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Li L, Yang X, Ren JS, Huang MZ, Zhao QW. Immunosuppressive agents in diabetes treatment: Hope or despair? World J Diabetes 2025; 16:100590. [DOI: 10.4239/wjd.v16.i5.100590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 01/19/2025] [Accepted: 03/05/2025] [Indexed: 04/25/2025] Open
Abstract
Exploration of immunosuppressive agents for the treatment of diabetes is a burgeoning field that has captured the attention of the medical community. The innovative approach of using these agents to combat diabetes is driven by their diverse capabilities to regulate the immune system, which is pivotal for disease pathogenesis. The primary objective is to enhance the management of blood glucose levels, which is a critical factor in the daily life of diabetic patients. This comprehensive review delves into the therapeutic horizons opened by immunosuppressive agents, particularly their potential impact on type 1 and type 2 diabetes mellitus, and their utility in the transplantation process. The complex etiology of diabetes, which involves a delicate interplay of genetic, environmental, and immunological factors, presents a multifaceted target landscape for these therapies. The agents discussed in the review, including CD3 inhibitors, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin G, Janus kinase inhibitors, anti-thymocyte globulin, tumor necrosis factor-α inhibitors, CD20 inhibitors, alefacept, and alemtuzumab, each bring a unique mechanism to the table, offering a tailored approach to immune modulation. As research progresses, emphasis is being placed on evaluating the long-term efficacy and safety of these agents to pave the way for more personalized and effective diabetes management strategies.
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Affiliation(s)
- Lu Li
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Xi Yang
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jin-Shuai Ren
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Ming-Zhu Huang
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Qing-Wei Zhao
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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Karin M, Kim JY. MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives. Mol Oncol 2025; 19:275-294. [PMID: 38874196 PMCID: PMC11793012 DOI: 10.1002/1878-0261.13685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 04/15/2024] [Accepted: 06/04/2024] [Indexed: 06/15/2024] Open
Abstract
Hepatocellular carcinoma is one of the deadliest and fastest-growing cancers. Among HCC etiologies, metabolic dysfunction-associated fatty liver disease (MAFLD) has served as a major HCC driver due to its great potential for increasing cirrhosis. The obesogenic environment fosters a positive energy balance and results in a continuous rise of obesity and metabolic syndrome. However, it is difficult to understand how metabolic complications lead to the poor prognosis of liver diseases and which molecular mechanisms are underpinning MAFLD-driven HCC development. Thus, suitable preclinical models that recapitulate human etiologies are essentially required. Numerous preclinical models have been created but not many mimicked anthropometric measures and the course of disease progression shown in the patients. Here we review the literature on adipose tissues, liver-related HCC etiologies and recently discovered genetic mutation signatures found in MAFLD-driven HCC patients. We also critically review current rodent models suggested for MAFLD-driven HCC study.
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Affiliation(s)
- Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of MedicineUniversity of California San DiegoLa JollaCAUSA
| | - Ju Youn Kim
- Department of Molecular and Life ScienceHanyang University ERICAAnsanKorea
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Martí-Carvajal AJ, Gemmato-Valecillos MA, Monge Martín D, Dayer M, Alegría-Barrero E, De Sanctis JB, Parise Vasco JM, Riera Lizardo RJ, Nicola S, Martí-Amarista CE, Correa-Pérez A. Interleukin-receptor antagonist and tumour necrosis factor inhibitors for the primary and secondary prevention of atherosclerotic cardiovascular diseases. Cochrane Database Syst Rev 2024; 9:CD014741. [PMID: 39297531 PMCID: PMC11411914 DOI: 10.1002/14651858.cd014741.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/21/2024]
Abstract
BACKGROUND Atherosclerotic cardiovascular disease (ACVD) is worsened by chronic inflammatory diseases. Interleukin receptor antagonists (IL-RAs) and tumour necrosis factor-alpha (TNF) inhibitors have been studied to see if they can prevent cardiovascular events. OBJECTIVES The purpose of this study was to assess the clinical benefits and harms of IL-RAs and TNF inhibitors in the primary and secondary prevention of ACVD. SEARCH METHODS The Cochrane Heart Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, EBSCO CINAHL plus, and clinical trial registries for ongoing and unpublished studies were searched in February 2024. The reference lists of relevant studies, reviews, meta-analyses and health technology reports were searched to identify additional studies. No limitations on language, date of publication or study type were set. SELECTION CRITERIA RCTs that recruited people with and without pre-existing ACVD, comparing IL-RAs or TNF inhibitors versus placebo or usual care, were selected. The primary outcomes considered were all-cause mortality, myocardial infarction, unstable angina, and adverse events. DATA COLLECTION AND ANALYSIS Two or more review authors, working independently at each step, selected studies, extracted data, assessed the risk of bias and used GRADE to judge the certainty of evidence. MAIN RESULTS We included 58 RCTs (22,053 participants; 21,308 analysed), comparing medication efficacy with placebo or usual care. Thirty-four trials focused on primary prevention and 24 on secondary prevention. The interventions included IL-1 RAs (anakinra, canakinumab), IL-6 RA (tocilizumab), TNF-inhibitors (etanercept, infliximab) compared with placebo or usual care. The certainty of evidence was low to very low due to biases and imprecision; all trials had a high risk of bias. Primary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality(RR 0.33, 95% CI 0.01 to 7.58, 1 trial), myocardial infarction (RR 0.71, 95% CI 0.04 to 12.48, I² = 39%, 2 trials), unstable angina (RR 0.24, 95% CI 0.03 to 2.11, I² = 0%, 2 trials), stroke (RR 2.42, 95% CI 0.12 to 50.15; 1 trial), adverse events (RR 0.85, 95% CI 0.59 to 1.22, I² = 54%, 3 trials), or infection (rate ratio 0.84, 95% 0.55 to 1.29, I² = 0%, 4 trials). Evidence is very uncertain about whether anakinra and cankinumab may reduce heart failure (RR 0.21, 95% CI 0.05 to 0.94, I² = 0%, 3 trials). Peripheral vascular disease (PVD) was not reported as an outcome. IL-6 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.68, 95% CI 0.12 to 3.74, I² = 30%, 3 trials), myocardial infarction (RR 0.27, 95% CI 0.04 to1.68, I² = 0%, 3 trials), heart failure (RR 1.02, 95% CI 0.11 to 9.63, I² = 0%, 2 trials), PVD (RR 2.94, 95% CI 0.12 to 71.47, 1 trial), stroke (RR 0.34, 95% CI 0.01 to 8.14, 1 trial), or any infection (rate ratio 1.10, 95% CI: 0.88 to 1.37, I2 = 18%, 5 trials). Adverse events may increase (RR 1.13, 95% CI 1.04 to 1.23, I² = 33%, 5 trials). No trial assessed unstable angina. TNF inhibitors The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.78, 95% CI 0.63 to 4.99, I² = 10%, 3 trials), myocardial infarction (RR 2.61, 95% CI 0.11 to 62.26, 1 trial), stroke (RR 0.46, 95% CI 0.08 to 2.80, I² = 0%; 3 trials), heart failure (RR 0.85, 95% CI 0.06 to 12.76, 1 trial). Adverse events may increase (RR 1.13, 95% CI 1.01 to 1.25, I² = 51%, 13 trials). No trial assessed unstable angina or PVD. Secondary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.94, 95% CI 0.84 to 1.06, I² = 0%, 8 trials), unstable angina (RR 0.88, 95% CI 0.65 to 1.19, I² = 0%, 3 trials), PVD (RR 0.85, 95% CI 0.19 to 3.73, I² = 38%, 3 trials), stroke (RR 0.94, 95% CI 0.74 to 1.2, I² = 0%; 7 trials), heart failure (RR 0.91, 95% 0.5 to 1.65, I² = 0%; 7 trials), or adverse events (RR 0.92, 95% CI 0.78 to 1.09, I² = 3%, 4 trials). There may be little to no difference between the groups in myocardial infarction (RR 0.88, 95% CI 0.0.75 to 1.04, I² = 0%, 6 trials). IL6-RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.09, 95% CI 0.61 to 1.96, I² = 0%, 2 trials), myocardial infarction (RR 0.46, 95% CI 0.07 to 3.04, I² = 45%, 3 trials), unstable angina (RR 0.33, 95% CI 0.01 to 8.02, 1 trial), stroke (RR 1.03, 95% CI 0.07 to 16.25, 1 trial), adverse events (RR 0.89, 95% CI 0.76 to 1.05, I² = 0%, 2 trials), or any infection (rate ratio 0.66, 95% CI 0.32 to 1.36, I² = 0%, 4 trials). No trial assessed PVD or heart failure. TNF inhibitors The evidence is very uncertain about the effect of the intervention on all-cause mortality (RR 1.16, 95% CI 0.69 to 1.95, I² = 47%, 5 trials), heart failure (RR 0.92, 95% 0.75 to 1.14, I² = 0%, 4 trials), or adverse events (RR 1.15, 95% CI 0.84 to 1.56, I² = 32%, 2 trials). No trial assessed myocardial infarction, unstable angina, PVD or stroke. Adverse events may be underestimated and benefits inflated due to inadequate reporting. AUTHORS' CONCLUSIONS This Cochrane review assessed the benefits and harms of using interleukin-receptor antagonists and tumour necrosis factor inhibitors for primary and secondary prevention of atherosclerotic diseases compared with placebo or usual care. However, the evidence for the predetermined outcomes was deemed low or very low certainty, so there is still a need to determine whether these interventions provide clinical benefits or cause harm from this perspective. In summary, the different biases and imprecision in the included studies limit their external validity and represent a limitation to determining the effectiveness of the intervention for both primary and secondary prevention of ACVD.
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Key Words
- humans
- angina, unstable
- angina, unstable/mortality
- angina, unstable/prevention & control
- antibodies, monoclonal, humanized
- antibodies, monoclonal, humanized/administration & dosage
- antibodies, monoclonal, humanized/adverse effects
- atherosclerosis
- atherosclerosis/mortality
- atherosclerosis/prevention & control
- bias
- cause of death
- myocardial infarction
- myocardial infarction/mortality
- myocardial infarction/prevention & control
- primary prevention
- primary prevention/methods
- randomized controlled trials as topic
- receptors, interleukin-1
- receptors, interleukin-1/antagonists & inhibitors
- secondary prevention
- secondary prevention/methods
- tumor necrosis factor-alpha
- tumor necrosis factor-alpha/antagonists & inhibitors
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Affiliation(s)
- Arturo J Martí-Carvajal
- Universidad UTE, Facultad de Ciencias de la Salud Eugenio Espejo, Centro Asociado Cochrane Ecuador, Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC), Quito, Ecuador
- Facultad de Medicina (Centro Cochrane Madrid), Universidad Francisco de Vitoria, Madrid, Spain
- Cátedra Rectoral de Medicina Basada en la Evidencia, Universidad de Carabobo, Valencia , Venezuela
| | - Mario A Gemmato-Valecillos
- Icahn School of Medicine at Mount Sinai/ NYCHH Elmhurst Hospital Center, 79-01 Broadway, Elmhurst, New York 11373, USA
| | | | - Mark Dayer
- Cardiovascular Research Institute, Mater Private Network, Dublin, Ireland
- Faculty of Health, University of Plymouth, Plymouth, UK
| | | | - Juan Bautista De Sanctis
- Institute of Molecular and Translational Medicine, Palacky University, Faculty of Medicine and Dentistry, Olomouc, Czech Republic
| | - Juan Marcos Parise Vasco
- Universidad UTE, Facultad de Ciencias de la Salud Eugenio Espejo, Centro Asociado Cochrane Ecuador, Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC), Quito, Ecuador
| | - Ricardo J Riera Lizardo
- Cátedra Rectoral de Medicina Basada en la Evidencia, Universidad de Carabobo, Valencia, Venezuela
| | - Susana Nicola
- Universidad UTE, Facultad de Ciencias de la Salud Eugenio Espejo, Centro Asociado Cochrane Ecuador, Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC), Quito, Ecuador
| | | | - Andrea Correa-Pérez
- Faculty of Medicine, Universidad Francisco de Vitoria, Madrid, Spain
- Hospital Pharmacy and Medical Devices Department, Hospital Central de la Defensa "Gómez Ulla" CSVE, Madrid, Spain
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Rosen ED, Kajimura S. Is it time to rethink the relationship between adipose inflammation and insulin resistance? J Clin Invest 2024; 134:e184663. [PMID: 39225103 PMCID: PMC11364379 DOI: 10.1172/jci184663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024] Open
Affiliation(s)
- Evan D. Rosen
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Shingo Kajimura
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
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Varra FN, Varras M, Varra VK, Theodosis-Nobelos P. Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation‑mediating treatment options (Review). Mol Med Rep 2024; 29:95. [PMID: 38606791 PMCID: PMC11025031 DOI: 10.3892/mmr.2024.13219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 01/17/2024] [Indexed: 04/13/2024] Open
Abstract
Obesity reaches up to epidemic proportions globally and increases the risk for a wide spectrum of co‑morbidities, including type‑2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular diseases, non‑alcoholic fatty liver disease, kidney diseases, respiratory disorders, sleep apnea, musculoskeletal disorders and osteoarthritis, subfertility, psychosocial problems and certain types of cancers. The underlying inflammatory mechanisms interconnecting obesity with metabolic dysfunction are not completely understood. Increased adiposity promotes pro‑inflammatory polarization of macrophages toward the M1 phenotype, in adipose tissue (AT), with subsequent increased production of pro‑inflammatory cytokines and adipokines, inducing therefore an overall, systemic, low‑grade inflammation, which contributes to metabolic syndrome (MetS), insulin resistance (IR) and T2DM. Targeting inflammatory mediators could be alternative therapies to treat obesity, but their safety and efficacy remains to be studied further and confirmed in future clinical trials. The present review highlights the molecular and pathophysiological mechanisms by which the chronic low‑grade inflammation in AT and the production of reactive oxygen species lead to MetS, IR and T2DM. In addition, focus is given on the role of anti‑inflammatory agents, in the resolution of chronic inflammation, through the blockade of chemotactic factors, such as monocytes chemotractant protein‑1, and/or the blockade of pro‑inflammatory mediators, such as IL‑1β, TNF‑α, visfatin, and plasminogen activator inhibitor‑1, and/or the increased synthesis of adipokines, such as adiponectin and apelin, in obesity‑associated metabolic dysfunction.
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Affiliation(s)
- Fani-Niki Varra
- Department of Pharmacy, School of Health Sciences, Frederick University, Nicosia 1036, Cyprus
- Medical School, Dimocritus University of Thrace, Alexandroupolis 68100, Greece
| | - Michail Varras
- Fourth Department of Obstetrics and Gynecology, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece
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Kalantar GH, Saraswat S, SantaCruz-Calvo S, Gholamrezaeinejad F, Javidan A, Agrawal M, Liu R, Kern PA, Zhang XD, Nikolajczyk BS. Fasting and Glucose Metabolism Differentially Impact Peripheral Inflammation in Human Type 2 Diabetes. Nutrients 2024; 16:1404. [PMID: 38794641 PMCID: PMC11124302 DOI: 10.3390/nu16101404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/21/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024] Open
Abstract
Cytokines produced by peripheral T-helper 1/17 cells disproportionately contribute to the inflammation (i.e., metaflammation) that fuels type 2 diabetes (T2D) pathogenesis. Shifts in the nutrient milieu could influence inflammation through changes in T-cell metabolism. We aimed to determine whether changes in glucose utilization alter cytokine profiles in T2D. Peripheral blood mononuclear cells (PBMCs), CD4+ T-cells, and CD4+CD25- T-effector (Teff) cells were isolated from age-matched humans classified by glycemic control and BMI. Cytokines secreted by CD3/CD28-stimulated PBMCs and Teff were measured in supernatants with multiplex cytokine assays and a FLEXMAP-3D. Metabolic activity of stimulated CD4+ T-cells was measured by a Seahorse XFe96 analyzer. In this study, we demonstrated that T-cell stimulated PBMCs from non-fasted people with T2D produced higher amounts of cytokines compared to fasting. Although dysglycemia characterizes T2D, cytokine production by PBMCs or CD4+ T-cells in T2D was unaltered by hyperglycemic media. Moreover, pharmacological suppression of mitochondrial glucose oxidation did not change T-cell metabolism in T2D, yet enhanced cytokine competency. In conclusion, fasting and glucose metabolism differentially impact peripheral inflammation in human T2D, suggesting that glucose, along with fatty acid metabolites per our previous work, partner to regulate metaflammation. These data expose a major disconnect in the use of glycemic control drugs to target T2D-associated metaflammation.
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Affiliation(s)
- Gabriella H. Kalantar
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA;
| | - Shubh Saraswat
- Department of Biostatistics, University of Kentucky, Lexington, KY 40536, USA; (S.S.); (X.D.Z.)
| | - Sara SantaCruz-Calvo
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA (F.G.); (A.J.)
| | - Fatemeh Gholamrezaeinejad
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA (F.G.); (A.J.)
| | - Aida Javidan
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA (F.G.); (A.J.)
| | - Madhur Agrawal
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA (F.G.); (A.J.)
| | - Rui Liu
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA
| | - Philip A. Kern
- Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA;
- Barnstable Brown Diabetes and Obesity Research Center, University of Kentucky, Lexington, KY 40536, USA
| | - Xiaohua Douglas Zhang
- Department of Biostatistics, University of Kentucky, Lexington, KY 40536, USA; (S.S.); (X.D.Z.)
| | - Barbara S. Nikolajczyk
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA;
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA (F.G.); (A.J.)
- Barnstable Brown Diabetes and Obesity Research Center, University of Kentucky, Lexington, KY 40536, USA
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Nicholas DA, Mbongue JC, Garcia-Pérez D, Sorensen D, Ferguson Bennit H, De Leon M, Langridge WHR. Exploring the Interplay between Fatty Acids, Inflammation, and Type 2 Diabetes. IMMUNO 2024; 4:91-107. [PMID: 39606781 PMCID: PMC11600342 DOI: 10.3390/immuno4010006] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024] Open
Abstract
Around 285 million people worldwide currently have type 2 diabetes and it is projected that this number will be surpassed by 2030. Therefore, it is of the utmost importance to enhance our comprehension of the disease's development. The regulation of diet, obesity, and inflammation in type 2 diabetes is believed to play a crucial role in enhancing insulin sensitivity and reducing the risk of onset diabetes. Obesity leads to an increase in visceral adipose tissue, which is a prominent site of inflammation in type 2 diabetes. Dyslipidemia, on the other hand, plays a significant role in attracting activated immune cells such as macrophages, dendritic cells, T cells, NK cells, and B cells to visceral adipose tissue. These immune cells are a primary source of pro-inflammatory cytokines that are believed to promote insulin resistance. This review delves into the influence of elevated dietary free saturated fatty acids and examines the cellular and molecular factors associated with insulin resistance in the initiation of inflammation induced by obesity. Furthermore, it explores novel concepts related to diet-induced inflammation and its relationship with type 2 diabetes.
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Affiliation(s)
- Dequina A. Nicholas
- School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA
| | - Jacques C. Mbongue
- Department of Biological Sciences, School of Arts and Sciences, Oakwood University, Huntsville, AL 35896, USA
| | - Darysbel Garcia-Pérez
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
- Division of Molecular Genetics and Microbiology, School of Medicine Alumni Hall, Loma Linda University, Rm 102, 11021 Campus Street, Loma Linda, CA 92350, USA
| | - Dane Sorensen
- Center for Perinatal Biology, Division of Physiology, Loma Linda School of Medicine, Rm A572, 11234 Anderson Street, Loma Linda, CA 92350, USA
| | - Heather Ferguson Bennit
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
| | - Marino De Leon
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
| | - William H. R. Langridge
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
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Kueck PJ, Morris JK, Stanford JA. Current Perspectives: Obesity and Neurodegeneration - Links and Risks. Degener Neurol Neuromuscul Dis 2023; 13:111-129. [PMID: 38196559 PMCID: PMC10774290 DOI: 10.2147/dnnd.s388579] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 12/21/2023] [Indexed: 01/11/2024] Open
Abstract
Obesity is increasing in prevalence across all age groups. Long-term obesity can lead to the development of metabolic and cardiovascular diseases through its effects on adipose, skeletal muscle, and liver tissue. Pathological mechanisms associated with obesity include immune response and inflammation as well as oxidative stress and consequent endothelial and mitochondrial dysfunction. Recent evidence links obesity to diminished brain health and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Both AD and PD are associated with insulin resistance, an underlying syndrome of obesity. Despite these links, causative mechanism(s) resulting in neurodegenerative disease remain unclear. This review discusses relationships between obesity, AD, and PD, including clinical and preclinical findings. The review then briefly explores nonpharmacological directions for intervention.
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Affiliation(s)
- Paul J Kueck
- Department of Neurology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Jill K Morris
- Department of Neurology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
- University of Kansas Alzheimer’s Disease Research Center, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - John A Stanford
- University of Kansas Alzheimer’s Disease Research Center, University of Kansas Medical Center, Kansas City, KS, 66160, USA
- Landon Center on Aging, University of Kansas Medical Center, Kansas City, KS, 66160, USA
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9
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de Baat A, Trinh B, Ellingsgaard H, Donath MY. Physiological role of cytokines in the regulation of mammalian metabolism. Trends Immunol 2023:S1471-4906(23)00110-2. [PMID: 37423882 DOI: 10.1016/j.it.2023.06.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 06/09/2023] [Accepted: 06/09/2023] [Indexed: 07/11/2023]
Abstract
The innate cytokine system is involved in the response to excessive food intake. In this review, we highlight recent advances in our understanding of the physiological role of three prominent cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF), in mammalian metabolic regulation. This recent research highlights the pleiotropic and context-dependent functions in the immune-metabolic interplay. IL-1β is activated in response to overloaded mitochondrial metabolism, stimulates insulin secretion, and allocates energy to immune cells. IL-6 is released by contracting skeletal muscle and adipose tissue and directs energy from storing tissues to consuming tissues. TNF induces insulin resistance and prevents ketogenesis. Additionally, the therapeutic potential of modulating the activity of each cytokine is discussed.
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Affiliation(s)
- Axel de Baat
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Beckey Trinh
- The Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | - Helga Ellingsgaard
- The Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | - Marc Y Donath
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland.
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10
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Würfel M, Blüher M, Stumvoll M, Ebert T, Kovacs P, Tönjes A, Breitfeld J. Adipokines as Clinically Relevant Therapeutic Targets in Obesity. Biomedicines 2023; 11:biomedicines11051427. [PMID: 37239098 DOI: 10.3390/biomedicines11051427] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/04/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Adipokines provide an outstanding role in the comprehensive etiology of obesity and may link adipose tissue dysfunction to further metabolic and cardiovascular complications. Although several adipokines have been identified in terms of their physiological roles, many regulatory circuits remain unclear and translation from experimental studies to clinical applications has yet to occur. Nevertheless, due to their complex metabolic properties, adipokines offer immense potential for their use both as obesity-associated biomarkers and as relevant treatment strategies for overweight, obesity and metabolic comorbidities. To provide an overview of the current clinical use of adipokines, this review summarizes clinical studies investigating the potential of various adipokines with respect to diagnostic and therapeutic treatment strategies for obesity and linked metabolic disorders. Furthermore, an overview of adipokines, for which a potential for clinical use has been demonstrated in experimental studies to date, will be presented. In particular, promising data revealed that fibroblast growth factor (FGF)-19, FGF-21 and leptin offer great potential for future clinical application in the treatment of obesity and related comorbidities. Based on data from animal studies or other clinical applications in addition to obesity, adipokines including adiponectin, vaspin, resistin, chemerin, visfatin, bone morphogenetic protein 7 (BMP-7) and tumor necrosis factor alpha (TNF-α) provide potential for human clinical application.
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Affiliation(s)
- Marleen Würfel
- Department of Medicine III, Division of Endocrinology, Nephrology and Rheumatology, University of Leipzig, Liebigstr. 18, 04103 Leipzig, Germany
| | - Matthias Blüher
- Department of Medicine III, Division of Endocrinology, Nephrology and Rheumatology, University of Leipzig, Liebigstr. 18, 04103 Leipzig, Germany
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), Helmholtz Center Munich at the University of Leipzig and the University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Michael Stumvoll
- Department of Medicine III, Division of Endocrinology, Nephrology and Rheumatology, University of Leipzig, Liebigstr. 18, 04103 Leipzig, Germany
| | - Thomas Ebert
- Department of Medicine III, Division of Endocrinology, Nephrology and Rheumatology, University of Leipzig, Liebigstr. 18, 04103 Leipzig, Germany
| | - Peter Kovacs
- Department of Medicine III, Division of Endocrinology, Nephrology and Rheumatology, University of Leipzig, Liebigstr. 18, 04103 Leipzig, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Anke Tönjes
- Department of Medicine III, Division of Endocrinology, Nephrology and Rheumatology, University of Leipzig, Liebigstr. 18, 04103 Leipzig, Germany
| | - Jana Breitfeld
- Department of Medicine III, Division of Endocrinology, Nephrology and Rheumatology, University of Leipzig, Liebigstr. 18, 04103 Leipzig, Germany
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11
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Chavakis T, Alexaki VI, Ferrante AW. Macrophage function in adipose tissue homeostasis and metabolic inflammation. Nat Immunol 2023; 24:757-766. [PMID: 37012544 DOI: 10.1038/s41590-023-01479-0] [Citation(s) in RCA: 71] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 01/23/2023] [Indexed: 04/05/2023]
Abstract
Obesity-related metabolic organ inflammation contributes to cardiometabolic disorders. In obese individuals, changes in lipid fluxes and storage elicit immune responses in the adipose tissue (AT), including expansion of immune cell populations and qualitative changes in the function of these cells. Although traditional models of metabolic inflammation posit that these immune responses disturb metabolic organ function, studies now suggest that immune cells, especially AT macrophages (ATMs), also have important adaptive functions in lipid homeostasis in states in which the metabolic function of adipocytes is taxed. Adverse consequences of AT metabolic inflammation might result from failure to maintain local lipid homeostasis and long-term effects on immune cells beyond the AT. Here we review the complex function of ATMs in AT homeostasis and metabolic inflammation. Additionally, we hypothesize that trained immunity, which involves long-term functional adaptations of myeloid cells and their bone marrow progenitors, can provide a model by which metabolic perturbations trigger chronic systemic inflammation.
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Affiliation(s)
- Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
- Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
| | - Vasileia Ismini Alexaki
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Anthony W Ferrante
- Department of Medicine, Institute of Human Nutrition, Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
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12
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Ramser A, Dridi S. Hormonal regulation of visfatin and adiponectin system in quail muscle cells. Comp Biochem Physiol A Mol Integr Physiol 2023; 281:111425. [PMID: 37044369 DOI: 10.1016/j.cbpa.2023.111425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/08/2023] [Accepted: 04/08/2023] [Indexed: 04/14/2023]
Abstract
Visfatin and adiponectin are two adipokines known to regulate energy homeostasis and stress response within different peripheral tissues. Their role and regulation in highly metabolically active tissue such as the muscle is of particular interest. As modern poultry exhibit insulin resistance, obesity, and hyperglycemia along with a lack of insight into the regulation of these avian adipokines, we undertook the present work to determine the regulation of visfatin and adiponectin system by cytokines and obesity-related hormones in a relevant in vitro model of avian muscle, quail muscle (QM7) cells. Cells were treated with pro-inflammatory cytokine IL-6 (5 and 10 ng/mL) and TNFα (5 and 10 ng/mL), as well as leptin (10 and 100 ng/mL) and both orexin-A and orexin-B (ORX-A/B) (5 and 10 ng/mL). Results showed significant increases in visfatin mRNA abundance under both cytokines (IL-6 and TNFα), and down regulation with ORX-B treatment. Adiponectin expression was also upregulated by pro-inflammatory cytokines (IL-6 and TNFα), but down regulated by leptin, ORX-A, and ORXB. High doses of IL-6 and TNFα up regulated the expression of adiponectin receptors AdipoR1 and AdipoR2, respectively. Leptin and orexin treatments also down regulated both AdipoR1 and AdipoR2 expression. Taken together, this is the first report showing a direct response of visfatin and the adiponectin system to pro-inflammatory and obesity-related hormones in avian muscle cells.
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Affiliation(s)
- Alison Ramser
- University of Arkansas, Center of Excellence for Poultry Science, Fayetteville, AR 72701, USA
| | - Sami Dridi
- University of Arkansas, Center of Excellence for Poultry Science, Fayetteville, AR 72701, USA.
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13
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Abu Rached N, Gambichler T, Ocker L, Dietrich JW, Quast DR, Sieger C, Seifert C, Scheel C, Bechara FG. Screening for Diabetes Mellitus in Patients with Hidradenitis Suppurativa—A Monocentric Study in Germany. Int J Mol Sci 2023; 24:ijms24076596. [PMID: 37047569 PMCID: PMC10094965 DOI: 10.3390/ijms24076596] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/05/2023] Open
Abstract
Hidradenitis suppurativa (HS) is a chronic skin disease that is often associated with metabolic disorders. Diabetes mellitus (DM) is a frequent comorbidity in HS. There is currently no established screening for DM in HS patients. The aim of our study was to identify high-risk groups of HS patients that develop DM and to assess the frequency of different types of DM present in HS patients. To do so, we conducted a monocentric study in 99 patients with HS. All patients underwent detailed clinical and laboratory assessments, including the determination of glycated hemoglobin. Among the 20.2% of patients that presented with DM, type 2 was by far the most prevalent (19 out of 20 patients). Moreover, male gender, age, BMI, Hurley stage, modified Hidradenitis Suppurativa Score (mHSS), DLQI and hypertension all correlated with the glycated hemoglobin levels in the HS patients. In the multivariable analysis, Hurley stage III, older age, and higher BMI were significantly associated with DM. Specifically, patients at Hurley stage III were at a 5.3-fold increased risk of having DM type II compared to patients at earlier Hurley stages. Since many of the HS patients had not been diagnosed, our study reveals shortcomings in the screening for DM and suggest that this should be routinely performed in HS patients at high risk to avoid secondary complications.
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Affiliation(s)
- Nessr Abu Rached
- International Centre for Hidradenitis Suppurativa/Acne Inversa, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Thilo Gambichler
- International Centre for Hidradenitis Suppurativa/Acne Inversa, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Lennart Ocker
- International Centre for Hidradenitis Suppurativa/Acne Inversa, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Johannes W. Dietrich
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef Hospital, Ruhr University Bochum, NRW, Gudrunstr. 56, 44791 Bochum, Germany
- Diabetes Centre Bochum-Hattingen, St. Elisabeth-Hospital Blankenstein, Im Vogelsang 5-11, 45527 Hattingen, Germany
- Centre for Rare Endocrine Diseases, Ruhr Centre for Rare Diseases (CeSER), Ruhr University Bochum and Witten/Herdecke University, Alexandrinenstr. 5, 44791 Bochum, Germany
- Centre for Diabetes Technology, Catholic Hospitals Bochum, Gudrunstr. 56, 44791 Bochum, Germany
| | - Daniel R. Quast
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef Hospital, Ruhr University Bochum, NRW, Gudrunstr. 56, 44791 Bochum, Germany
- Diabetes Centre Bochum-Hattingen, St. Elisabeth-Hospital Blankenstein, Im Vogelsang 5-11, 45527 Hattingen, Germany
- Centre for Diabetes Technology, Catholic Hospitals Bochum, Gudrunstr. 56, 44791 Bochum, Germany
| | - Christina Sieger
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef Hospital, Ruhr University Bochum, NRW, Gudrunstr. 56, 44791 Bochum, Germany
- Diabetes Centre Bochum-Hattingen, St. Elisabeth-Hospital Blankenstein, Im Vogelsang 5-11, 45527 Hattingen, Germany
- Centre for Diabetes Technology, Catholic Hospitals Bochum, Gudrunstr. 56, 44791 Bochum, Germany
| | - Caroline Seifert
- International Centre for Hidradenitis Suppurativa/Acne Inversa, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Christina Scheel
- International Centre for Hidradenitis Suppurativa/Acne Inversa, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Falk G. Bechara
- International Centre for Hidradenitis Suppurativa/Acne Inversa, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, 44791 Bochum, Germany
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14
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Arefin A, Gage MC. Metformin, Empagliflozin, and Their Combination Modulate Ex-Vivo Macrophage Inflammatory Gene Expression. Int J Mol Sci 2023; 24:ijms24054785. [PMID: 36902218 PMCID: PMC10003317 DOI: 10.3390/ijms24054785] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 02/09/2023] [Accepted: 02/23/2023] [Indexed: 03/06/2023] Open
Abstract
Type-2 Diabetes Mellitus is a complex, chronic illness characterized by persistent high blood glucose levels. Patients can be prescribed anti-diabetes drugs as single agents or in combination depending on the severity of their condition. Metformin and empagliflozin are two commonly prescribed anti-diabetes drugs which reduce hyperglycemia, however their direct effects on macrophage inflammatory responses alone or in combination are unreported. Here, we show that metformin and empagliflozin elicit proinflammatory responses on mouse bone-marrow-derived macrophages with single agent challenge, which are modulated when added in combination. In silico docking experiments suggested that empagliflozin can interact with both TLR2 and DECTIN1 receptors, and we observed that both empagliflozin and metformin increase expression of Tlr2 and Clec7a. Thus, findings from this study suggest that metformin and empagliflozin as single agents or in combination can directly modulate inflammatory gene expression in macrophages and upregulate the expression of their receptors.
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Affiliation(s)
- Adittya Arefin
- Wolfson Institute for Biomedical Research, Division of Medicine, University College London, Gower Street, London WC1E 6BT, UK
| | - Matthew C. Gage
- Department of Comparative Biomedical Sciences, Royal Veterinary College, 4 Royal College Street, London NW1 0TU, UK
- Correspondence:
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15
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Braga-Basaria M, Travison TG, Taplin ME, Lin A, Dufour AB, Habtemariam D, Nguyen PL, Kibel AS, Ravi P, Bearup R, Kackley H, Kafel H, Reid K, Storer T, Simonson DC, McDonnell M, Basaria S. Gaining metabolic insight in older men undergoing androgen deprivation therapy for prostate cancer (the ADT & Metabolism Study): Protocol of a longitudinal, observational, cohort study. PLoS One 2023; 18:e0281508. [PMID: 36763576 PMCID: PMC9916640 DOI: 10.1371/journal.pone.0281508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 01/24/2023] [Indexed: 02/11/2023] Open
Abstract
Androgen deprivation therapy (ADT), a cornerstone of treatment for patients with locally advanced and metastatic prostate cancer, is associated with many adverse effects, including osteoporosis, sexual dysfunction, fatigue, and vasomotor symptoms. It is also associated with loss of muscle mass and increased adiposity. This change in body composition is likely the inciting event in the development of insulin resistance, an independent risk factor for diabetes mellitus and cardiovascular disease. Although the occurrence of insulin resistance during ADT has been reported, it remains unclear whether this insulin resistance is primarily hepatic or muscular. Similarly, the mechanisms that lead to insulin resistance also remain unknown. The ADT & Metabolism Study was designed to address these knowledge gaps, as the elucidation of the predominant site of insulin resistance will allow prevention strategies and the use of targeted, tissue-specific insulin-sensitizing agents in patients undergoing ADT. This prospective, mechanistic, single-center, 24-week, observational cohort study will enroll treatment-naïve adult men with prostate cancer about to undergo surgical or medical ADT for at least 24 weeks (ADT group; n = 50) and a control group of men who had undergone radical prostatectomy and are in remission (non-ADT group, n = 25). The primary outcome is to determine the site of insulin resistance (skeletal muscle or liver) using frequent sampling oral glucose tolerance test at baseline and 12 and 24 weeks after commencement of ADT (ADT group) or after enrollment in the study (non-ADT group). Secondary outcomes will assess changes in hepatic and intramyocellular fat (using magnetic resonance spectroscopy), inflammatory markers, adipokines, free fatty acids, and changes in body composition (assessed using dual-energy x-ray absorptiometry) and their correlation with the development of insulin resistance. Exploratory outcomes will include changes in muscle performance, physical function, physical activity, vitality, and sexual drive.
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Affiliation(s)
- Milena Braga-Basaria
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Thomas G. Travison
- Department of Medicine, Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Mary-Ellen Taplin
- Lank Center for Genitourinary Oncology and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Alexander Lin
- Department of Radiology, Center for Clinical Spectroscopy, Brigham and Women’s Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Alyssa B. Dufour
- Department of Medicine, Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Daniel Habtemariam
- Department of Medicine, Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Paul L. Nguyen
- Department of Radiation Oncology, Brigham and Women’s Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Adam S. Kibel
- Division of Urology, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Praful Ravi
- Lank Center for Genitourinary Oncology and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Richelle Bearup
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Hannah Kackley
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Hussein Kafel
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Kieran Reid
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Thomas Storer
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Donald C. Simonson
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Marie McDonnell
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Shehzad Basaria
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
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16
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Johnston EK, Abbott RD. Adipose Tissue Paracrine-, Autocrine-, and Matrix-Dependent Signaling during the Development and Progression of Obesity. Cells 2023; 12:407. [PMID: 36766750 PMCID: PMC9913478 DOI: 10.3390/cells12030407] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/19/2023] [Accepted: 01/23/2023] [Indexed: 01/27/2023] Open
Abstract
Obesity is an ever-increasing phenomenon, with 42% of Americans being considered obese (BMI ≥ 30) and 9.2% being considered morbidly obese (BMI ≥ 40) as of 2016. With obesity being characterized by an abundance of adipose tissue expansion, abnormal tissue remodeling is a typical consequence. Importantly, this pathological tissue expansion is associated with many alterations in the cellular populations and phenotypes within the tissue, lending to cellular, paracrine, mechanical, and metabolic alterations that have local and systemic effects, including diabetes and cardiovascular disease. In particular, vascular dynamics shift during the progression of obesity, providing signaling cues that drive metabolic dysfunction. In this review, paracrine-, autocrine-, and matrix-dependent signaling between adipocytes and endothelial cells is discussed in the context of the development and progression of obesity and its consequential diseases, including adipose fibrosis, diabetes, and cardiovascular disease.
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Affiliation(s)
| | - Rosalyn D. Abbott
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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17
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Okdahl T, Wegeberg AM, Pociot F, Brock B, Størling J, Brock C. Low-grade inflammation in type 2 diabetes: a cross-sectional study from a Danish diabetes outpatient clinic. BMJ Open 2022; 12:e062188. [PMID: 36517105 PMCID: PMC9756179 DOI: 10.1136/bmjopen-2022-062188] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES To investigate low-grade inflammation in type 2 diabetes and explore associations to clinical aspects as well as microvascular and macrovascular complications. DESIGN Cross-sectional analysis. SETTING The outpatient diabetes clinic at the Department of Endocrinology at Aalborg University Hospital, Denmark. PARTICIPANTS 100 participants with type 2 diabetes confirmed by a haemoglobin A1c (HbA1c)≥6.5% for a minimum of 1 year and 21 healthy controls. OUTCOME MEASURES Serum levels of 27 inflammation-related biomarkers measured by immunoassay. Associations with microvascular and macrovascular complications, body weight, glycaemic control, medication and sex were investigated in the diabetes cohort. RESULTS Serum levels of tumour necrosis factor (TNF)-α and eotaxin were elevated in type 2 diabetes (p<0.05), while interleukin (IL)-7 was decreased (p<0.001). IL-12/IL-23p40, IL-15, macrophage-derived chemokine (MDC) and C reactive protein (CRP) levels were increased with body weight (p<0.05), while eotaxin and TNF-α were increased with elevated HbA1c levels (p<0.04). Dipeptidyl peptidase-4 inhibitor therapy was associated with lower levels of induced protein-10, MDC and thymus and activation regulated chemokine (p<0.02), while females had higher levels of MDC (p=0.027). Individuals with ≥3 diabetic complications had elevated levels of IL-6, IL-10, IL-12/IL-23p40, IL-15 and CRP compared with those with ≤3 (p<0.05). CONCLUSION The level of low-grade inflammation in type 2 diabetes is associated with obesity, glycaemic regulation, therapeutical management, sex and complications. Our results underline the importance of addressing inflammatory issues in type 2 diabetes, as these may predispose for crippling comorbidities.
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Affiliation(s)
- Tina Okdahl
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Anne-Marie Wegeberg
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Thisted Research Unit, Aalborg University Hospital Thisted, Thisted, Denmark
| | - Flemming Pociot
- Steno Diabetes Center Copenhagen, Capital Region of Denmark, Herlev, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Kobenhavn, Denmark
| | - Birgitte Brock
- Steno Diabetes Center Copenhagen, Capital Region of Denmark, Herlev, Denmark
| | - Joachim Størling
- Steno Diabetes Center Copenhagen, Capital Region of Denmark, Herlev, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Kobenhavn, Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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18
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Hassan NF, Hassan AH, El-Ansary MR. Cytokine modulation by etanercept ameliorates metabolic syndrome and its related complications induced in rats administered a high-fat high-fructose diet. Sci Rep 2022; 12:20227. [PMID: 36418417 PMCID: PMC9684438 DOI: 10.1038/s41598-022-24593-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 11/17/2022] [Indexed: 11/25/2022] Open
Abstract
The aim of the present study was to investigate the effect of etanercept (ETA)-an anti-tumor necrosis factor α (TNF-α) monoclonal antibody-on metabolic disorders such as obesity, hypertension, dyslipidemia, and insulin resistance associated with the metabolic syndrome (MS). MS was induced in rats via high-fat high-fructose (HFHF) administration for 8 weeks. Rats were divided into three groups: negative control, HFHF model, and ETA-treated groups [HFHF + ETA (0.8 mg/kg/twice weekly, subcutaneously) administered in the last 4 weeks]. ETA effectively diminished the prominent features of MS via a significant reduction in the percent body weight gain along with the modulation of adipokine levels, resulting in a significant elevation of serum adiponectin consistent with TNF-α and serum leptin level normalization. Moreover, ETA enhanced dyslipidemia and the elevated blood pressure. ETA managed the prominent features of MS and its associated complications via the downregulation of the hepatic inflammatory pathway that induces nonalcoholic steatohepatitis (NASH)-from the expression of Toll-like receptor 4, nuclear factor kappa B, and TNF-α until that of transforming growth factor-in addition to significant improvements in glucose utilization, insulin sensitivity, and liver function parameter activity and histopathological examination. ETA was effective for the treatment of all prominent features of MS and its associated complications, such as type II diabetes mellitus and NASH.
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Affiliation(s)
- Noha F. Hassan
- grid.440876.90000 0004 0377 3957Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Azza H. Hassan
- grid.7776.10000 0004 0639 9286Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - Mona R. El-Ansary
- grid.440876.90000 0004 0377 3957Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
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19
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Sheikh-Ahmad M, Nakhleh A, Riskin A, Yovanovich E, Chen-Konak L, Reut M, Saiegh L. The correlation between testosterone, inflammation and cytokine status in type-2 diabetes men. Andrologia 2022; 54:e14526. [PMID: 35796052 DOI: 10.1111/and.14526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/09/2022] [Accepted: 06/26/2022] [Indexed: 11/27/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is believed to cause hypogonadism through increasing pro-inflammatory cytokines. Tumour necrosis factor-α (TNF-α) is a primary cytokine associated with T2DM. The study explored the association between total testosterone (TT) level and cytokines status in 53 adult males, 27 T2DM (T2DM group) and 26 non-T2DM (control group). Blood samples evaluated fasting plasma glucose, HbA1c, insulin, HOMA-IR, FSH, LH, TT, prolactin, estradiol, cortisol, cortisol-binding globulin, C-reactive protein and eight cytokines (Interferon-gamma, IL-10, IL-13, IL-17A, IL-4, IL-23, IL-6, TNF-α). Data are presented as a median with interquartile interval. TT concentration was lower in the T2DM group [10.9 nmol/L (7.1-12.2) vs. 12.3 nmol/L (10.7-14.9) in control, p = 0.008]. CRP and cortisol in T2DM patients were higher than in control (p = 0.031 and 0.041 respectively). TT was negatively correlated with HOMA-IR, body mass index (BMI) and FSH (p = 0.028, 0.019 and 0.006 respectively). Multiple linear regression models showed that lower TT values were predictable by a linear combination of the independent variables: TNF-α, BMI and T2DM (p = 0.047, 0.023 and 0.019 respectively). High CRP and cortisol levels in T2DM patients suggest an inflammatory state. TT levels associated with TNF-α suggest a role of this cytokine in the aetiology of hypogonadism in T2DM patients.
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Affiliation(s)
| | - Afif Nakhleh
- Diabetes and Endocrinology Clinic, Maccabi Healthcare Services, Haifa, Israel
| | - Arieh Riskin
- Ruth & Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.,Department of Neonatology, Bnai Zion Medical Center, Haifa, Israel
| | | | | | - Maria Reut
- Institute of endocrinology, Bnai Zion Medical Center, Israel
| | - Leonard Saiegh
- Institute of endocrinology, Bnai Zion Medical Center, Israel.,Ruth & Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
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20
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Stanimirovic J, Radovanovic J, Banjac K, Obradovic M, Essack M, Zafirovic S, Gluvic Z, Gojobori T, Isenovic ER. Role of C-Reactive Protein in Diabetic Inflammation. Mediators Inflamm 2022; 2022:3706508. [PMID: 35620114 PMCID: PMC9129992 DOI: 10.1155/2022/3706508] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/20/2022] [Accepted: 04/29/2022] [Indexed: 01/08/2023] Open
Abstract
Even though type 2 diabetes mellitus (T2DM) represents a worldwide chronic health issue that affects about 462 million people, specific underlying determinants of insulin resistance (IR) and impaired insulin secretion are still unknown. There is growing evidence that chronic subclinical inflammation is a triggering factor in the origin of T2DM. Increased C-reactive protein (CRP) levels have been linked to excess body weight since adipocytes produce tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), which are pivotal factors for CRP stimulation. Furthermore, it is known that hepatocytes produce relatively low rates of CRP in physiological conditions compared to T2DM patients, in which elevated levels of inflammatory markers are reported, including CRP. CRP also participates in endothelial dysfunction, the production of vasodilators, and vascular remodeling, and increased CRP level is closely associated with vascular system pathology and metabolic syndrome. In addition, insulin-based therapies may alter CRP levels in T2DM. Therefore, determining and clarifying the underlying CRP mechanism of T2DM is imperative for novel preventive and diagnostic procedures. Overall, CRP is one of the possible targets for T2DM progression and understanding the connection between insulin and inflammation may be helpful in clinical treatment and prevention approaches.
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Affiliation(s)
- Julijana Stanimirovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Jelena Radovanovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Katarina Banjac
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Milan Obradovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Magbubah Essack
- King Abdullah University of Science and Technology (KAUST), Computer, Electrical, and Mathematical Sciences and Engineering (CEMSE) Division, Computational Bioscience Research Center (CBRC), Thuwal, Saudi Arabia
| | - Sonja Zafirovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- University Clinical-Hospital Centre Zemun-Belgrade, Clinic of Internal Medicine, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Takashi Gojobori
- King Abdullah University of Science and Technology (KAUST), Computer, Electrical, and Mathematical Sciences and Engineering (CEMSE) Division, Computational Bioscience Research Center (CBRC), Thuwal, Saudi Arabia
| | - Esma R. Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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21
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Infante M, Padilla N, Alejandro R, Caprio M, Della-Morte D, Fabbri A, Ricordi C. Diabetes-Modifying Antirheumatic Drugs: The Roles of DMARDs as Glucose-Lowering Agents. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:571. [PMID: 35629988 PMCID: PMC9143119 DOI: 10.3390/medicina58050571] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/14/2022] [Accepted: 04/18/2022] [Indexed: 02/06/2023]
Abstract
Systemic inflammation represents a shared pathophysiological mechanism which underlies the frequent clinical associations among chronic inflammatory rheumatic diseases (CIRDs), insulin resistance, type 2 diabetes (T2D), and chronic diabetes complications, including cardiovascular disease. Therefore, targeted anti-inflammatory therapies are attractive and highly desirable interventions to concomitantly reduce rheumatic disease activity and to improve glucose control in patients with CIRDs and comorbid T2D. Therapeutic approaches targeting inflammation may also play a role in the prevention of prediabetes and diabetes in patients with CIRDs, particularly in those with traditional risk factors and/or on high-dose corticosteroid therapy. Recently, several studies have shown that different disease-modifying antirheumatic drugs (DMARDs) used for the treatment of CIRDs exert antihyperglycemic properties by virtue of their anti-inflammatory, insulin-sensitizing, and/or insulinotropic effects. In this view, DMARDs are promising drug candidates that may potentially reduce rheumatic disease activity, ameliorate glucose control, and at the same time, prevent the development of diabetes-associated cardiovascular complications and metabolic dysfunctions. In light of their substantial antidiabetic actions, some DMARDs (such as hydroxychloroquine and anakinra) could be alternatively termed "diabetes-modifying antirheumatic drugs", since they may be repurposed for co-treatment of rheumatic diseases and comorbid T2D. However, there is a need for future randomized controlled trials to confirm the beneficial metabolic and cardiovascular effects as well as the safety profile of distinct DMARDs in the long term. This narrative review aims to discuss the current knowledge about the mechanisms behind the antihyperglycemic properties exerted by a variety of DMARDs (including synthetic and biologic DMARDs) and the potential use of these agents as antidiabetic medications in clinical settings.
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Affiliation(s)
- Marco Infante
- Clinical Cell Transplant Program (CCTP), Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136, USA; (R.A.); (C.R.)
- Department of Systems Medicine, Diabetes Research Institute Federation (DRIF), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
- Section of Endocrinology, UniCamillus, Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131 Rome, Italy
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Via Cola di Rienzo 28, 00192 Rome, Italy
| | - Nathalia Padilla
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Colonia Centroamérica L-823, Managua 14048, Nicaragua;
| | - Rodolfo Alejandro
- Clinical Cell Transplant Program (CCTP), Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136, USA; (R.A.); (C.R.)
| | - Massimiliano Caprio
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Roma, Via di Val Cannuta 247, 00166 Rome, Italy;
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy;
| | - David Della-Morte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy;
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
- Department of Neurology, Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, 1120 NW 14th St., Miami, FL 33136, USA
| | - Andrea Fabbri
- Department of Systems Medicine, Diabetes Research Institute Federation (DRIF), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Camillo Ricordi
- Clinical Cell Transplant Program (CCTP), Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136, USA; (R.A.); (C.R.)
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22
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Akam EY, Nuako AA, Daniel AK, Stanford FC. Racial Disparities and Cardiometabolic Risk: New Horizons of Intervention and Prevention. Curr Diab Rep 2022; 22:129-136. [PMID: 35175453 PMCID: PMC9908372 DOI: 10.1007/s11892-022-01451-6] [Citation(s) in RCA: 7] [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] [Accepted: 01/03/2022] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW Cardiometabolic diseases are a leading cause of morbidity and mortality in the USA and disproportionately impact racial and ethnic minorities. Multiple factors contribute to this disparity including genetic and socioeconomic factors, the latter of which contributes to disparities both through systemic barriers such as healthcare access and by directly impacting metabolism through epigenetics and environment-related alterations in the gut microbiome. This review will discuss advances in medicine that can be used to identify, prognosticate, and treat cardiometabolic diseases, and how these may be used to address existing disparities. RECENT FINDINGS There is growing research aimed at identifying novel cardiometabolic disease targets and expanding the use of existing pharmacotherapies based on comorbidities. Advances in metabolomics and genomics can give insight into an individual's unique biochemical profile, providing the means for earlier identification of disease and specific treatment targets. Moreover, developments in telehealth and related medical device technologies can expand access to underserved minority populations and improve control of chronic conditions such as diabetes and hypertension. Precision medicine may be integral to bridging the racial gap in cardiometabolic disease outcomes. Developments in genomics, metabolomics, wearable medical devices, and telehealth can result in personalized treatments for patients that account for the socioeconomic and genetic factors that contribute to poor health outcomes in minorities. As research in this field rapidly progresses, special efforts must be made to ensure inclusion of racial and ethnic minority populations in clinical research and equal access to all treatment modalities.
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Affiliation(s)
- Eftitan Y Akam
- Massachusetts General Hospital Department of Medicine, 55 Fruit Street, Boston, MA, 02114, USA.
- Massachusetts General Hospital Department of Pediatrics, 55 Fruit Street, Boston, MA, 02114, USA.
- Harvard Medical School, Boston, MA, 02115, USA.
| | - Akua A Nuako
- Massachusetts General Hospital Department of Medicine, 55 Fruit Street, Boston, MA, 02114, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Afkera K Daniel
- Massachusetts General Hospital Department of Medicine, 55 Fruit Street, Boston, MA, 02114, USA
- Massachusetts General Hospital Department of Pediatrics, 55 Fruit Street, Boston, MA, 02114, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Fatima Cody Stanford
- Harvard Medical School, Boston, MA, 02115, USA
- Massachusetts General Hospital, MGH Weight Center, Department of Medicine-Division of Endocrinology-Neuroendocrine, Department of Pediatrics-Division of Endocrinology, Nutrition Obesity Research Center at Harvard (NORCH), 50 Staniford Street, Boston, MA, 02114, USA
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23
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Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflammation in obesity, diabetes, and related disorders. Immunity 2022; 55:31-55. [PMID: 35021057 PMCID: PMC8773457 DOI: 10.1016/j.immuni.2021.12.013] [Citation(s) in RCA: 858] [Impact Index Per Article: 286.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 12/13/2021] [Accepted: 12/17/2021] [Indexed: 01/13/2023]
Abstract
Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), β-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders. We discuss how chronic tissue inflammation results in IR, impaired insulin secretion, glucose intolerance, and T2D and review the effect of inflammation on diabetic complications and on the relationship between T2D and other pathologies. In this context, we discuss current therapeutic options for the treatment of metabolic disease, advances in the clinic and the potential of immune-modulatory approaches.
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Affiliation(s)
- Theresa V. Rohm
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Daniel T. Meier
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland
| | - Jerrold M. Olefsky
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Marc Y. Donath
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland.,Correspondence:
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24
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SantaCruz-Calvo S, Bharath L, Pugh G, SantaCruz-Calvo L, Lenin RR, Lutshumba J, Liu R, Bachstetter AD, Zhu B, Nikolajczyk BS. Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities. Nat Rev Endocrinol 2022; 18:23-42. [PMID: 34703027 PMCID: PMC11005058 DOI: 10.1038/s41574-021-00575-1] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/17/2021] [Indexed: 02/07/2023]
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are increasing in prevalence owing to decreases in physical activity levels and a shift to diets that include addictive and/or high-calorie foods. These changes are associated with the adoption of modern lifestyles and the presence of an obesogenic environment, which have resulted in alterations to metabolism, adaptive immunity and endocrine regulation. The size and quality of adipose tissue depots in obesity, including the adipose tissue immune compartment, are critical determinants of overall health. In obesity, chronic low-grade inflammation can occur in adipose tissue that can progress to systemic inflammation; this inflammation contributes to the development of insulin resistance, T2DM and other comorbidities. An improved understanding of adaptive immune cell dysregulation that occurs during obesity and its associated metabolic comorbidities, with an appreciation of sex differences, will be critical for repurposing or developing immunomodulatory therapies to treat obesity and/or T2DM-associated inflammation. This Review critically discusses how activation and metabolic reprogramming of lymphocytes, that is, T cells and B cells, triggers the onset, development and progression of obesity and T2DM. We also consider the role of immunity in under-appreciated comorbidities of obesity and/or T2DM, such as oral cavity inflammation, neuroinflammation in Alzheimer disease and gut microbiome dysbiosis. Finally, we discuss previous clinical trials of anti-inflammatory medications in T2DM and consider the path forward.
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Affiliation(s)
- Sara SantaCruz-Calvo
- Department of Pharmacology and Nutritional Sciences and the Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA.
| | - Leena Bharath
- Department of Nutrition and Public Health, Merrimack College, North Andover, MA, USA
| | - Gabriella Pugh
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA
| | - Lucia SantaCruz-Calvo
- Department of Chemistry and Food Technology, Technical University of Madrid, Madrid, Spain
| | - Raji Rajesh Lenin
- Department of Pharmacology and Nutritional Sciences and the Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA
| | - Jenny Lutshumba
- Department of Neuroscience, University of Kentucky, Lexington, KY, USA
| | - Rui Liu
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA
| | | | - Beibei Zhu
- Department of Pharmacology and Nutritional Sciences and the Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA
| | - Barbara S Nikolajczyk
- Department of Pharmacology and Nutritional Sciences and the Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA.
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25
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Balak DMW, Piaserico S, Kasujee I. Non-Alcoholic Fatty Liver Disease (NAFLD) in Patients with Psoriasis: A Review of the Hepatic Effects of Systemic Therapies. PSORIASIS (AUCKLAND, N.Z.) 2021; 11:151-168. [PMID: 34909410 PMCID: PMC8665778 DOI: 10.2147/ptt.s342911] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022]
Abstract
There is increasing interest in the association between psoriasis and non-alcoholic fatty liver disease (NAFLD), which is a prevalent liver disease characterized by excessive fat storage and inflammation that can progress to fibrosis and cancer. Patients with psoriasis have a two-fold higher risk to develop NAFLD and a higher risk to progress to more severe liver disease. Psoriasis and NAFLD share common risk factors such as smoking, alcohol consumption, and the presence of metabolic syndrome and its component disorders. In addition, both psoriasis and NAFLD hinge upon a systemic low-grade inflammation that can lead to a vicious cycle of progressive liver damage in NAFLD as well as worsening of the underlying psoriasis. Other important shared pathophysiological pathways include peripheral insulin resistance and oxidative stress. NAFLD should receive clinical awareness as important comorbidity in psoriasis. In this review, we assess the recent literature on the epidemiological and pathophysiological relationship of psoriasis and NAFLD, discuss the clinical implications of NAFLD in psoriasis patients, and summarize the hepatotoxic and hepatoprotective potential of systemic psoriasis therapies.
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Affiliation(s)
- Deepak M W Balak
- Department of Dermatology, LangeLand Ziekenhuis, Zoetermeer, the Netherlands.,Department of Dermatology, Ghent University Hospital, Ghent, Belgium
| | - Stefano Piaserico
- Dermatology Unit, Department of Medicine, University of Padova, Padova, Italy
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26
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Murphy AJ, Febbraio MA. Immune-based therapies in cardiovascular and metabolic diseases: past, present and future. Nat Rev Immunol 2021; 21:669-679. [PMID: 34285393 DOI: 10.1038/s41577-021-00580-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2021] [Indexed: 02/02/2023]
Abstract
Cardiometabolic disorders were originally thought to be driven primarily by changes in lipid metabolism that cause the accumulation of lipids in organs, thereby impairing their function. Thus, in the setting of cardiovascular disease, statins - a class of lipid-lowering drugs - have remained the frontline therapy. In the past 20 years, seminal discoveries have revealed a central role of both the innate and adaptive immune system in driving cardiometabolic disorders. As such, it is now appreciated that immune-based interventions may have an important role in reducing death and disability from cardiometabolic disorders. However, to date, there have been a limited number of clinical trials exploring this interventional strategy. Nonetheless, elegant preclinical research suggests that immune-targeted therapies can have a major impact in treating cardiometabolic disease. Here, we discuss the history and recent advancements in the use of immunotherapies to treat cardiometabolic disorders.
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Affiliation(s)
- Andrew J Murphy
- Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
| | - Mark A Febbraio
- Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
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27
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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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28
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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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29
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Fuchs A, Samovski D, Smith GI, Cifarelli V, Farabi SS, Yoshino J, Pietka T, Chang SW, Ghosh S, Myckatyn TM, Klein S. Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease. Gastroenterology 2021; 161:968-981.e12. [PMID: 34004161 PMCID: PMC8900214 DOI: 10.1053/j.gastro.2021.05.008] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/21/2021] [Accepted: 05/06/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD. METHODS Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N = 14); (2) obese with normal IHTG content (OB-NL; N = 28); and (3) obese with NAFLD (OB-NAFLD; N = 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants. RESULTS Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes. CONCLUSIONS Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262).
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Affiliation(s)
- Anja Fuchs
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA,These authors contributed equally
| | - Dmitri Samovski
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA,These authors contributed equally
| | - Gordon I. Smith
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA,These authors contributed equally
| | - Vincenza Cifarelli
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
| | - Sarah S. Farabi
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
| | - Jun Yoshino
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
| | - Terri Pietka
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
| | - Shin-Wen Chang
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Sarbani Ghosh
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Terence M. Myckatyn
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Samuel Klein
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri.
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30
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Mondanelli G, Albini E, Orecchini E, Pallotta MT, Belladonna ML, Ricci G, Grohmann U, Orabona C. Pathogenetic Interplay Between IL-6 and Tryptophan Metabolism in an Experimental Model of Obesity. Front Immunol 2021; 12:713989. [PMID: 34394118 PMCID: PMC8361489 DOI: 10.3389/fimmu.2021.713989] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/19/2021] [Indexed: 12/12/2022] Open
Abstract
Obesity is a metabolic disease characterized by a state of chronic, low-grade inflammation and dominated by pro-inflammatory cytokines such as IL-6. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that catalyzes the first step in the kynurenine pathway by transforming l-tryptophan (Trp) into l-kynurenine (Kyn), a metabolite endowed with anti-inflammatory and immunoregulatory effects. In dendritic cells, IL-6 induces IDO1 proteasomal degradation and shuts down IDO1-mediated immunosuppressive effects. In tumor cells, IL-6 upregulates IDO1 expression and favors tumor immune escape mechanisms. To investigate the role of IDO1 and its possible relationship with IL-6 in obesity, we induced the disease by feeding mice with a high fat diet (HFD). Mice on a standard diet were used as control. Experimental obesity was associated with high IDO1 expression and Kyn levels in the stromal vascular fraction of visceral white adipose tissue (SVF WAT). IDO1-deficient mice on HFD gained less weight and were less insulin resistant as compared to wild type counterparts. Administration of tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, to mice on HFD significantly reduced weight gain, controlled adipose tissue hypertrophy, increased insulin sensitivity, and induced a better glucose tolerance. TCZ also induced a dramatic inhibition of IDO1 expression and Kyn production in the SVF WAT. Thus our data indicated that the IL-6/IDO1 axis may play a pathogenetic role in a chronic, low-grade inflammation condition, and, perhaps most importantly, IL-6R blockade may be considered a valid option for obesity treatment.
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Affiliation(s)
- Giada Mondanelli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Elisa Albini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Elena Orecchini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | | | - Giovanni Ricci
- Service Center for Pre-clinical Research, University of Perugia, Perugia, Italy
| | - Ursula Grohmann
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Ciriana Orabona
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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31
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Zhang Q, Yang M, Xiao Y, Han Y, Yang S, Sun L. Towards Better Drug Repositioning: Targeted Immunoinflammatory Therapy for Diabetic Nephropathy. Curr Med Chem 2021; 28:1003-1024. [PMID: 31701843 DOI: 10.2174/0929867326666191108160643] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/23/2019] [Accepted: 09/26/2019] [Indexed: 11/22/2022]
Abstract
Diabetic nephropathy (DN) is one of the most common and important microvascular complications of diabetes mellitus (DM). The main clinical features of DN are proteinuria and a progressive decline in renal function, which are associated with structural and functional changes in the kidney. The pathogenesis of DN is multifactorial, including genetic, metabolic, and haemodynamic factors, which can trigger a sequence of events. Controlling metabolic risks such as hyperglycaemia, hypertension, and dyslipidaemia is not enough to slow the progression of DN. Recent studies emphasized immunoinflammation as a critical pathogenic factor in the progression of DN. Therefore, targeting inflammation is considered a potential and novel treatment strategy for DN. In this review, we will briefly introduce the inflammatory process of DN and discuss the anti-inflammatory effects of antidiabetic drugs when treating DN.
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Affiliation(s)
- Qin Zhang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ying Xiao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yachun Han
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shikun Yang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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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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Rajesh Y, Sarkar D. Association of Adipose Tissue and Adipokines with Development of Obesity-Induced Liver Cancer. Int J Mol Sci 2021; 22:ijms22042163. [PMID: 33671547 PMCID: PMC7926723 DOI: 10.3390/ijms22042163] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/20/2022] Open
Abstract
Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.
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Affiliation(s)
- Yetirajam Rajesh
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Massey Cancer Center, Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA
- Correspondence: ; Tel.: +1-804-827-2339
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Ferriere A, Santa P, Garreau A, Bandopadhyay P, Blanco P, Ganguly D, Sisirak V. Self-Nucleic Acid Sensing: A Novel Crucial Pathway Involved in Obesity-Mediated Metaflammation and Metabolic Syndrome. Front Immunol 2021; 11:624256. [PMID: 33574823 PMCID: PMC7870860 DOI: 10.3389/fimmu.2020.624256] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/10/2020] [Indexed: 12/18/2022] Open
Abstract
Obesity and overweight are a global health problem affecting almost one third of the world population. There are multiple complications associated with obesity including metabolic syndrome that commonly lead to development of type II diabetes and non-alcoholic fatty liver disease. The development of metabolic syndrome and severe complications associated with obesity is attributed to the chronic low-grade inflammation that occurs in metabolic tissues such as the liver and the white adipose tissue. In recent years, nucleic acids (mostly DNA), which accumulate systemically in obese individuals, were shown to aberrantly activate innate immune responses and thus to contribute to metabolic tissue inflammation. This minireview will focus on (i) the main sources and forms of nucleic acids that accumulate during obesity, (ii) the sensing pathways required for their detection, and (iii) the key cellular players involved in this process. Fully elucidating the role of nucleic acids in the induction of inflammation induced by obesity would promote the identification of new and long-awaited therapeutic approaches to limit obesity-mediated complications.
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Affiliation(s)
| | - Pauline Santa
- CNRS-UMR 5164, Immunoconcept, Bordeaux University, Bordeaux, France
| | - Anne Garreau
- CNRS-UMR 5164, Immunoconcept, Bordeaux University, Bordeaux, France
| | - Purbita Bandopadhyay
- IICB-Translational Research Unit of Excellence, Division of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Patrick Blanco
- CNRS-UMR 5164, Immunoconcept, Bordeaux University, Bordeaux, France.,Immunology and Immunogenetic Department, Bordeaux University Hospital, Bordeaux, France
| | - Dipyaman Ganguly
- IICB-Translational Research Unit of Excellence, Division of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Vanja Sisirak
- CNRS-UMR 5164, Immunoconcept, Bordeaux University, Bordeaux, France
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Smith AD, Fan A, Qin B, Desai N, Zhao A, Shea-Donohue T. IL-25 Treatment Improves Metabolic Syndrome in High-Fat Diet and Genetic Models of Obesity. Diabetes Metab Syndr Obes 2021; 14:4875-4887. [PMID: 34992396 PMCID: PMC8710075 DOI: 10.2147/dmso.s335761] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 11/23/2021] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Endemic obesity is considered the driving force for the dramatic increase in incidence of type 2 diabetes (T2D). There is mounting evidence that chronic, low-grade inflammation driven by Th1/Th17 cells and M1 macrophages, is a critical link between obesity and insulin resistance. IL-25 promotes development of a Th2 immune response and M2 macrophages that counteract the inflammation associated with obesity and T2D. METHODS Mice were fed a high-fat diet (HFD) for 16 weeks and then treated with IL-25 or BSA as a control for 21 days. Body weight, blood glucose levels, intraperitoneal glucose tolerance, and gene expression were evaluated in mice treated with BSA or IL-25. Ob/ob mice fed a normal control diet were also treated with BSA or IL-25 and body weight and blood glucose levels were measured. Transepithelial electrical resistance and sodium-linked glucose absorption were determined in muscle-free small intestinal tissue and glucose absorption assessed in vitro in intestinal epithelial and skeletal muscle cell lines. RESULTS Administration of IL-25 to HFD fed mice reversed glucose intolerance, an effect mediated in part by reduction in SGLT-1 activity and Glut2 expression. Importantly, the improved glucose tolerance in HFD mice treated with IL-25 was maintained for several weeks post-treatment indicating long-term changes in glucose metabolism in obese mice. Glucose intolerance was also reversed by IL-25 treatment in genetically obese ob/ob mice without inducing weight loss. In vitro studies demonstrated that glucose absorption was inhibited by IL-25 treatment in the epithelial IPEC-1 cells but increased glucose absorption in the L6 skeletal muscle cells. This supports a direct cell-specific effect of IL-25 on glucose metabolism. CONCLUSION These results suggest that the IL-25 pathway may be a useful target for the treatment of metabolic syndrome.
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Affiliation(s)
- Allen D Smith
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD, USA
- Correspondence: Allen D Smith Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD, USATel +1 301-504-8577Fax +1- 301 504-9062 Email
| | - Anya Fan
- Department of Radiation Oncology University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bolin Qin
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD, USA
| | - Neemesh Desai
- Department of Radiation Oncology University of Maryland School of Medicine, Baltimore, MD, USA
| | - Aiping Zhao
- Department of Radiation Oncology University of Maryland School of Medicine, Baltimore, MD, USA
| | - Terez Shea-Donohue
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA
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Aging and Immunometabolic Adaptations to Thermogenesis. Ageing Res Rev 2020; 63:101143. [PMID: 32810648 DOI: 10.1016/j.arr.2020.101143] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/20/2020] [Accepted: 08/10/2020] [Indexed: 12/14/2022]
Abstract
Brown and subcutaneous adipose tissues play a key role in non-shivering thermogenesis both in mice and human, and their activation by adrenergic stimuli promotes energy expenditure, reduces adiposity, and protects against age-related metabolic diseases such as type 2 diabetes (T2D). Low-grade inflammation and insulin resistance characterize T2D. Even though the decline of thermogenic adipose tissues is well-established during ageing, the mechanisms by which this event affects immune system and contributes to the development of T2D is still poorly defined. It is emerging that activation of thermogenic adipose tissues promotes type 2 immunity skewing, limiting type 1 inflammation. Of note, metabolic substrates sustaining type 1 inflammation (e.g. glucose and succinate) are also used by activated adipocytes to promote thermogenesis. Keeping in mind this aspect, a nutrient competition between adipocytes and adipose tissue immune cell infiltrates could be envisaged. Herein, we reviewed the metabolic rewiring of adipocytes during thermogenesis in order to give important insight into the anti-inflammatory role of thermogenic adipose tissues and delineate how their decline during ageing may favor the setting of low-grade inflammatory states that predispose to type 2 diabetes in elderly. A brief description about the contribution of adipokines secreted by thermogenic adipocytes in modulation of immune cell activation is also provided. Finally, we have outlined experimental flow chart procedures and provided technical advices to investigate the physiological processes leading to thermogenic adipose tissue impairment that are behind the immunometabolic decline during aging.
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Christ A, Lauterbach M, Latz E. Western Diet and the Immune System: An Inflammatory Connection. Immunity 2020; 51:794-811. [PMID: 31747581 DOI: 10.1016/j.immuni.2019.09.020] [Citation(s) in RCA: 494] [Impact Index Per Article: 98.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 07/24/2019] [Accepted: 09/24/2019] [Indexed: 02/06/2023]
Abstract
The consumption of Western-type calorically rich diets combined with chronic overnutrition and a sedentary lifestyle in Western societies evokes a state of chronic metabolic inflammation, termed metaflammation. Metaflammation contributes to the development of many prevalent non-communicable diseases (NCDs), and these lifestyle-associated pathologies represent a rising public health problem with global epidemic dimensions. A better understanding of how modern lifestyle and Western diet (WD) activate immune cells is essential for the development of efficient preventive and therapeutic strategies for common NCDs. Here, we review the current mechanistic understanding of how the Western lifestyle can induce metaflammation, and we discuss how this knowledge can be translated to protect the public from the health burden associated with their selected lifestyle.
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Affiliation(s)
- Anette Christ
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn 53127, Germany; Department of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA
| | - Mario Lauterbach
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn 53127, Germany
| | - Eicke Latz
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn 53127, Germany; Department of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA; Center of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany.
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Vorotnikov AV, Stafeev IS, Menshikov MY, Shestakova MV, Parfyonova YV. Latent Inflammation and Defect in Adipocyte Renewal as a Mechanism of Obesity-Associated Insulin Resistance. BIOCHEMISTRY (MOSCOW) 2019; 84:1329-1345. [DOI: 10.1134/s0006297919110099] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Korman NJ. Management of psoriasis as a systemic disease: what is the evidence? Br J Dermatol 2019; 182:840-848. [PMID: 31225638 PMCID: PMC7187293 DOI: 10.1111/bjd.18245] [Citation(s) in RCA: 282] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/19/2019] [Indexed: 12/16/2022]
Abstract
Background Psoriasis is a chronic, systemic immune‐mediated disease characterized by development of erythematous, indurated, scaly, pruritic and often painful skin plaques. Psoriasis pathogenesis is driven by proinflammatory cytokines and psoriasis is associated with increased risk for comorbidities, including, but not limited to, psoriatic arthritis, cardiovascular disease, diabetes mellitus, obesity, inflammatory bowel disease and nonalcoholic fatty liver disease compared with the general population. Objectives To explore the pathophysiological relationship between psoriasis and its common comorbidities and discuss the need for new treatment paradigms that include strategies to reduce systemic inflammation in patients with moderate‐to‐severe psoriasis. Methods This narrative review summarizes the published evidence related to the ability of biological therapies to ameliorate the consequences of systemic inflammation in patients with psoriasis. Results Current evidence suggests that preventing damage associated with inflammation, and preventing development of future inflammatory damage and comorbidities, may be a potentially achievable treatment goal for many patients with moderate‐to‐severe plaque psoriasis when biological therapies are utilized early in the disease. Encouraging data from recent studies suggest that the loftier goal of reversing existing inflammatory damage and improving signs and symptoms of inflammatory comorbidities could also possibly be attainable. Conclusions Results from ongoing prospective studies regarding the effects of biologics on markers of systemic inflammation in patients with psoriasis will strengthen the clinical evidence base that can be used to inform treatment decisions for patients with moderate‐to‐severe psoriasis. What's already known about this topic?
Psoriasis is a systemic inflammatory disease and treatments are needed to optimize patient outcomes. What does this study add?
This review discusses new psoriasis treatment paradigms that may potentially reduce effects of systemic inflammation. Evidence demonstrating that biological treatment may prevent or reverse inflammatory damage associated with psoriasis comorbidities is reviewed. Linked Comment:https://doi.org/10.1111/bjd.18456
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Affiliation(s)
- N J Korman
- Department of Dermatology, Case Western Reserve University, Cleveland, OH, U.S.A.,University Hospitals Cleveland Medical Center, Cleveland, OH, U.S.A
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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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Lang Q, Yidong X, Xueguang Z, Sixian W, Wenming X, Tao Z. ETA-mediated anti-TNF-α therapy ameliorates the phenotype of PCOS model induced by letrozole. PLoS One 2019; 14:e0217495. [PMID: 31170164 PMCID: PMC6553850 DOI: 10.1371/journal.pone.0217495] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 05/13/2019] [Indexed: 01/08/2023] Open
Abstract
Chronic inflammation is a typical characteristic of polycystic ovary syndrome (PCOS), in which, tumor necrosis factor (TNF)-α plays an important role. We investigated whether anti-TNF-α therapy can alleviate the core phenotypes of PCOS. In pubertal female Wistar rats, release pellets of letrozole (LET) were administered continuously for 90 days to induce PCOS-like phenotypes, followed by treatment with etanercept (ETA), a TNF-α inhibitor. ETA significantly inhibited increases in body weight and androgen, TNF-α, and MCP-1 levels, excessive recruitment of lipid droplets, altered levels of pre-adipose differentiation markers, and abnormal development of follicles. In addition, TNF-α and testosterone (T) levels in the rat sera were significantly positively correlated. Further experiments were performed to investigate the relationship between TNF-α and androgen. Persistent exposure of the RAW 264.7 cell line to low doses of testosterone significantly enhanced TNF-α expression and activated the NF-κB signaling pathway, which were blocked by ETA. Furthermore, treatment with TNF-α promoted the production of testosterone in KGN granulosa cells by reducing CYP19A1 expression, whereas ETA treatment blocked this process. In conclusion, anti-TNF-α therapy with ETA may be an efficient method to alleviate PCOS, whose underlying mechanism may be associated with its ability to reduce excessive androgen levels.
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Affiliation(s)
- Qin Lang
- Reproductive Medical Center, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xie Yidong
- Reproductive Medical Center, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhang Xueguang
- Sichuan University–The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wu Sixian
- Sichuan University–The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China
| | - Xu Wenming
- Sichuan University–The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- * E-mail: (ZT); (XW)
| | - Zuo Tao
- Sichuan University–The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- * E-mail: (ZT); (XW)
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Ad'hiah AH, Mahmood AS, Al-kazaz AKA, Mayouf KK. Gene expression and six single nucleotide polymorphisms of interleukin-6 in rheumatoid arthritis: A case-control study in Iraqi patients. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2018.08.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Affiliation(s)
- Ali H. Ad'hiah
- Tropical-Biological Research Unit, College of Science, University of Baghdad, Baghdad, Iraq
| | - Aseel S. Mahmood
- Biotechnology Department, College of Science, University of Baghdad, Baghdad, Iraq
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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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Dhorepatil A, Ball S, Ghosh RK, Kondapaneni M, Lavie CJ. Canakinumab: Promises and Future in Cardiometabolic Diseases and Malignancy. Am J Med 2019; 132:312-324. [PMID: 30832770 DOI: 10.1016/j.amjmed.2018.10.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 09/29/2018] [Accepted: 10/01/2018] [Indexed: 12/18/2022]
Abstract
Inflammation has proven in multiple studies to be responsible for the progression of cardiometabolic diseases and malignancies. The interleukin family has been critically associated with progression of atherosclerosis, insulin resistance, and various malignancies. Given the advent of pharmacologic interleukin-1 (IL-1) inhibition, this pathway can potentially be targeted to improve outcomes. In the recently concluded Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial, investigators looked at the potential role of IL-1 (especially IL-1β) inhibition in halting the progression of atherosclerosis. In the subset analysis of the data from this trial, IL-1β inhibition with canakinumab was found to have beneficial effects in other cardiometabolic diseases characterized by inflammation, like diabetes, stroke, and chronic kidney disease, and also in patients with lung cancer. In this article, we will try to review the current literature on the role of canakinumab in the treatment of cardiometabolic diseases and malignancies.
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Affiliation(s)
- Aneesh Dhorepatil
- Department of Cardiology, Case Western Reserve University, Heart and Vascular Institute, MetroHealth Medical Center, Cleveland, Ohio
| | - Somedeb Ball
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock
| | - Raktim K Ghosh
- Department of Cardiology, Case Western Reserve University, Heart and Vascular Institute, MetroHealth Medical Center, Cleveland, Ohio.
| | - Meera Kondapaneni
- Department of Cardiology, Case Western Reserve University, Heart and Vascular Institute, MetroHealth Medical Center, Cleveland, Ohio
| | - Carl J Lavie
- Department of Cardiology, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, the University of Queensland School of Medicine, New Orleans, La
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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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Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev 2018; 98:2133-2223. [PMID: 30067154 PMCID: PMC6170977 DOI: 10.1152/physrev.00063.2017] [Citation(s) in RCA: 1653] [Impact Index Per Article: 236.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/22/2018] [Accepted: 03/24/2018] [Indexed: 12/15/2022] Open
Abstract
The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.
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Affiliation(s)
- Max C Petersen
- Departments of Internal Medicine and Cellular & Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine , New Haven, Connecticut
| | - Gerald I Shulman
- Departments of Internal Medicine and Cellular & Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine , New Haven, Connecticut
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Gonzalez LL, Garrie K, Turner MD. Type 2 diabetes - An autoinflammatory disease driven by metabolic stress. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3805-3823. [PMID: 30251697 DOI: 10.1016/j.bbadis.2018.08.034] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 08/27/2018] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes has traditionally been viewed as a metabolic disorder characterised by chronic high glucose levels, insulin resistance, and declining insulin secretion from the pancreas. Modern lifestyle, with abundant nutrient supply and reduced physical activity, has resulted in dramatic increases in the rates of obesity-associated disease conditions, including diabetes. The associated excess of nutrients induces a state of systemic low-grade chronic inflammation that results from production and secretion of inflammatory mediators from the expanded pool of activated adipocytes. Here, we review the mechanisms by which obesity induces adipose tissue dysregulation, detailing the roles of adipose tissue secreted factors and their action upon other cells and tissues central to glucose homeostasis and type 2 diabetes. Furthermore, given the emerging importance of adipokines, cytokines and chemokines in disease progression, we suggest that type 2 diabetes should now be viewed as an autoinflammatory disease, albeit one that is driven by metabolic dysregulation.
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Affiliation(s)
- Laura L Gonzalez
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom
| | - Karin Garrie
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom
| | - Mark D Turner
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom.
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WITHDRAWN: Cytokines and fatty liver diseases. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2018.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Everett BM, Donath MY, Pradhan AD, Thuren T, Pais P, Nicolau JC, Glynn RJ, Libby P, Ridker PM. Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes. J Am Coll Cardiol 2018; 71:2392-2401. [PMID: 29544870 DOI: 10.1016/j.jacc.2018.03.002] [Citation(s) in RCA: 221] [Impact Index Per Article: 31.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 02/28/2018] [Accepted: 03/01/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND Subclinical inflammation mediated in part by interleukin (IL)-1β participates in peripheral insulin resistance and impaired pancreatic insulin secretion. OBJECTIVES The authors tested the hypothesis that the IL-1β inhibitor canakinumab reduces incident diabetes. METHODS The authors randomized 10,061 patients with prior myocardial infarction and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/l to placebo or canakinumab at doses of 50 mg, 150 mg, or 300 mg subcutaneously once every 3 months. The authors tested the effects of canakinumab on major cardiovascular events in patients with and without diabetes at baseline, and evaluated as a pre-specified analysis whether canakinumab would reduce the risk of adjudicated cases of new-onset type 2 diabetes among those with protocol-defined pre-diabetes at trial entry. The authors also evaluated the effect of canakinumab on fasting plasma glucose and glycosylated hemoglobin (HbA1c) in patients with and without established diabetes. RESULTS Of the participants, 4,057 (40.3%) had baseline diabetes, 4,960 (49.3%) had pre-diabetes, and 1,044 (10.4%) had normal glucose levels. Among those without diabetes, increasing tertiles of hsCRP at baseline associated with an increased risk of developing diabetes during the median follow-up period of 3.7 years (incidence rates 3.2, 4.1, and 4.4 per 100 person-years; p = 0.003). Canakinumab 150 mg as compared with placebo had similar magnitude effects on major cardiovascular event rates among those with diabetes (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.70 to 1.03), pre-diabetes (HR: 0.86; 95% CI: 0.70 to 1.06), and normoglycemia (HR: 0.81; 95% CI: 0.49 to 1.35). Despite large reductions in hsCRP and IL-6, canakinumab did not reduce the incidence of new-onset diabetes, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 4.2, 4.2, 4.4, and 4.1, respectively (log-rank p = 0.84). The HR comparing all canakinumab doses to placebo was 1.02 (95% CI: 0.87 to 1.19; p = 0.82). Canakinumab reduced HbA1c during the first 6 to 9 months of treatment, but no consistent long-term benefits on HbA1c or fasting plasma glucose were observed. CONCLUSIONS Although IL-1β inhibition with canakinumab had similar effects on major cardiovascular events among those with and without diabetes, treatment over a median period of 3.7 years did not reduce incident diabetes. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846).
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Affiliation(s)
- Brendan M Everett
- Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Marc Y Donath
- Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland
| | - Aruna D Pradhan
- Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Department of Medicine, VA Boston Medical Center, West Roxbury, Massachusetts
| | - Tom Thuren
- Novartis Pharmaceutical Corporation, East Hanover, New Jersey, and Basel, Switzerland
| | - Prem Pais
- St. John's Research Institute, Bangalore, India
| | - Jose C Nicolau
- Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Robert J Glynn
- Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts
| | - Peter Libby
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Paul M Ridker
- Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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