL4-related inflammation in the progression of DM. Future experiments may investigate if CCL4 could be a potential target for blood sugar control in clinical DM.
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MESH Headings
- Animals
- Blood Glucose/metabolism
- Cell Line
- Chemokine CCL4/immunology
- Chemokine CCL4/metabolism
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/immunology
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Type 1/blood
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/immunology
- Diabetes Mellitus, Type 2/metabolism
- Female
- Glucose Tolerance Test
- Humans
- Inflammation/immunology
- Inflammation/metabolism
- Insulin/blood
- Insulin/metabolism
- Insulin-Secreting Cells/immunology
- Insulin-Secreting Cells/metabolism
- Islets of Langerhans/cytology
- Islets of Langerhans/immunology
- Islets of Langerhans/metabolism
- Male
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Pancreas/cytology
- Pancreas/metabolism
- Mice
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Affiliation(s)
- Ting-Ting Chang
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Liang-Yu Lin
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jaw-Wen Chen
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
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Wang CR, Tsai HW. Anti- and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. World J Diabetes 2021; 12:238-260. [PMID: 33758645 PMCID: PMC7958474 DOI: 10.4239/wjd.v12.i3.238] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/07/2021] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
In addition to β-cell failure with inadequate insulin secretion, the crucial mechanism leading to establishment of diabetes mellitus (DM) is the resistance of target cells to insulin, i.e. insulin resistance (IR), indicating a requirement of beyond-normal insulin concentrations to maintain euglycemic status and an ineffective strength of transduction signaling from the receptor, downstream to the substrates of insulin action. IR is a common feature of most metabolic disorders, particularly type II DM as well as some cases of type I DM. A variety of human inflammatory disorders with increased levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, have been reported to be associated with an increased risk of IR. Autoimmune-mediated arthritis conditions, including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with the involvement of proinflammatory cytokines as their central pathogenesis, have been demonstrated to be associated with IR, especially during the active disease state. There is an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders. In this review, we focus on the effects of anti-TNF-α- and non-TNF-α-targeted therapies on IR in patients with RA, PsA and AS. Anti-TNF-α therapy, IL-1 blockade, IL-6 antagonist, Janus kinase inhibitor and phospho-diesterase type 4 blocker can reduce IR and improve diabetic hyper-glycemia in autoimmune-mediated arthritis.
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Affiliation(s)
- Chrong-Reen Wang
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70403, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan
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10
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Pezhman L, Tahrani A, Chimen M. Dysregulation of Leukocyte Trafficking in Type 2 Diabetes: Mechanisms and Potential Therapeutic Avenues. Front Cell Dev Biol 2021; 9:624184. [PMID: 33692997 PMCID: PMC7937619 DOI: 10.3389/fcell.2021.624184] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 02/04/2021] [Indexed: 12/18/2022] Open
Abstract
Type 2 Diabetes Mellitus (T2DM) is a chronic inflammatory disorder that is characterized by chronic hyperglycemia and impaired insulin signaling which in addition to be caused by common metabolic dysregulations, have also been associated to changes in various immune cell number, function and activation phenotype. Obesity plays a central role in the development of T2DM. The inflammation originating from obese adipose tissue develops systemically and contributes to insulin resistance, beta cell dysfunction and hyperglycemia. Hyperglycemia can also contribute to chronic, low-grade inflammation resulting in compromised immune function. In this review, we explore how the trafficking of innate and adaptive immune cells under inflammatory condition is dysregulated in T2DM. We particularly highlight the obesity-related accumulation of leukocytes in the adipose tissue leading to insulin resistance and beta-cell dysfunction and resulting in hyperglycemia and consequent changes of adhesion and migratory behavior of leukocytes in different vascular beds. Thus, here we discuss how potential therapeutic targeting of leukocyte trafficking could be an efficient way to control inflammation as well as diabetes and its vascular complications.
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Affiliation(s)
- Laleh Pezhman
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Abd Tahrani
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.,Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, United Kingdom.,University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Myriam Chimen
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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11
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Chaurasia B, Talbot CL, Summers SA. Adipocyte Ceramides-The Nexus of Inflammation and Metabolic Disease. Front Immunol 2020; 11:576347. [PMID: 33072120 PMCID: PMC7538607 DOI: 10.3389/fimmu.2020.576347] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 08/20/2020] [Indexed: 12/21/2022] Open
Abstract
Adipose depots are heterogeneous tissues that store and sense fuel levels. Through the secretion of lipids, cytokines, and protein hormones (adipokines), they communicate with other organ systems, informing them of the organism's nutritional status. The adipose tissues include diverse types of adipocytes (white, beige, and brown) distinguished by the number/size of lipid droplets, mitochondrial density, and thermogenic capacity. Moreover, they include a spectrum of immune cells that modulate metabolic activity and tissue remodeling. The unique characteristics and interplay of these cells control the production of ceramides, a class of nutrient signals derived from fat and protein metabolism that modulate adipocyte function to regulate glucose and lipid metabolism. The excessive accumulation of ceramides contributes to the adipose tissue inflammation and dysfunction that underlies cardiometabolic disease. Herein we review findings on this important class of lipid species and discuss their role at the convergence point that links overnutrition/inflammation to key features of the metabolic syndrome.
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Affiliation(s)
- Bhagirath Chaurasia
- Division of Endocrinology, Department of Internal Medicine, Carver College of Medicine and the Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, United States
| | - Chad Lamar Talbot
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT, United States
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT, United States
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12
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Kahn CR, Wang G, Lee KY. Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J Clin Invest 2020; 129:3990-4000. [PMID: 31573548 DOI: 10.1172/jci129187] [Citation(s) in RCA: 405] [Impact Index Per Article: 81.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Over the past decade, great progress has been made in understanding the complexity of adipose tissue biology and its role in metabolism. This includes new insights into the multiple layers of adipose tissue heterogeneity, not only differences between white and brown adipocytes, but also differences in white adipose tissue at the depot level and even heterogeneity of white adipocytes within a single depot. These inter- and intra-depot differences in adipocytes are developmentally programmed and contribute to the wide range of effects observed in disorders with fat excess (overweight/obesity) or fat loss (lipodystrophy). Recent studies also highlight the underappreciated dynamic nature of adipose tissue, including potential to undergo rapid turnover and dedifferentiation and as a source of stem cells. Finally, we explore the rapidly expanding field of adipose tissue as an endocrine organ, and how adipose tissue communicates with other tissues to regulate systemic metabolism both centrally and peripherally through secretion of adipocyte-derived peptide hormones, inflammatory mediators, signaling lipids, and miRNAs packaged in exosomes. Together these attributes and complexities create a robust, multidimensional signaling network that is central to metabolic homeostasis.
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Affiliation(s)
- C Ronald Kahn
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Guoxiao Wang
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Kevin Y Lee
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, and.,The Diabetes Institute, Ohio University, Athens, Ohio, USA
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Arivazhagan L, Ruiz HH, Wilson R, Manigrasso M, Gugger PF, Fisher EA, Moore KJ, Ramasamy R, Schmidt AM. An Eclectic Cast of Cellular Actors Orchestrates Innate Immune Responses in the Mechanisms Driving Obesity and Metabolic Perturbation. Circ Res 2020; 126:1565-1589. [PMID: 32437306 PMCID: PMC7250004 DOI: 10.1161/circresaha.120.315900] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The escalating problem of obesity and its multiple metabolic and cardiovascular complications threatens the health and longevity of humans throughout the world. The cause of obesity and one of its chief complications, insulin resistance, involves the participation of multiple distinct organs and cell types. From the brain to the periphery, cell-intrinsic and intercellular networks converge to stimulate and propagate increases in body mass and adiposity, as well as disturbances of insulin sensitivity. This review focuses on the roles of the cadre of innate immune cells, both those that are resident in metabolic organs and those that are recruited into these organs in response to cues elicited by stressors such as overnutrition and reduced physical activity. Beyond the typical cast of innate immune characters invoked in the mechanisms of metabolic perturbation in these settings, such as neutrophils and monocytes/macrophages, these actors are joined by bone marrow-derived cells, such as eosinophils and mast cells and the intriguing innate lymphoid cells, which are present in the circulation and in metabolic organ depots. Upon high-fat feeding or reduced physical activity, phenotypic modulation of the cast of plastic innate immune cells ensues, leading to the production of mediators that affect inflammation, lipid handling, and metabolic signaling. Furthermore, their consequent interactions with adaptive immune cells, including myriad T-cell and B-cell subsets, compound these complexities. Notably, many of these innate immune cell-elicited signals in overnutrition may be modulated by weight loss, such as that induced by bariatric surgery. Recently, exciting insights into the biology and pathobiology of these cell type-specific niches are being uncovered by state-of-the-art techniques such as single-cell RNA-sequencing. This review considers the evolution of this field of research on innate immunity in obesity and metabolic perturbation, as well as future directions.
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Affiliation(s)
- Lakshmi Arivazhagan
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Henry H. Ruiz
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Robin Wilson
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Michaele Manigrasso
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Paul F. Gugger
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Edward A. Fisher
- The Leon H. Charney Division of Cardiology, Department of Medicine, The Marc and Ruti Bell Program in Vascular Biology, NYU Langone Medical Center, New York 10016
- NYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, New York 10016
| | - Kathryn J. Moore
- The Leon H. Charney Division of Cardiology, Department of Medicine, The Marc and Ruti Bell Program in Vascular Biology, NYU Langone Medical Center, New York 10016
- NYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, New York 10016
| | - Ravichandran Ramasamy
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Ann Marie Schmidt
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
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14
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Zhu Q, An YA, Kim M, Zhang Z, Zhao S, Zhu Y, Asterholm IW, Kusminski CM, Scherer PE. Suppressing adipocyte inflammation promotes insulin resistance in mice. Mol Metab 2020; 39:101010. [PMID: 32408016 PMCID: PMC7272509 DOI: 10.1016/j.molmet.2020.101010] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/17/2020] [Accepted: 04/20/2020] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE Obesity-induced insulin resistance is closely associated with chronic subclinical inflammation in white adipose tissue. However, the mechanistic involvement of adipocyte-derived inflammation under these disease conditions remains unclear. Our aim was to investigate the relative inflammation-related contributions of adipocytes and macrophages to insulin sensitivity. METHODS RIDα/β is an adenoviral protein complex that inhibits several inflammatory pathways, including TLR4, TNFα, and IL1β signaling. We generated novel mouse models with adipocyte-specific and macrophage-specific doxycycline (dox)-inducible RIDα/β-transgenic mice (RIDad and RIDmac mice, respectively). RESULTS RIDα/β induction significantly reduced LPS-stimulated inflammatory markers, such as Tnf, Il1b, and Saa3 in adipose tissues. Surprisingly, RIDad mice had elevated levels of postprandial glucose and insulin and exhibited glucose intolerance and insulin resistance, even under chow-fed conditions. Moreover, the RIDad mice displayed further insulin resistance under obesogenic (high-fat diet, HFD) conditions despite reduced weight gain. In addition, under pre-existing obese and inflamed conditions on an HFD, subsequent induction of RIDα/β in RIDad mice reduced body weight gain, further exacerbating glucose tolerance, enhancing insulin resistance and fatty liver, and reducing adiponectin levels. This occurred despite effective suppression of the inflammatory pathways (including TNFα and IL1β). In contrast, RIDmac mice, upon HFD feeding, displayed similar weight gain, comparable adiponectin levels, and insulin sensitivity, suggesting that the inflammatory properties of macrophages did not exert a negative impact on metabolic readouts. RIDα/β expression and the ensuing suppression of inflammation in adipocytes enhanced adipose tissue fibrosis and reduced vascularization. CONCLUSION Our novel findings further corroborate our previous observations suggesting that suppressing adipocyte inflammation impairs adipose tissue function and promotes insulin resistance, despite beneficial effects on weight gain.
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Affiliation(s)
- Qingzhang Zhu
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yu A An
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Min Kim
- Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, South Korea
| | - Zhuzhen Zhang
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Shangang Zhao
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yi Zhu
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ingrid Wernstedt Asterholm
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Christine M Kusminski
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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15
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Zatterale F, Longo M, Naderi J, Raciti GA, Desiderio A, Miele C, Beguinot F. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front Physiol 2020; 10:1607. [PMID: 32063863 PMCID: PMC7000657 DOI: 10.3389/fphys.2019.01607] [Citation(s) in RCA: 594] [Impact Index Per Article: 118.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 12/23/2019] [Indexed: 12/13/2022] Open
Abstract
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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Affiliation(s)
- Federica Zatterale
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Michele Longo
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Jamal Naderi
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Gregory Alexander Raciti
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Antonella Desiderio
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Claudia Miele
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Francesco Beguinot
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
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16
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Ruscitti P, Masedu F, Alvaro S, Airò P, Battafarano N, Cantarini L, Cantatore FP, Carlino G, D'Abrosca V, Frassi M, Frediani B, Iacono D, Liakouli V, Maggio R, Mulè R, Pantano I, Prevete I, Sinigaglia L, Valenti M, Viapiana O, Cipriani P, Giacomelli R. Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial. PLoS Med 2019; 16:e1002901. [PMID: 31513665 PMCID: PMC6742232 DOI: 10.1371/journal.pmed.1002901] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 08/09/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis). METHODS AND FINDINGS This study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: -0.85, p < 0.001, 95% CI -1.28 to -0.42) and 6 months (β: -1.05, p < 0.001, 95% CI -1.50 to -0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (β: -1.04, p < 0.001, 95% CI -1.52 to -0.55) and 6 months (β: -1.24, p < 0.001, 95% CI -1.75 to -0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs. CONCLUSIONS In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D. TRIAL REGISTRATION The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481.
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MESH Headings
- Aged
- Antirheumatic Agents/adverse effects
- Antirheumatic Agents/therapeutic use
- Arthritis, Rheumatoid/blood
- Arthritis, Rheumatoid/diagnosis
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/immunology
- Biomarkers/blood
- Blood Glucose/drug effects
- Blood Glucose/metabolism
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/diagnosis
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/immunology
- Female
- Glycated Hemoglobin/metabolism
- Humans
- Interleukin 1 Receptor Antagonist Protein/adverse effects
- Interleukin 1 Receptor Antagonist Protein/therapeutic use
- Italy
- Male
- Middle Aged
- Receptors, Interleukin-1/antagonists & inhibitors
- Receptors, Interleukin-1/immunology
- Time Factors
- Treatment Outcome
- Tumor Necrosis Factor Inhibitors/adverse effects
- Tumor Necrosis Factor Inhibitors/therapeutic use
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Affiliation(s)
- Piero Ruscitti
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Francesco Masedu
- Division of Medical Statistics, Department of Biotechnological and Applied Clinical Science, University of L'Aquila, L'Aquila, Italy
| | - Saverio Alvaro
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Paolo Airò
- Rheumatology and Clinical Immunology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | | | - Luca Cantarini
- Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Francesco Paolo Cantatore
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia Medical School, Foggia, Italy
| | - Giorgio Carlino
- Rheumatology Service, ASL Lecce—DSS Casarano and Gallipoli (LE), Casarano (LE), Italy
| | - Virginia D'Abrosca
- Division of Rheumatology, Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, Naples, Italy
| | - Micol Frassi
- Rheumatology and Clinical Immunology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Bruno Frediani
- Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Daniela Iacono
- Division of Rheumatology, Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, Naples, Italy
| | - Vasiliki Liakouli
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Roberta Maggio
- Rheumatology Service, ASL Lecce—DSS Casarano and Gallipoli (LE), Casarano (LE), Italy
| | - Rita Mulè
- Rheumatology Unit, S.Orsola-Malpighi Teaching Hospital, Bologna, Italy
| | - Ilenia Pantano
- Division of Rheumatology, Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, Naples, Italy
| | - Immacolata Prevete
- Rheumatology Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy
| | - Luigi Sinigaglia
- Department of Rheumatology, Gaetano Pini Institute, Milan, Italy
| | - Marco Valenti
- Division of Medical Statistics, Department of Biotechnological and Applied Clinical Science, University of L'Aquila, L'Aquila, Italy
| | - Ombretta Viapiana
- Rheumatology Unit, Department of Medicine, University of Verona, Verona, Italy
| | - Paola Cipriani
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Roberto Giacomelli
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
- * E-mail:
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17
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Donath MY, Meier DT, Böni-Schnetzler M. Inflammation in the Pathophysiology and Therapy of Cardiometabolic Disease. Endocr Rev 2019; 40:1080-1091. [PMID: 31127805 PMCID: PMC6624792 DOI: 10.1210/er.2019-00002] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 04/15/2019] [Indexed: 12/22/2022]
Abstract
The role of chronic inflammation in the pathogenesis of type 2 diabetes mellitus and associated complications is now well established. Therapeutic interventions counteracting metabolic inflammation improve insulin secretion and action and glucose control and may prevent long-term complications. Thus, a number of anti-inflammatory drugs approved for the treatment of other inflammatory conditions are evaluated in patients with metabolic syndrome. Most advanced are clinical studies with IL-1 antagonists showing improved β-cell function and glycemia and prevention of cardiovascular diseases and heart failure. However, alternative anti-inflammatory treatments, alone or in combinations, may turn out to be more effective, depending on genetic predispositions, duration, and manifestation of the disease. Thus, there is a great need for comprehensive and well-designed clinical studies to implement anti-inflammatory drugs in the treatment of patients with metabolic syndrome and its associated conditions.
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Affiliation(s)
- Marc Y Donath
- Clinic of Endocrinology, Diabetes and Metabolism and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Daniel T Meier
- Clinic of Endocrinology, Diabetes and Metabolism and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Marianne Böni-Schnetzler
- Clinic of Endocrinology, Diabetes and Metabolism and Department of Biomedicine, University of Basel, Basel, Switzerland
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18
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Tsalamandris S, Antonopoulos AS, Oikonomou E, Papamikroulis GA, Vogiatzi G, Papaioannou S, Deftereos S, Tousoulis D. The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives. Eur Cardiol 2019; 14:50-59. [PMID: 31131037 PMCID: PMC6523054 DOI: 10.15420/ecr.2018.33.1] [Citation(s) in RCA: 774] [Impact Index Per Article: 129.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Diabetes is a complex metabolic disorder affecting the glucose status of the human body. Chronic hyperglycaemia related to diabetes is associated with end organ failure. The clinical relationship between diabetes and atherosclerotic cardiovascular disease is well established. This makes therapeutic approaches that simultaneously target diabetes and atherosclerotic disease an attractive area for research. The majority of people with diabetes fall into two broad pathogenetic categories, type 1 or type 2 diabetes. The role of obesity, adipose tissue, gut microbiota and pancreatic beta cell function in diabetes are under intensive scrutiny with several clinical trials to have been completed while more are in development. The emerging role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease. After an extensive review of the possible mechanisms that drive the metabolic pattern in T1D and T2D and the inflammatory pathways that are involved, it becomes ever clearer that future research should focus on a model of combined suppression for various inflammatory response pathways.
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Affiliation(s)
- Sotirios Tsalamandris
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Alexios S Antonopoulos
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Evangelos Oikonomou
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - George-Aggelos Papamikroulis
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Georgia Vogiatzi
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Spyridon Papaioannou
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Spyros Deftereos
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Dimitris Tousoulis
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
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19
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de Candia P, Prattichizzo F, Garavelli S, De Rosa V, Galgani M, Di Rella F, Spagnuolo MI, Colamatteo A, Fusco C, Micillo T, Bruzzaniti S, Ceriello A, Puca AA, Matarese G. Type 2 Diabetes: How Much of an Autoimmune Disease? Front Endocrinol (Lausanne) 2019; 10:451. [PMID: 31333589 PMCID: PMC6620611 DOI: 10.3389/fendo.2019.00451] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 06/21/2019] [Indexed: 01/12/2023] Open
Abstract
Type 2 diabetes (T2D) is characterized by a progressive status of chronic, low-grade inflammation (LGI) that accompanies the whole trajectory of the disease, from its inception to complication development. Accumulating evidence is disclosing a long list of possible "triggers" of inflammatory responses, many of which are promoted by unhealthy lifestyle choices and advanced age. Diabetic patients show an altered number and function of immune cells, of both innate and acquired immunity. Reactive autoantibodies against islet antigens can be detected in a subpopulation of patients, while emerging data are also suggesting an altered function of specific T lymphocyte populations, including T regulatory (Treg) cells. These observations led to the hypothesis that part of the inflammatory response mounting in T2D is attributable to an autoimmune phenomenon. Here, we review recent data supporting this framework, with a specific focus on both tissue resident and circulating Treg populations. We also propose that selective interception (or expansion) of T cell subsets could be an alternative avenue to dampen inappropriate inflammatory responses without compromising immune responses.
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Affiliation(s)
- Paola de Candia
- IRCCS MultiMedica, Milan, Italy
- *Correspondence: Paola de Candia
| | | | - Silvia Garavelli
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), Naples, Italy
| | - Veronica De Rosa
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), Naples, Italy
- Unità di NeuroImmunologia, Fondazione Santa Lucia, Rome, Italy
| | - Mario Galgani
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), Naples, Italy
| | - Francesca Di Rella
- Dipartimento di Senologia, Oncologia Medica, IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Maria Immacolata Spagnuolo
- Dipartimento di Scienze Mediche Traslazionali, Università Degli Studi di Napoli “Federico II”, Naples, Italy
| | - Alessandra Colamatteo
- Treg Cell Laboratory, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi di Napoli “Federico II”, Naples, Italy
| | - Clorinda Fusco
- Treg Cell Laboratory, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi di Napoli “Federico II”, Naples, Italy
| | - Teresa Micillo
- Dipartimento di Biologia, Università Degli Studi di Napoli “Federico II”, Naples, Italy
| | - Sara Bruzzaniti
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), Naples, Italy
| | - Antonio Ceriello
- IRCCS MultiMedica, Milan, Italy
- Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Annibale A. Puca
- IRCCS MultiMedica, Milan, Italy
- Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi, Italy
| | - Giuseppe Matarese
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), Naples, Italy
- Treg Cell Laboratory, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi di Napoli “Federico II”, Naples, Italy
- Giuseppe Matarese
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20
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Guzik TJ, Skiba DS, Touyz RM, Harrison DG. The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res 2018; 113:1009-1023. [PMID: 28838042 PMCID: PMC5852626 DOI: 10.1093/cvr/cvx108] [Citation(s) in RCA: 291] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 07/05/2017] [Indexed: 12/15/2022] Open
Abstract
Adipose tissue (AT) dysfunction, characterized by loss of its homeostatic functions, is a hallmark of non-communicable diseases. It is characterized by chronic low-grade inflammation and is observed in obesity, metabolic disorders such as insulin resistance and diabetes. While classically it has been identified by increased cytokine or chemokine expression, such as increased MCP-1, RANTES, IL-6, interferon (IFN) gamma or TNFα, mechanistically, immune cell infiltration is a prominent feature of the dysfunctional AT. These immune cells include M1 and M2 macrophages, effector and memory T cells, IL-10 producing FoxP3+ T regulatory cells, natural killer and NKT cells and granulocytes. Immune composition varies, depending on the stage and the type of pathology. Infiltrating immune cells not only produce cytokines but also metalloproteinases, reactive oxygen species, and chemokines that participate in tissue remodelling, cell signalling, and regulation of immunity. The presence of inflammatory cells in AT affects adjacent tissues and organs. In blood vessels, perivascular AT inflammation leads to vascular remodelling, superoxide production, endothelial dysfunction with loss of nitric oxide (NO) bioavailability, contributing to vascular disease, atherosclerosis, and plaque instability. Dysfunctional AT also releases adipokines such as leptin, resistin, and visfatin that promote metabolic dysfunction, alter systemic homeostasis, sympathetic outflow, glucose handling, and insulin sensitivity. Anti-inflammatory and protective adiponectin is reduced. AT may also serve as an important reservoir and possible site of activation in autoimmune-mediated and inflammatory diseases. Thus, reciprocal regulation between immune cell infiltration and AT dysfunction is a promising future therapeutic target.
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Affiliation(s)
- Tomasz J Guzik
- British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, UK.,Translational Medicine Laboratory, Department of Internal Medicine, Jagiellonian University, Collegium Medicum, Krakow, Poland
| | - Dominik S Skiba
- British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, UK.,Translational Medicine Laboratory, Department of Internal Medicine, Jagiellonian University, Collegium Medicum, Krakow, Poland
| | - Rhian M Touyz
- British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, UK
| | - David G Harrison
- British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, UK.,Department of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA
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Shimobayashi M, Albert V, Woelnerhanssen B, Frei IC, Weissenberger D, Meyer-Gerspach AC, Clement N, Moes S, Colombi M, Meier JA, Swierczynska MM, Jenö P, Beglinger C, Peterli R, Hall MN. Insulin resistance causes inflammation in adipose tissue. J Clin Invest 2018. [PMID: 29528335 DOI: 10.1172/jci96139] [Citation(s) in RCA: 312] [Impact Index Per Article: 44.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Obesity is a major risk factor for insulin resistance and type 2 diabetes. In adipose tissue, obesity-mediated insulin resistance correlates with the accumulation of proinflammatory macrophages and inflammation. However, the causal relationship of these events is unclear. Here, we report that obesity-induced insulin resistance in mice precedes macrophage accumulation and inflammation in adipose tissue. Using a mouse model that combines genetically induced, adipose-specific insulin resistance (mTORC2-knockout) and diet-induced obesity, we found that insulin resistance causes local accumulation of proinflammatory macrophages. Mechanistically, insulin resistance in adipocytes results in production of the chemokine monocyte chemoattractant protein 1 (MCP1), which recruits monocytes and activates proinflammatory macrophages. Finally, insulin resistance (high homeostatic model assessment of insulin resistance [HOMA-IR]) correlated with reduced insulin/mTORC2 signaling and elevated MCP1 production in visceral adipose tissue from obese human subjects. Our findings suggest that insulin resistance in adipose tissue leads to inflammation rather than vice versa.
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Affiliation(s)
| | | | | | - Irina C Frei
- Biozentrum, University of Basel, Basel, Switzerland
| | | | | | | | - Suzette Moes
- Biozentrum, University of Basel, Basel, Switzerland
| | | | | | | | - Paul Jenö
- Biozentrum, University of Basel, Basel, Switzerland
| | | | - Ralph Peterli
- Department of Surgery, St. Claraspital, Basel, Switzerland
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22
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Wang N, Tian X, Chen Y, Tan HQ, Xie PJ, Chen SJ, Fu YC, Chen YX, Xu WC, Wei CJ. Low dose doxycycline decreases systemic inflammation and improves glycemic control, lipid profiles, and islet morphology and function in db/db mice. Sci Rep 2017; 7:14707. [PMID: 29089617 PMCID: PMC5666019 DOI: 10.1038/s41598-017-14408-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 10/09/2017] [Indexed: 02/05/2023] Open
Abstract
The aim of this study was to determine whether low dose doxycycline as an anti-inflammatory agent could improve glucose metabolism in diabetic animals. Therefore, doxycycline was supplemented in drinking water to 6-week-old male db/db mice for 10 weeks. Doxycycline reduced perirenal/epididymal fat, Lee's index, and liver cholesterol. Blood HDL-cholesterol increased, but total cholesterol and aspartate transaminase decreased. Glucose and insulin tolerances were improved, accompanying with reduced fasting blood glucose, insulin, HOMA-IR and advanced glycation end products. Islet number, β-cell percentage and mass increased, while islet size decreased. Consistently, less apoptosis but more β-cell proliferation were found in islets of treated mice. Freshly isolated islets from treated mice showed higher insulin content and enhanced glucose stimulated insulin secretion (GSIS). In addition, purified islets of Balb/c mice showed increased GSIS after cultivation in vitro with doxycycline, but not with chloramphenicol and levofloxacin. Inflammation markers, including lipopolysaccharides (LPS) and C-reactive protein (CRP) in serum as well as CD68-positive cells in treated islets, decreased significantly. Finally, LPS stimulated the production of inflammatory factors but inhibited GSIS of MIN6 cells; however, the effects were completely reversed by doxycycline. The results support further study of possible long-term usage of sub-antimicrobial doxycycline in diabetic patients.
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Affiliation(s)
- Na Wang
- Multidisciplinary Research Center, Shantou University, Shantou, 515063, Guangdong, China
| | - Xiong Tian
- Multidisciplinary Research Center, Shantou University, Shantou, 515063, Guangdong, China
| | - Yu Chen
- Multidisciplinary Research Center, Shantou University, Shantou, 515063, Guangdong, China
| | - Hui-Qi Tan
- Multidisciplinary Research Center, Shantou University, Shantou, 515063, Guangdong, China
| | - Pei-Jian Xie
- Multidisciplinary Research Center, Shantou University, Shantou, 515063, Guangdong, China
| | - Shao-Jun Chen
- Multidisciplinary Research Center, Shantou University, Shantou, 515063, Guangdong, China
| | - Yu-Cai Fu
- Laboratory of Cell Senescence, Shantou University Medical College, Shantou, Guangdong, 515041, China
| | - Yi-Xin Chen
- Department of Endocrinology, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, China
| | - Wen-Can Xu
- Department of Endocrinology, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, China.
| | - Chi-Ju Wei
- Multidisciplinary Research Center, Shantou University, Shantou, 515063, Guangdong, China.
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23
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Frydrych LM, Fattahi F, He K, Ward PA, Delano MJ. Diabetes and Sepsis: Risk, Recurrence, and Ruination. Front Endocrinol (Lausanne) 2017; 8:271. [PMID: 29163354 PMCID: PMC5670360 DOI: 10.3389/fendo.2017.00271] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 09/27/2017] [Indexed: 12/16/2022] Open
Abstract
Sepsis develops when an infection surpasses local tissue containment. A series of dysregulated physiological responses are generated, leading to organ dysfunction and a 10% mortality risk. When patients with sepsis demonstrate elevated serum lactates and require vasopressor therapy to maintain adequate blood pressure in the absence of hypovolemia, they are in septic shock with an in-hospital mortality rate >40%. With improvements in intensive care treatment strategies, overall sepsis mortality has diminished to ~20% at 30 days; however, mortality continues to steadily climb after recovery from the acute event. Traditionally, it was thought that the complex interplay between inflammatory and anti-inflammatory responses led to sepsis-induced organ dysfunction and mortality. However, a closer examination of those who die long after sepsis subsides reveals that many initial survivors succumb to recurrent, nosocomial, and secondary infections. The comorbidly challenged, physiologically frail diabetic individuals suffer the highest infection rates. Recent reports suggest that even after clinical "recovery" from sepsis, persistent alterations in innate and adaptive immune responses exists resulting in chronic inflammation, immune suppression, and bacterial persistence. As sepsis-associated immune defects are associated with increased mortality long-term, a potential exists for immune modulatory therapy to improve patient outcomes. We propose that diabetes causes a functional immune deficiency that directly reduces immune cell function. As a result, patients display diminished bactericidal clearance, increased infectious complications, and protracted sepsis mortality. Considering the substantial expansion of the elderly and obese population, global adoption of a Western diet and lifestyle, and multidrug resistant bacterial emergence and persistence, diabetic mortality from sepsis is predicted to rise dramatically over the next two decades. A better understanding of the underlying diabetic-induced immune cell defects that persist following sepsis are crucial to identify potential therapeutic targets to bolster innate and adaptive immune function, prevent infectious complications, and provide more durable diabetic survival.
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Affiliation(s)
- Lynn M. Frydrych
- Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Fatemeh Fattahi
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Katherine He
- Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Peter A. Ward
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Matthew J. Delano
- Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, MI, United States
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24
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Euphorbia kansui Attenuates Insulin Resistance in Obese Human Subjects and High-Fat Diet-Induced Obese Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:9058956. [PMID: 29234441 PMCID: PMC5646343 DOI: 10.1155/2017/9058956] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 07/20/2017] [Accepted: 08/27/2017] [Indexed: 01/10/2023]
Abstract
Background Obesity is a main cause of insulin resistance (IR), metabolic syndrome, and fatty liver diseases. This study evaluated Euphorbia kansui radix (Euphorbia) as a potential treatment option for obesity and obesity-induced IR in obese human and high-fat diet- (HFD-) induced obese mice. Methods In the human study, we analyzed the body weight change of 14 patients who took a single dose of 6 g of Euphorbia powder. In the animal study, male mice were divided into three groups: normal chow, HFD, and Euphorbia (high-fat diet and 100 mg/Kg Euphorbia once per week). Body weight, epididymal fat pad weight, fasting blood glucose, fasting insulin, HOMA-IR, and oral glucose tolerance test were measured. Also, macrophage infiltration and expression of CD68, tumor necrosis factor- (TNF-) α, interferon- (IFN-) γ, and interleukin- (IL-) 6 genes in the liver and adipose tissue were analyzed. Results The human study showed that Euphorbia has a potential effect on body weight loss. In the in vivo study, body weight, epididymal fat weight, glucose level, IR, expression of CD68, TNF-α, IFN-r, and IL-6 genes, and macrophages in liver and adipose tissue were significantly reduced by Euphorbia. Conclusions These results suggest that Euphorbia attenuates obesity and insulin resistance via anti-inflammatory effects.
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25
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Goldfine AB, Shoelson SE. Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest 2017; 127:83-93. [PMID: 28045401 DOI: 10.1172/jci88884] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Obesity-related sub-acute chronic inflammation has been associated with incident type 2 diabetes and atherosclerotic cardiovascular disease. Inflammation is increasingly considered to be a pathologic mediator of these commonly co-occurring diseases. A growing number of preclinical and clinical studies support the inflammatory hypothesis, but clinical trials to confirm the therapeutic potential to target inflammation to treat or prevent cardiometabolic conditions are still ongoing. There are multiple inflammatory signaling pathways. Regulation is complex, with substantial crosstalk across these multiple pathways. The activity of select pathways may be differentially regulated in different tissues. Pharmacologic approaches to diabetes management may have direct or indirect antiinflammatory effects, the latter potentially attributable to an improved metabolic state. Conversely, some antiinflammatory approaches may affect glucose metabolism and cardiovascular health. To date, clinical trials suggest that targeting one portion of the inflammatory cascade may differentially affect dysglycemia and atherothrombosis. Understanding the underlying biological processes may contribute to the development of safe and effective therapies, although a single approach may not be sufficient for optimal management of both metabolic and athrothrombotic disease states.
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26
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Kusminski CM, Bickel PE, Scherer PE. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat Rev Drug Discov 2016; 15:639-660. [PMID: 27256476 DOI: 10.1038/nrd.2016.75] [Citation(s) in RCA: 510] [Impact Index Per Article: 56.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Adipose tissue regulates numerous physiological processes, and its dysfunction in obese humans is associated with disrupted metabolic homeostasis, insulin resistance and type 2 diabetes mellitus (T2DM). Although several US-approved treatments for obesity and T2DM exist, these are limited by adverse effects and a lack of effective long-term glucose control. In this Review, we provide an overview of the role of adipose tissue in metabolic homeostasis and assess emerging novel therapeutic strategies targeting adipose tissue, including adipokine-based strategies, promotion of white adipose tissue beiging as well as reduction of inflammation and fibrosis.
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Affiliation(s)
- Christine M Kusminski
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center
| | - Perry E Bickel
- Division of Endocrinology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center
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27
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Kraakman MJ, Dragoljevic D, Kammoun HL, Murphy AJ. Is the risk of cardiovascular disease altered with anti-inflammatory therapies? Insights from rheumatoid arthritis. Clin Transl Immunology 2016; 5:e84. [PMID: 27350883 PMCID: PMC4910124 DOI: 10.1038/cti.2016.31] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 04/12/2016] [Accepted: 04/12/2016] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. Atherosclerosis is the most common form of CVD, which is complex and multifactorial with an elevated risk observed in people with either metabolic or inflammatory diseases. Accumulating evidence now links obesity with a state of chronic low-grade inflammation and has renewed our understanding of this condition and its associated comorbidities. An emerging theme linking disease states with atherosclerosis is the increased production of myeloid cells, which can initiate and exacerbate atherogenesis. Although anti-inflammatory drug treatments exist and have been successfully used to treat inflammatory conditions such as rheumatoid arthritis (RA), a commonly observed side effect is dyslipidemia, inadvertently, a major risk factor for the development of atherosclerosis. The mechanisms leading to dyslipidemia associated with anti-inflammatory drug use and whether CVD risk is actually increased by this dyslipidemia are of great therapeutic importance and currently remain poorly understood. Here we review recent data providing links between inflammation, hematopoiesis, dyslipidemia and CVD risk in the context of anti-inflammatory drug use.
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Affiliation(s)
- Michael J Kraakman
- Department of Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Dragana Dragoljevic
- Department of Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Immunology, Monash University, Melbourne, Victoria, Australia
| | - Helene L Kammoun
- Department of Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Immunology, Monash University, Melbourne, Victoria, Australia
| | - Andrew J Murphy
- Department of Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Immunology, Monash University, Melbourne, Victoria, Australia
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28
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Donath MY. Multiple benefits of targeting inflammation in the treatment of type 2 diabetes. Diabetologia 2016; 59:679-82. [PMID: 26868493 DOI: 10.1007/s00125-016-3873-z] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 12/30/2015] [Indexed: 01/21/2023]
Abstract
The association between the metabolic syndrome and a pathological activation of the innate immune system is now well established. Thus, defective insulin secretion and action are due, at least in part, to islet, liver and fat inflammation in type 2 diabetes. Furthermore, an inflammatory process also seems to be involved in the development of cardiovascular, renal and ophthalmological complications of this disease. Interestingly, several other inflammatory diseases are associated with the metabolic syndrome, such as psoriasis, gout and rheumatic arthritis. The aim of this review is to discuss the clinical progress of anti-inflammatory drugs in the treatment of type 2 diabetes and then speculate on the possible further development of these drugs, with the aim of using the drugs in combination in order to combat the multiple manifestations of inflammatory diseases. This review summarises a presentation given at the 'Islet inflammation in type 2 diabetes' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Simone Baltrusch, DOI: 10.1007/s00125-016-3891-x , and Jerry Nadler and colleagues, DOI: 10.1007/s00125-016-3890-y ) and a commentary by the Session Chair, Piero Marchetti (DOI: 10.1007/s00125-016-3875-x ).
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Affiliation(s)
- Marc Y Donath
- Endocrinology, Diabetes & Metabolism and Department of Biomedicine, University Hospital Basel, CH-4031, Basel, Switzerland.
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29
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Knudsen SH, Pedersen BK. Targeting Inflammation Through a Physical Active Lifestyle and Pharmaceuticals for the Treatment of Type 2 Diabetes. Curr Diab Rep 2015; 15:82. [PMID: 26358738 DOI: 10.1007/s11892-015-0642-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Evidence exists that interleukin (IL)-1β is involved in pancreatic β-cell damage, whereas TNF-α appears to be a key molecule in peripheral insulin resistance. Although increased plasma levels of IL-6 are seen in individuals with type 2 diabetes, mechanistic studies suggest that moderate acute elevations in IL-6, as provoked by exercise, exert anti-inflammatory effects by an inhibition of TNF-α and by stimulating IL-1 receptor antagonist (ra), thereby limiting IL-1β signaling. A number of medical treatments have anti-inflammatory effects. IL-1 antagonists have been tested in clinical studies and appear very promising. Also, there is a potential for anti-TNF-α strategies and salsalate has been shown to improve insulin sensitivity in clinical trials. Furthermore, the anti-inflammatory potential of statins, antagonists of the renin-angiotensin system, and glucose-lowering agents are discussed. While waiting for the outcome of long-term clinical pharmacological trials, it should be emphasized that physical activity represents a natural strong anti-inflammatory intervention with little or no side effects.
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Affiliation(s)
- Sine Haugaard Knudsen
- Centre of Inflammation and Metabolism/Centre of Physical Activity Research (CIM/CFAS), Rigshospitalet, University of Copenhagen, Section 7641, Blegdamsvej 9, DK-2100, Copenhagen, Denmark
| | - Bente Klarlund Pedersen
- Centre of Inflammation and Metabolism/Centre of Physical Activity Research (CIM/CFAS), Rigshospitalet, University of Copenhagen, Section 7641, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
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30
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N-3 Polyunsaturated Fatty Acids and Inflammation in Obesity: Local Effect and Systemic Benefit. BIOMED RESEARCH INTERNATIONAL 2015; 2015:581469. [PMID: 26339623 PMCID: PMC4538411 DOI: 10.1155/2015/581469] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 01/11/2015] [Indexed: 12/19/2022]
Abstract
Overwhelming consensus emerges among countless evidences that obesity is characterized by a chronic low-grade inflammation in the adipose tissue (AT), which subsequently develops into a systemic inflammatory state contributing to obesity-associated diseases. N-3 Polyunsaturated fatty acids (n-3 PUFA), known as important modulators participating in inflammatory process, turn out to be an effective mitigating strategy dealing with local and systemic inflammation observed in obesity. Some of the effects of n-3 PUFA are brought about by regulation of gene expression through interacting with nuclear receptors and transcription factors; other effects are elicited by modulation of the amount and type of mediator derived from PUFAs. The metabolic effects of n-3 PUFA mainly result from their interactions with several organ systems, not limited to AT. Notably, the attenuation of inflammation in hard-hit AT, in turn, contributes to reducing circulating concentrations of proinflammatory cytokines and detrimental metabolic derivatives, which is beneficial for the function of other involved organs. The present review highlights a bridging mechanism between n-3 PUFA-mediated inflammation relief in AT and systemic benefits.
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Ruscitti P, Cipriani P, Di Benedetto P, Liakouli V, Berardicurti O, Carubbi F, Ciccia F, Alvaro S, Triolo G, Giacomelli R. Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1β via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a possible implication for therapeutic decision in these patients. Clin Exp Immunol 2015; 182:35-44. [PMID: 26095630 DOI: 10.1111/cei.12667] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/04/2015] [Indexed: 12/23/2022] Open
Abstract
A better understanding about the mechanisms involved in the pathogenesis of type 2 diabetes mellitus (T2D) showed that inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin (IL)-1β play a pivotal role, mirroring data largely reported in rheumatoid arthritis (RA). IL-1β is produced mainly by monocytes (MO), and hyperglycaemia may be able to modulate, in the cytoplasm of these cells, the assembly of a nucleotide-binding domain and leucine-rich repeat containing family pyrin (NLRP3)-inflammosome, a cytosolic multi-protein platform where the inactive pro-IL-1β is cleaved into active form, via caspase-1 activity. In this paper, we evaluated the production of IL-1 β and TNF, in peripheral blood MO of patients affected by RA or T2D or both diseases, in order to understand if an alteration of the glucose metabolism may influence their proinflammatory status. Our data showed, after 24 h of incubation with different glucose concentrations, a significantly increased production of IL-1β and TNF in all evaluated groups when compared with healthy controls. However, a significant increase of IL-1β secretion by T2D/RA was observed when compared with other groups. The analysis of relative mRNA expression confirmed these data. After 24 h of incubation with different concentrations of glucose, our results showed a significant increase in NLRP3 expression. In this work, an increased production of IL-1β by MO obtained from patients affected by both RA and T2D via NLRP3-inflammasome activation may suggest a potential IL-1β targeted therapy in these patients.
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Affiliation(s)
- P Ruscitti
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila
| | - P Cipriani
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila
| | - P Di Benedetto
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila
| | - V Liakouli
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila
| | - O Berardicurti
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila
| | - F Carubbi
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila
| | - F Ciccia
- Division of Rheumatology, Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - S Alvaro
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila
| | - G Triolo
- Division of Rheumatology, Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - R Giacomelli
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila
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Burska AN, Sakthiswary R, Sattar N. Effects of Tumour Necrosis Factor Antagonists on Insulin Sensitivity/Resistance in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. PLoS One 2015; 10:e0128889. [PMID: 26110878 PMCID: PMC4482317 DOI: 10.1371/journal.pone.0128889] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 05/02/2015] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Beyond the joints, TNFi (tumour necrosis factor inhibitor) therapy may confer systemic benefits in rheumatoid arthritis (RA). Several studies have investigated the role of TNFi on insulin resistance/sensitivity (IR/IS). This question is of general interest given the emerging evidence linking inflammation and insulin resistance. The main aim of this review was to summarise the published data and to determine the effects of TNFi on IR/IS. METHODS We searched the PubMed and ISI Web of Knowledge databases for studies which examined the effects of TNFi on IR/IS. The studies were assessed independently by two reviewers according to a pre-specified protocol. The data on Homeostatic Model Assessment for Insulin resistance (HOMA) and Quantitative Insulin Sensitivity Check Index (QUICKI) were pooled and reported as standard difference in means (SDM) with 95% confidence interval (CI) using a random-effects model. RESULTS A total of eight studies with 260 subjects met the selection criteria. The duration of the studies was from 8 weeks to 12 months. There was statistically significant reduction in HOMA index in six out of eight studies and four reported significant increment in QUICKI. The pooled analysis revealed significant reduction in HOMA [SDM-0.148, 95%CI[-0.278 to -0.017], p=0.026] and increment in QUICKI [SDM 0.312, 95%CI[0.019 to 0.606], p=0.037] with TNFi. CONCLUSION There is emerging evidence to support that TNFi therapy improves IS and reduces IR in RA. Further, well conducted trials are needed to determine if such effects translate to lower incidence of diabetes in RA or other autoimmune conditions on biologic therapy.
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Affiliation(s)
- Agata N. Burska
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
| | | | - Naveed Sattar
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
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Papaetis GS, Papakyriakou P, Panagiotou TN. Central obesity, type 2 diabetes and insulin: exploring a pathway full of thorns. Arch Med Sci 2015; 11:463-82. [PMID: 26170839 PMCID: PMC4495144 DOI: 10.5114/aoms.2015.52350] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2013] [Revised: 06/20/2013] [Accepted: 07/04/2013] [Indexed: 12/19/2022] Open
Abstract
The prevalence of type 2 diabetes (T2D) is rapidly increasing. This is strongly related to the contemporary lifestyle changes that have resulted in increased rates of overweight individuals and obesity. Central (intra-abdominal) obesity is observed in the majority of patients with T2D. It is associated with insulin resistance, mainly at the level of skeletal muscle, adipose tissue and liver. The discovery of macrophage infiltration in the abdominal adipose tissue and the unbalanced production of adipocyte cytokines (adipokines) was an essential step towards novel research perspectives for a better understanding of the molecular mechanisms governing the development of insulin resistance. Furthermore, in an obese state, the increased cellular uptake of non-esterified fatty acids is exacerbated without any subsequent β-oxidation. This in turn contributes to the accumulation of intermediate lipid metabolites that cause defects in the insulin signaling pathway. This paper examines the possible cellular mechanisms that connect central obesity with defects in the insulin pathway. It discusses the discrepancies observed from studies organized in cell cultures, animal models and humans. Finally, it emphasizes the need for therapeutic strategies in order to achieve weight reduction in overweight and obese patients with T2D.
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Affiliation(s)
- Georgios S. Papaetis
- Diabetes Clinic, Paphos, Cyprus
- Diabetes Clinic, 3 Department of Medicine, University of Athens Medical School, ‘Sotiria’ General Hospital, Athens, Greece
| | | | - Themistoklis N. Panagiotou
- Diabetes Clinic, 3 Department of Medicine, University of Athens Medical School, ‘Sotiria’ General Hospital, Athens, Greece
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34
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Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov 2014; 13:465-76. [PMID: 24854413 DOI: 10.1038/nrd4275] [Citation(s) in RCA: 523] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The role of inflammation in the pathogenesis of type 2 diabetes and associated complications is now well established. Several conditions that are driven by inflammatory processes are also associated with diabetes, including rheumatoid arthritis, gout, psoriasis and Crohn's disease, and various anti-inflammatory drugs have been approved or are in late stages of development for the treatment of these conditions. This review discusses the rationale for the use of some of these anti-inflammatory treatments in patients with diabetes and what we could expect from their use. Future immunomodulatory treatments may not target a specific disease, but could instead act on a dysfunctional pathway that causes several conditions associated with the metabolic syndrome.
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Affiliation(s)
- Marc Y Donath
- Endocrinology, Diabetes & Metabolism, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland
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35
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Blüher M. Adipokines - removing road blocks to obesity and diabetes therapy. Mol Metab 2014; 3:230-40. [PMID: 24749053 PMCID: PMC3986498 DOI: 10.1016/j.molmet.2014.01.005] [Citation(s) in RCA: 161] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 01/03/2014] [Accepted: 01/06/2014] [Indexed: 12/16/2022] Open
Abstract
Prevention of obesity and therapeutic weight loss interventions have provided only limited long term success. Therefore there is an urgent need to develop novel pharmacological treatment strategies, which target mechanisms underlying positive energy balance, excessive fat accumulation and adverse fat distribution. Adipokines may have potential for future pharmacological treatment strategies of obesity and metabolic diseases, because they are involved in the regulation of appetite and satiety, energy expenditure, endothelial function, blood pressure, insulin sensitivity, adipogenesis, fat distribution and insulin secretion and others. There are important road blocks on the way from an adipokine candidate to the clinical use a therapeutic compound. Such road blocks include an incomplete understanding of the mechanism of action, resistance to a specific adipokine, side effects of the adipokine and others. This review focuses on the potential of selected adipokines as therapeutic tools or targets and discusses important road blocks, which currently prevent their clinical use.
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Affiliation(s)
- Matthias Blüher
- Department of Medicine, University of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany
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36
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Lee BC, Lee J. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta Mol Basis Dis 2013; 1842:446-62. [PMID: 23707515 DOI: 10.1016/j.bbadis.2013.05.017] [Citation(s) in RCA: 478] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 05/07/2013] [Accepted: 05/13/2013] [Indexed: 02/07/2023]
Abstract
There is increasing evidence showing that inflammation is an important pathogenic mediator of the development of obesity-induced insulin resistance. It is now generally accepted that tissue-resident immune cells play a major role in the regulation of this obesity-induced inflammation. The roles that adipose tissue (AT)-resident immune cells play have been particularly extensively studied. AT contains most types of immune cells and obesity increases their numbers and activation levels, particularly in AT macrophages (ATMs). Other pro-inflammatory cells found in AT include neutrophils, Th1 CD4 T cells, CD8 T cells, B cells, DCs, and mast cells. However, AT also contains anti-inflammatory cells that counter the pro-inflammatory immune cells that are responsible for the obesity-induced inflammation in this tissue. These anti-inflammatory cells include regulatory CD4 T cells (Tregs), Th2 CD4 T cells, and eosinophils. Hence, AT inflammation is shaped by the regulation of pro- and anti-inflammatory immune cell homeostasis, and obesity skews this balance towards a more pro-inflammatory status. Recent genetic studies revealed several molecules that participate in the development of obesity-induced inflammation and insulin resistance. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation and insulin resistance are discussed, with particular attention being placed on the roles of the cellular players in these pathogeneses. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
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Affiliation(s)
- Byung-Cheol Lee
- The Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Korea
| | - Jongsoon Lee
- The Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
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37
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Grant RW, Dixit VD. Mechanisms of disease: inflammasome activation and the development of type 2 diabetes. Front Immunol 2013; 4:50. [PMID: 23483669 PMCID: PMC3592198 DOI: 10.3389/fimmu.2013.00050] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 02/10/2013] [Indexed: 12/23/2022] Open
Abstract
Over the recent past, the importance of aberrant immune cell activation as one of the contributing mechanisms to the development of insulin-resistance and type 2 diabetes (T2D) has been recognized. Among the panoply of pro-inflammatory cytokines that are linked to chronic metabolic diseases, new data suggests that interleukin-1β (IL-1β) may play an important role in initiating and sustaining inflammation-induced organ dysfunction in T2D. Therefore, factors that control secretion of bioactive IL-1β have therapeutic implications. In this regard, the identification of multiprotein scaffolding complexes, "inflammasomes," has been a great advance in our understanding of this process. The secretion of bioactive IL-1β is predominantly controlled by activation of caspase-1 through assembly of a multiprotein scaffold, "inflammasome" that is composed of NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) ASC (apoptosis associated speck-like protein containing a CARD) and procaspase-1. The NLRP3 inflammasome appears to be an important sensor of metabolic dysregulation and controls obesity-associated insulin resistance and pancreatic beta cell dysfunction. Initial clinical "proof of concept" studies suggest that blocking IL-1β may favorably modulate factors related to development and treatment of T2D. However, this potential therapeutic approach remains to be fully substantiated through phase-II clinical studies. Here, we outline the new immunological mechanisms that link metabolic dysfunction to the emergence of chronic inflammation and discuss the opportunities and challenges of future therapeutic approaches to dampen NLRP3 inflammasome activation or IL-1β signaling for controlling type 2 diabetes.
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Affiliation(s)
- Ryan W Grant
- Immunobiology Laboratory, Pennington Biomedical Research Center, Louisiana State University System Baton Rouge, LA, USA
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38
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Abstract
Chronic inflammation is a characteristic of obesity and is associated with accompanying insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Although proinflammatory cytokines are known for their detrimental effects on adipose tissue function and insulin sensitivity, their beneficial effects in the regulation of metabolism have not drawn sufficient attention. In obesity, inflammation is initiated by a local hypoxia to augment angiogenesis and improve adipose tissue blood supply. A growing body of evidence suggests that macrophages and proinflammatory cytokines are essential for adipose remodeling and adipocyte differentiation. Phenotypes of multiple lines of transgenic mice consistently suggest that proinflammatory cytokines increase energy expenditure and act to prevent obesity. Removal of proinflammatory cytokines by gene knockout decreases energy expenditure and induces adult-onset obesity. In contrast, elevation of proinflammatory cytokines augments energy expenditure and decreases the risk for obesity. Anti-inflammatory therapies have been tested in more than a dozen clinical trials to improve insulin sensitivity and glucose homeostasis in patients with T2DM, and the results are not encouraging. One possible explanation is that anti-inflammatory therapies also attenuate the beneficial effects of inflammation in stimulating energy expenditure, which may have limited the efficacy of the treatment by promoting energy accumulation. Thus, the positive effects of proinflammatory events should be considered in evaluating the impact of inflammation in obesity and type 2 diabetes.
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Affiliation(s)
- Jianping Ye
- Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State Univ. System, Baton Rouge, LA 70808, USA.
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Nikolajczyk BS, Jagannathan-Bogdan M, Denis GV. The outliers become a stampede as immunometabolism reaches a tipping point. Immunol Rev 2013; 249:253-75. [PMID: 22889227 DOI: 10.1111/j.1600-065x.2012.01142.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Obesity and Type 2 diabetes mellitus (T2D) are characterized by pro-inflammatory alterations in the immune system including shifts in leukocyte subset differentiation and in cytokine/chemokine balance. The chronic, low-grade inflammation resulting largely from changes in T-cell, B-cell, and myeloid compartments promotes and/or exacerbates insulin resistance (IR) that, together with pancreatic islet failure, defines T2D. Animal model studies show that interruption of immune cell-mediated inflammation by any one of several methods almost invariably results in the prevention or delay of obesity and/or IR. However, anti-inflammatory therapies have had a modest impact on established T2D in clinical trials. These seemingly contradictory results indicate that a more comprehensive understanding of human IR/T2D-associated immune cell function is needed to leverage animal studies into clinical treatments. Important outstanding analyses include identifying potential immunological checkpoints in disease etiology, detailing immune cell/adipose tissue cross-talk, and defining strengths/weaknesses of model organism studies to determine whether we can harness the promising new field of immunometabolism to curb the global obesity and T2D epidemics.
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40
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Abstract
The two types of adipose tissue in humans, white and brown, have distinct developmental origins and functions. Human white adipose tissue plays a pivotal role in maintaining whole-body energy homeostasis by storing triglycerides when energy is in surplus, releasing free fatty acids as a fuel during energy shortage, and secreting adipokines that are important for regulating lipid and glucose metabolism. The size of white adipose mass needs to be kept at a proper set point. Dramatic expansion of white fat mass causes obesity—now become a global epidemic disease—and increases the risk for the development of many life-threatening diseases. The absence of white adipose tissue or abnormal white adipose tissue redistribution leads to lipodystrophy, a condition often associated with metabolic disorders. Brown adipose tissue is a thermogenic organ whose mass is inversely correlated with body mass index and age. Therapeutic approaches targeting adipose tissue have been proven to be effective in improving obesity-related metabolic disorders, and promising new therapies could be developed in the near future.
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Affiliation(s)
- Bin Feng
- Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
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41
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Mandrup-Poulsen T. Interleukin-1 antagonists and other cytokine blockade strategies for type 1 diabetes. Rev Diabet Stud 2012; 9:338-47. [PMID: 23804271 PMCID: PMC3740701 DOI: 10.1900/rds.2012.9.338] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Revised: 02/07/2013] [Accepted: 02/08/2013] [Indexed: 01/01/2023] Open
Abstract
Proinflammatory cytokines stimulate adaptive immunity and attenuate T cell regulation and tolerance induction. They also profoundly impair β-cell function, proliferation, and viability, activities of similar importance in the context of type 1 diabetes (T1D). Detailed knowledge of the molecular mechanisms of β-cell toxicity has been gathered within the last 2-3 decades. However, the efficacy of individual proinflammatory cytokine blockade in animal models of T1D has been inconsistent and generally modest, except in the context of islet transplantation. This suggests that the timing of the cytokine blockade relative to anti-β-cell immune activation is critical, and that combination therapy may be required. In randomized, placebo-controlled, clinical trials of limited power, TNF-α (but not IL-1) blockade has yielded moderate but significant improvements in glycemia, insulin requirement, and β-cell function. The safety experience with anti-cytokine biologics is still very limited in T1D. However, combinations with other biologics, at doses of adaptive and innate immune inhibitors/modulators that are suboptimal or ineffective in themselves, may generate synergies of true therapeutic benefit and safety in T1D. Critical and balanced appraisal of the preclinical and clinical evidence of efficacy and safety of anti-immune, anti-inflammatory, and anti-dysmetabolic therapeutics should thus guide future studies to move closer to novel treatments, targeting the underlying causes of β-cell failure and destruction in T1D.
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Affiliation(s)
- Thomas Mandrup-Poulsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
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42
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Romeo GR, Lee J, Shoelson SE. Metabolic syndrome, insulin resistance, and roles of inflammation--mechanisms and therapeutic targets. Arterioscler Thromb Vasc Biol 2012; 32:1771-6. [PMID: 22815343 DOI: 10.1161/atvbaha.111.241869] [Citation(s) in RCA: 268] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Obesity and its comorbidities, including type 2 diabetes mellitus and cardiovascular disease, are associated with a state of chronic low-grade inflammation that can be detected both systemically and within specific tissues. Areas of active investigation focus on the molecular bases of metabolic inflammation and potential pathogenic roles in insulin resistance, diabetes, and cardiovascular disease. An increased accumulation of macrophages occurring in obese adipose tissue has emerged as a key process in metabolic inflammation. Recent studies have also begun to unravel the heterogeneity of adipose tissue macrophages, and their physical and functional interactions with adipocytes, endothelial cells, and other immune cells within the adipose tissue microenvironment. Translating the information gathered from experimental models of insulin resistance and diabetes into meaningful therapeutic interventions is a tantalizing goal with long-term global health implications. In this context, ongoing clinical studies are testing the effects of targeting inflammation systemically on metabolic and cardiovascular outcomes.
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Affiliation(s)
- Giulio R Romeo
- Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
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43
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Molecular targets related to inflammation and insulin resistance and potential interventions. J Biomed Biotechnol 2012; 2012:379024. [PMID: 23049242 PMCID: PMC3463198 DOI: 10.1155/2012/379024] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Revised: 09/13/2012] [Accepted: 09/13/2012] [Indexed: 12/18/2022] Open
Abstract
Inflammation and insulin resistance are common in several chronic diseases, such as obesity, type 2 diabetes mellitus, metabolic syndrome, cancer, and cardiovascular diseases. Various studies show a relationship between these two factors, although the mechanisms involved are not completely understood yet. Here, we discuss the molecular basis of insulin resistance and inflammation and the molecular aspects on inflammatory pathways interfering in insulin action. Moreover, we explore interventions based on molecular targets for preventing or treating correlated disorders, advances for a better characterization, and understanding of the mechanisms and mediators involved in the different inflammatory and insulin resistance conditions. Finally, we address biotechnological studies for the development of new potential therapies and interventions.
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44
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Emanuela F, Grazia M, Marco DR, Maria Paola L, Giorgio F, Marco B. Inflammation as a Link between Obesity and Metabolic Syndrome. J Nutr Metab 2012; 2012:476380. [PMID: 22523672 PMCID: PMC3317136 DOI: 10.1155/2012/476380] [Citation(s) in RCA: 196] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Revised: 10/19/2011] [Accepted: 11/03/2011] [Indexed: 12/14/2022] Open
Abstract
The metabolic syndrome is a complex of clinical features leading to an increased risk for cardiovascular disease and type 2 diabetes mellitus in both sexes. Visceral obesity and insulin resistance are considered the main features determining the negative cardiovascular profile in metabolic syndrome. The aim of this paper is to highlight the central role of obesity in the development of a chronic low-grade inflammatory state that leads to insulin resistance, endothelial and microvascular dysfunctions. It is thought that the starting signal of this inflammation is overfeeding and the pathway origins in all the metabolic cells; the subsequent increase in cytokine production recruits immune cells in the extracellular environment inducing an overall systemic inflammation. This paper focuses on the molecular and cellular inflammatory mechanisms studied until now.
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Affiliation(s)
- Faloia Emanuela
- Division of Endocrinology, Polytechnic University of Marche, via Conca 71, 60126 Ancona, Italy
| | - Michetti Grazia
- Division of Endocrinology, Polytechnic University of Marche, via Conca 71, 60126 Ancona, Italy
| | - De Robertis Marco
- Division of Endocrinology, Polytechnic University of Marche, via Conca 71, 60126 Ancona, Italy
| | - Luconi Maria Paola
- Division of Endocrinology, Polytechnic University of Marche, via Conca 71, 60126 Ancona, Italy
| | - Furlani Giorgio
- Division of Endocrinology, Polytechnic University of Marche, via Conca 71, 60126 Ancona, Italy
| | - Boscaro Marco
- Division of Endocrinology, Polytechnic University of Marche, via Conca 71, 60126 Ancona, Italy
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45
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Lukens JR, Dixit VD, Kanneganti TD. Inflammasome activation in obesity-related inflammatory diseases and autoimmunity. Contemp Clin Trials 2012; 32:592-604. [PMID: 21794210 DOI: 10.1016/j.cct.2011.04.006] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Revised: 04/08/2011] [Accepted: 04/13/2011] [Indexed: 02/06/2023]
Abstract
The inflammasome is a highly regulated protein complex that triggers caspase-1 activation and subsequent secretion of IL-1β and IL-18. Recognition of microbial components and danger signals by NOD-like receptor (NLR) family members in the cytosol promotes inflammasome activation and downstream inflammatory cytokine production. Pathogen recognition by NLRs and downstream release of inflammasome-derived cytokines are important in host defense against numerous infections. Recent studies have also identified a unique role for inflammasome regulation in the induction and pathogenesis of multiple autoimmune and inflammatory disorders. We now know that obesity-related factors and endogenous markers of cellular stress can lead to unchecked activation of the inflammasome and provoke inflammation and subsequent destruction of vital organs. This review will highlight recent findings that link inflammasome signaling to the progression of autoinflammatory and autoimmune diseases. We will focus on the contribution of inflammasome activation to the pathogenesis of autoinflammatory and autoimmune diseases that are of major significance to human health including type 2 diabetes, atherosclerosis, multiple sclerosis, and type 1 diabetes.
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Affiliation(s)
- John R Lukens
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
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46
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Gao ZG, Ye JP. Why do anti-inflammatory therapies fail to improve insulin sensitivity? Acta Pharmacol Sin 2012; 33:182-8. [PMID: 22036866 PMCID: PMC3270211 DOI: 10.1038/aps.2011.131] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Accepted: 09/06/2011] [Indexed: 12/25/2022]
Abstract
Chronic inflammation occurs in obese conditions in both humans and animals. It also contributes to the pathogenesis of type 2 diabetes (T2D) through insulin resistance, a status in which the body loses its ability to respond to insulin. Inflammation impairs insulin signaling through the functional inhibition of IRS-1 and PPARγ. Insulin sensitizers (such as rosiglitazone and pioglitazone) inhibit inflammation while improving insulin sensitivity. Therefore, anti-inflammatory agents have been suggested as a treatment strategy for insulin resistance. This strategy has been tested in laboratory studies and clinical trials for more than 10 years; however, no significant progress has been made in any of the model systems. This status has led us to re-evaluate the biological significance of chronic inflammation in obesity. Recent studies have consistently asserted that obesity-associated inflammation helps to maintain insulin sensitivity. Inflammation stimulates local adipose tissue remodeling and promotes systemic energy expenditure. We propose that these beneficial activities of inflammation provide an underlying mechanism for the failure of anti-inflammatory therapy in the treatment of insulin resistance. Current literature will be reviewed in this article to present evidence that supports this viewpoint.
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Affiliation(s)
- Zhan-guo Gao
- Antioxidant and Gene Regulation Lab, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA
| | - Jian-ping Ye
- Antioxidant and Gene Regulation Lab, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA
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Kim CS, Kim JG, Lee BJ, Choi MS, Choi HS, Kawada T, Lee KU, Yu R. Deficiency for costimulatory receptor 4-1BB protects against obesity-induced inflammation and metabolic disorders. Diabetes 2011; 60:3159-68. [PMID: 21998397 PMCID: PMC3219944 DOI: 10.2337/db10-1805] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Inflammation is an important factor in the development of insulin resistance, type 2 diabetes, and fatty liver disease. As a member of the tumor necrosis factor receptor superfamily (TNFRSF9) expressed on immune cells, 4-1BB/CD137 provides a bidirectional inflammatory signal through binding to its ligand 4-1BBL. Both 4-1BB and 4-1BBL have been shown to play an important role in the pathogenesis of various inflammatory diseases. RESEARCH DESIGN AND METHODS Eight-week-old male 4-1BB-deficient and wild-type (WT) mice were fed a high-fat diet (HFD) or a regular diet for 9 weeks. RESULTS We demonstrate that 4-1BB deficiency protects against HFD-induced obesity, glucose intolerance, and fatty liver disease. The 4-1BB-deficient mice fed an HFD showed less body weight gain, adiposity, adipose infiltration of macrophages/T cells, and tissue levels of inflammatory cytokines (e.g., TNF-α, interleukin-6, and monocyte chemoattractant protein-1 [MCP-1]) compared with HFD-fed control mice. HFD-induced glucose intolerance/insulin resistance and fatty liver were also markedly attenuated in the 4-1BB-deficient mice. CONCLUSIONS These findings suggest that 4-1BB and 4-1BBL may be useful therapeutic targets for combating obesity-induced inflammation and metabolic disorders.
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Affiliation(s)
- Chu-Sook Kim
- Department of Food Science and Nutrition, University of Ulsan, Ulsan, South Korea
| | - Jae Geun Kim
- Department of Biological Science, University of Ulsan, Ulsan, South Korea
| | - Byung-Ju Lee
- Department of Biological Science, University of Ulsan, Ulsan, South Korea
| | - Myung-Sook Choi
- Department of Food Science and Nutrition, Kyungpook National University, Daegu, South Korea
| | - Hye-Sun Choi
- Department of Biological Science, University of Ulsan, Ulsan, South Korea
| | - Teruo Kawada
- Graduate School of Agriculture, Kyoto University, Uji, Kyoto, Japan
| | - Ki-Up Lee
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, South Korea
| | - Rina Yu
- Department of Food Science and Nutrition, University of Ulsan, Ulsan, South Korea
- Corresponding author: Rina Yu,
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48
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Abstract
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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49
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Stanley TL, Zanni MV, Johnsen S, Rasheed S, Makimura H, Lee H, Khor VK, Ahima RS, Grinspoon SK. TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J Clin Endocrinol Metab 2011; 96:E146-50. [PMID: 21047923 PMCID: PMC3038481 DOI: 10.1210/jc.2010-1170] [Citation(s) in RCA: 249] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
CONTEXT AND OBJECTIVE Obesity is associated with activation of the TNF-α system, increased inflammatory markers, and insulin resistance. Although studies in rodents suggest that attenuation of TNF activity improves glucose homeostasis, the effect of prolonged inhibition of TNF-α with etanercept on inflammation and glucose homeostasis in a human model of obesity is not known. DESIGN AND PARTICIPANTS Forty obese subjects with features of metabolic syndrome were randomized to etanercept or placebo, 50 mg twice weekly for 3 months, followed by 50 mg once weekly for 3 months. OUTCOME MEASURES Subjects underwent oral glucose tolerance testing and measurement of serum inflammatory biomarkers and adipokines. Subcutaneous fat biopsy was performed in a subset for measurement of adipokine and TNF-α mRNA expression. RESULTS Visceral adiposity was significantly associated with serum concentrations of TNF receptor 1 (TNFR1), TNFR2, and vascular cell adhesion molecule-1 and adipose tissue expression of TNF-α and SOCS-3 (all P < 0.05). Insulin resistance as assessed by homeostasis model assessment was significantly associated with TNFR1, C-reactive protein, IL-6, and soluble intracellular adhesion molecule-1 (sICAM-1) (all P < 0.05). Etanercept significantly improved fasting glucose (treatment effect vs. placebo over 6 months, -10.8 ± 4.4%, P = 0.02). Etanercept also increased the ratio of high molecular weight adiponectin to total adiponectin (+22.1 ± 9.2% vs. placebo, P = 0.02), and decreased levels of sICAM-1 (-11 ± 2% vs. placebo, P < 0.0001). In contrast, body composition, lipids, C-reactive protein, and IL-6 were unchanged after 6 months. CONCLUSIONS Prolonged therapy with etanercept improved fasting glucose, increased the ratio of high molecular weight to total adiponectin, and decreased sICAM-1 in obese subjects with abnormal glucose homeostasis and significant subclinical inflammation.
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Affiliation(s)
- Takara L Stanley
- Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
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50
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Abstract
An expanding spectrum of acute and chronic inflammatory diseases is considered 'autoinflammatory' diseases. This review considers autoinflammatory diseases as being distinct from 'autoimmune' diseases. Autoimmune diseases are associated with dysfunctional T cells and treated with 'biologicals', including antitumour necrosis factorα, CTLA-Ig, anti-IL-12/23, anti-CD20, anti-IL-17 and anti-IL-6 receptor. In contrast, autoinflammatory diseases are uniquely attributed to a dysfunctional monocyte caspase 1 activity and secretion of IL-1β; indeed, blocking IL-1β results in a rapid and sustained reduction in the severity of most autoinflammatory diseases. Flares of gout, type 2 diabetes, heart failure and smouldering multiple myeloma are examples of seemingly unrelated diseases, which are uniquely responsive to IL 1β neutralization.
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Affiliation(s)
- C A Dinarello
- Department of Medicine, University of Colorado, Aurora, CO, USA.
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