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1
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Burger K, Jung F, Baumann A, Brandt A, Staltner R, Sánchez V, Bergheim I. TNFα is a key trigger of inflammation in diet-induced non-obese MASLD in mice. Redox Biol 2023; 66:102870. [PMID: 37683301 PMCID: PMC10493600 DOI: 10.1016/j.redox.2023.102870] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 08/28/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023] Open
Abstract
Tumor necrosis factor alpha (TNFα) is thought to be a critical factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we determined the effects of a treatment with the anti-TNFα antibody infliximab and a genetic deletion of TNFα, respectively, in the development of non-obese diet-induced early metabolic dysfunction-associated steatohepatitis (MASH) in mice. The treatment with infliximab improved markers of liver damage in mice with pre-existing early MASH. In TNFα-/- mice, the development of early signs of MASH and insulin resistance was significantly attenuated compared to wild-type animals. While mRNA expression of proinflammatory cytokines like interleukin 1β (Il1b) and interleukin 6 (Il6) were significantly lower in livers of MASH-diet-fed TNFα-/- mice compared to wild-type mice with early MASH, markers of intestinal barrier function were similarly impaired in both MASH-diet-fed groups compared to controls. Our data suggest that TNFα is a key regulator of hepatic inflammation and insulin resistance associated with the development of early non-obese MASH.
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Affiliation(s)
- Katharina Burger
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Finn Jung
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Anja Baumann
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Annette Brandt
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Raphaela Staltner
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Victor Sánchez
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria.
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2
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Frankowski R, Kobierecki M, Wittczak A, Różycka-Kosmalska M, Pietras T, Sipowicz K, Kosmalski M. Type 2 Diabetes Mellitus, Non-Alcoholic Fatty Liver Disease, and Metabolic Repercussions: The Vicious Cycle and Its Interplay with Inflammation. Int J Mol Sci 2023; 24:ijms24119677. [PMID: 37298632 DOI: 10.3390/ijms24119677] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/12/2023] Open
Abstract
The prevalence of metabolic-related disorders, such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (DM2), has been increasing. Therefore, developing improved methods for the prevention, treatment, and detection of these two conditions is also necessary. In this study, our primary focus was on examining the role of chronic inflammation as a potential link in the pathogenesis of these diseases and their interconnections. A comprehensive search of the PubMed database using keywords such as "non-alcoholic fatty liver disease", "type 2 diabetes mellitus", "chronic inflammation", "pathogenesis", and "progression" yielded 177 relevant papers for our analysis. The findings of our study revealed intricate relationships between the pathogenesis of NAFLD and DM2, emphasizing the crucial role of inflammatory processes. These connections involve various molecular functions, including altered signaling pathways, patterns of gene methylation, the expression of related peptides, and up- and downregulation of several genes. Our study is a foundational platform for future research into the intricate relationship between NAFLD and DM2, allowing for a better understanding of the underlying mechanisms and the potential for introducing new treatment standards.
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Affiliation(s)
- Rafał Frankowski
- Students' Research Club, Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
| | - Mateusz Kobierecki
- Students' Research Club, Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
| | - Andrzej Wittczak
- Students' Research Club, Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
| | | | - Tadeusz Pietras
- Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
| | - Kasper Sipowicz
- Department of Interdisciplinary Disability Studies, The Maria Grzegorzewska University in Warsaw, 02-353 Warsaw, Poland
| | - Marcin Kosmalski
- Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
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3
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Dludla PV, Mabhida SE, Ziqubu K, Nkambule BB, Mazibuko-Mbeje SE, Hanser S, Basson AK, Pheiffer C, Kengne AP. Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress. World J Diabetes 2023; 14:130-146. [PMID: 37035220 PMCID: PMC10075035 DOI: 10.4239/wjd.v14.i3.130] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/26/2022] [Accepted: 02/28/2023] [Indexed: 03/15/2023] Open
Abstract
Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes (T2D). Beyond the detrimental effects of insulin resistance, inflammation and oxidative stress have emerged as critical features of T2D that define β-cell dysfunction. Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models and in people with T2D. Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D. Such effects illustrate a pathological relationship between an abnormal inflammatory response and generation of oxidative stress during the progression of T2D. The current review explores preclinical and clinical research on the patho-logical implications of inflammation and oxidative stress during the development of β-cell dysfunction in T2D. Moreover, important molecular mechanisms and relevant biomarkers involved in this process are discussed to divulge a pathological link between inflammation and oxidative stress during β-cell failure in T2D. Underpinning the clinical relevance of the review, a systematic analysis of evidence from randomized controlled trials is covered, on the potential therapeutic effects of some commonly used antidiabetic agents in modulating inflammatory makers to improve β-cell function.
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Affiliation(s)
- Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Sihle E Mabhida
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
| | - Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mmabatho 2745, South Africa
| | - Bongani B Nkambule
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | | | - Sidney Hanser
- Department of Physiology and Environmental Health, University of Limpopo, Sovenga 0727, South Africa
| | - Albert Kotze Basson
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Carmen Pheiffer
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
| | - Andre Pascal Kengne
- Department of Medicine, University of Cape Town, Cape Town 7500, South Africa
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Tygerberg 7505, South Africa
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4
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Pintarič M, Langerholc T. Probiotic Mechanisms Affecting Glucose Homeostasis: A Scoping Review. Life (Basel) 2022; 12:1187. [PMID: 36013366 PMCID: PMC9409775 DOI: 10.3390/life12081187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/28/2022] [Accepted: 07/29/2022] [Indexed: 02/08/2023] Open
Abstract
The maintenance of a healthy status depends on the coexistence between the host organism and the microbiota. Early studies have already focused on the nutritional properties of probiotics, which may also contribute to the structural changes in the gut microbiota, thereby affecting host metabolism and homeostasis. Maintaining homeostasis in the body is therefore crucial and is reflected at all levels, including that of glucose, a simple sugar molecule that is an essential fuel for normal cellular function. Despite numerous clinical studies that have shown the effect of various probiotics on glucose and its homeostasis, knowledge about the exact function of their mechanism is still scarce. The aim of our review was to select in vivo and in vitro studies in English published in the last eleven years dealing with the effects of probiotics on glucose metabolism and its homeostasis. In this context, diverse probiotic effects at different organ levels were highlighted, summarizing their potential mechanisms to influence glucose metabolism and its homeostasis. Variations in results due to different methodological approaches were discussed, as well as limitations, especially in in vivo studies. Further studies on the interactions between probiotics, host microorganisms and their immunity are needed.
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Affiliation(s)
- Maša Pintarič
- Department of Microbiology, Biochemistry, Molecular Biology and Biotechnology, Faculty of Agriculture and Life Sciences, University of Maribor, Pivola 10, 2311 Hoče, Slovenia;
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Shu J, Li N, Wei W, Zhang L. Detection of molecular signatures and pathways shared by Alzheimer's disease and type 2 diabetes. Gene 2022; 810:146070. [PMID: 34813915 DOI: 10.1016/j.gene.2021.146070] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 10/21/2021] [Accepted: 11/16/2021] [Indexed: 01/12/2023]
Abstract
Alzheimer's disease (AD) and type 2 diabetes (T2D) are common in the general elderly population, conferring heavy individual, social, and economic stresses on families and society. Accumulating evidence indicates T2D to be a risk factor for AD. However, the underlying mechanisms for this association are largely unknown. This study aimed to identify the shared molecular signatures between AD and T2D through integrated analysis of temporal cortex gene expression data. Gene Ontology (GO) and pathway enrichment analysis, protein over-representation analysis, protein-protein interaction, DEG-transcription factor interactions, DEG-microRNA interactions, protein-drug interactions, gene-disease association analysis, and protein subcellular localization analysis of the common DEGs were performed. We identified 16 common DEGs between the two datasets, which were mainly enriched in the biological processes of apoptosis, autophagy, inflammation, and hemostasis. We also identified five hub proteins encoded by the DEGs, five central regulatory transcription factors, and six microRNAs. Protein-drug interaction analysis showed C1QB to be associated with different drugs. Gene-disease association analysis revealed that hub genes, SFN and ITGB2, were actively engaged in other diseases. Collectively, these findings provide new insights into shared molecular mechanisms between AD and T2D and provide novel candidate targets for therapeutic intervention.
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Affiliation(s)
- Jun Shu
- Department of Neurology, Cognitive Disorders Center, Huadong Hospital, Fudan University, No. 221, West Yan An Road, Shanghai, China
| | - Nan Li
- Department of Neurology, Cognitive Disorders Center, Huadong Hospital, Fudan University, No. 221, West Yan An Road, Shanghai, China
| | - Wenshi Wei
- Department of Neurology, Cognitive Disorders Center, Huadong Hospital, Fudan University, No. 221, West Yan An Road, Shanghai, China.
| | - Li Zhang
- Department of Neurology, Cognitive Disorders Center, Huadong Hospital, Fudan University, No. 221, West Yan An Road, Shanghai, China.
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Nellaiappan K, Preeti K, Khatri DK, Singh SB. Diabetic Complications: An Update on Pathobiology and Therapeutic Strategies. Curr Diabetes Rev 2022; 18:e030821192146. [PMID: 33745424 DOI: 10.2174/1573399817666210309104203] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/28/2020] [Accepted: 01/19/2021] [Indexed: 12/20/2022]
Abstract
Despite the advent of novel therapies which manage and control diabetes well, the increased risk of morbidity and mortality in diabetic subjects is associated with the devastating secondary complications it produces. Long-standing diabetes majorly drives cellular and molecular alterations, which eventually damage both small and large blood vessels. The complications are prevalent both in type I and type II diabetic subjects. The microvascular complications include diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, while the macrovascular complications include diabetic heart disease and stroke. The current therapeutic strategy alleviates the complications to some extent but does not cure or prevent them. Also, the recent clinical trial outcomes in this field are disappointing. Success in the drug discovery of diabetic complications may be achieved by a better understanding of the underlying pathophysiology and by recognising the crucial factors contributing to the development and progression of the disease. In this review, we discuss the well-studied cellular mechanisms leading to the development and progression of diabetic complications. In addition, we also highlight the various therapeutic paradigms currently in clinical practice.
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Affiliation(s)
- Karthika Nellaiappan
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana-500037,India
| | - Kumari Preeti
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana-500037,India
| | - Dharmendra Kumar Khatri
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana-500037,India
| | - Shashi Bala Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana-500037,India
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7
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Zaidi H, Byrkjeland R, Njerve IU, Åkra S, Solheim S, Arnesen H, Seljeflot I, Opstad TB. Adiponectin in relation to exercise and physical performance in patients with type 2 diabetes and coronary artery disease. Adipocyte 2021; 10:612-620. [PMID: 34779349 PMCID: PMC8726619 DOI: 10.1080/21623945.2021.1996699] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Introduction: Adipokines, expressed by adipose tissue (AT), have been associated with metabolic disturbances and coronary artery disease (CAD). The impact of exercise training on the AT in patients suffering from both diabetes and CAD is unknown. To gain knowledge on changes in ATs’ inflammatory profile in such a population, we investigated the effects of long-term exercise on selected adipokines and their associations with physical performance and glucometabolic variables. Adiponectin was selected based on its anti-atherogenic and anti-diabetic properties and visfatin and tumour necrosis factor (TNF) for their association with atherosclerosis and metabolic disorders. Not many studies have focused on the effects of long-term exercise training on adipokines in patients with concomitant T2DM and CAD. Methods: Patients with type 2 diabetes and CAD (n = 137), 41–81 years, 17.2% females, were randomized in a 1:1 manner to an exercise group, who underwent 1 year of 150 min weekly combined strength and endurance exercise, or a control group. AT from the gluteal region and blood samples were obtained at baseline and after 12 months, along with a physical performance test, assessed by the VO2 peak. Circulating protein levels were measured by ELISA. RNA was extracted from AT and expression levels were relatively quantified by PCR. Results: After 1 year, no significant difference in the change in the investigated markers between the intervention group and the control group was observed. Changes in circulating adiponectin and VO2 peak correlated in the total population (r = 0.256, p = 0.008). At baseline, circulating adiponectin and TNF correlated inversely with insulin and with C-peptide and VO2peak, respectively (p < 0.001, all). Conclusion: In this population with concomitant diabetes and CAD, ATs’ inflammatory profile remained unchanged apparently after 1 year of exercise intervention. Changes in the VO2peak were nevertheless, related to changes in circulating adiponectin levels. Trial registration: http://www.clinicaltrials.gov NCT01232608.
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Affiliation(s)
- Hani Zaidi
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Norway
- Faculty of Medicine, University of Oslo, Oslo Norway
| | - Rune Byrkjeland
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Norway
| | - Ida U. Njerve
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Norway
| | - Sissel Åkra
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Norway
| | - Svein Solheim
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Norway
| | - Harald Arnesen
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Norway
- Faculty of Medicine, University of Oslo, Oslo Norway
| | - Ingebjørg Seljeflot
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Norway
- Faculty of Medicine, University of Oslo, Oslo Norway
| | - Trine B. Opstad
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Norway
- Faculty of Medicine, University of Oslo, Oslo Norway
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8
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Xu R, Wang Z. Involvement of Transcription Factor FoxO1 in the Pathogenesis of Polycystic Ovary Syndrome. Front Physiol 2021; 12:649295. [PMID: 33746783 PMCID: PMC7973228 DOI: 10.3389/fphys.2021.649295] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/15/2021] [Indexed: 11/13/2022] Open
Abstract
FoxO1 is a member of the forkhead transcription factor family subgroup O (FoxO), which is expressed in many cell types, and participates in various pathophysiological processes, including cell proliferation, apoptosis, autophagy, metabolism, inflammatory response, cytokine expression, immune differentiation, and oxidative stress resistance. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in the women of childbearing age, which is regulated via a variety of signaling pathways. Currently, the specific mechanism underlying the pathogenesis of PCOS is still unclear. As an important transcription factor, FoxO1 activity might be involved in the pathophysiology of PCOS. PCOS has been associated with insulin resistance and low-grade inflammatory response. Therefore, the studies regarding the role of FoxO1 in the incidence and associated complications of PCOS will help provide novel ideas for establishing the treatment strategy of PCOS.
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Affiliation(s)
- Renfeng Xu
- Provincial Key Laboratory for Developmental Biology and Neurosciences, Provincial University Key Laboratory of Sport and Health Science, Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Zhengchao Wang
- Provincial Key Laboratory for Developmental Biology and Neurosciences, Provincial University Key Laboratory of Sport and Health Science, Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, China
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9
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Wang CR, Tsai HW. Anti- and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. World J Diabetes 2021; 12:238-260. [PMID: 33758645 PMCID: PMC7958474 DOI: 10.4239/wjd.v12.i3.238] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/07/2021] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
In addition to β-cell failure with inadequate insulin secretion, the crucial mechanism leading to establishment of diabetes mellitus (DM) is the resistance of target cells to insulin, i.e. insulin resistance (IR), indicating a requirement of beyond-normal insulin concentrations to maintain euglycemic status and an ineffective strength of transduction signaling from the receptor, downstream to the substrates of insulin action. IR is a common feature of most metabolic disorders, particularly type II DM as well as some cases of type I DM. A variety of human inflammatory disorders with increased levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, have been reported to be associated with an increased risk of IR. Autoimmune-mediated arthritis conditions, including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with the involvement of proinflammatory cytokines as their central pathogenesis, have been demonstrated to be associated with IR, especially during the active disease state. There is an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders. In this review, we focus on the effects of anti-TNF-α- and non-TNF-α-targeted therapies on IR in patients with RA, PsA and AS. Anti-TNF-α therapy, IL-1 blockade, IL-6 antagonist, Janus kinase inhibitor and phospho-diesterase type 4 blocker can reduce IR and improve diabetic hyper-glycemia in autoimmune-mediated arthritis.
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Affiliation(s)
- Chrong-Reen Wang
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70403, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan
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10
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van Niekerk G, Dalgleish AG, Joubert F, Joubert A, Engelbrecht AM. The immuno-oncological implications of insulin. Life Sci 2020; 264:118716. [PMID: 33159956 DOI: 10.1016/j.lfs.2020.118716] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/27/2020] [Accepted: 11/02/2020] [Indexed: 11/29/2022]
Abstract
Emerging evidence has implicated insulin in regulating the phenotypes of various immune cells through canonical downstream signalling effectors of insulin, namely, the PI3K/Akt/mTOR pathway. Notably, these signalling components also exhibit crosstalk with other immune signalling pathways, such as the JAK/STAT pathway (activated by cytokines and growth factors), and, importantly, are also negatively regulated by the immune checkpoint blockers (ICBs), PD-1 and CTLA-4. Here, we point out recent findings, suggesting that insulin may promote a pro-inflammatory phenotype with potential implications on ICB therapy. As an example, the contemporary paradigm holds that, while T cell receptor recognition of distinct MHC-expressed epitopes ensures specificity, co-activation of CD28 along with signal inputs form various cytokines and insulin operates to 'fine-tune' the immune response via PI3K and other downstream signalling molecules. These considerations highlight the urgent need for focused investigations into the role of insulin in regulating immune cell function in the context of ICB therapies.
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Affiliation(s)
- Gustav van Niekerk
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa.
| | - Angus G Dalgleish
- Department of Cellular and Molecular Medicine, St George's University of London, London, UK
| | - Fourie Joubert
- Department of Biochemistry, Genetics and Microbiology, Centre for Bioinformatics and Computational Biology, University of Pretoria, Pretoria, South Africa
| | - Annie Joubert
- Department of Physiology, University of Pretoria, Pretoria, South Africa
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
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11
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Bashir H, Ahmad Bhat S, Majid S, Hamid R, Koul RK, Rehman MU, Din I, Ahmad Bhat J, Qadir J, Masood A. Role of inflammatory mediators (TNF-α, IL-6, CRP), biochemical and hematological parameters in type 2 diabetes mellitus patients of Kashmir, India. Med J Islam Repub Iran 2020; 34:5. [PMID: 32284929 PMCID: PMC7139256 DOI: 10.34171/mjiri.34.5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Indexed: 12/29/2022] Open
Abstract
Background: Type II Diabetes mellitus (T2DM) is a multifactorial disease and a leading cause of premature deaths. Inflammatory cytokines are reported that they have potential to enhance insulin resistance and hence T2DM. Assessment of immunological profile in T2DM patients of Kashmir valley is unclear. So, detection of cytokines is relevant to determine the extent and direction of immune responses. The current research was taken to study the role of inflammatory mediators in T2DM along with insulin sensitivity, biochemical and hematological parameters in mountainous valley of Kashmiri population. Methods: A total of 340 subjects were selected in this study among them 160 were T2DM cases and 180 were healthy controls. Serum expression of inflammatory mediators (TNF-α and IL-6 ) were quantified by ELISA technique, WBC count was measured on Sysmax (Germany) hematology analyzer, biochemical and Immunoassay parameters were done on Abbott c4000 (USA) and Abbott C1000 (USA) fully automatic analyzer. Data was analyzed using statistical 'software SPSS 16.1' (Chicago, IL). For all assessments, p<0.05 were considered statistically significant. Results: The expressions of candidate cytokines (TNF-α, IL-6, CRP, and WBC) were highly significant (p<0.001) in T2DM. Among inflammatory mediators, TNF-α shows a positive correlation (p<0.001) with glycemic profile and insulin sensitivity in T2DM cases in comparison with healthy normal. Biochemical (fasting sugar, HbA1c, insulin resistance, lipid profile) and anthropometric (BMI) parameters were highly significant (p<0.001) in T2DM cases as compared to non-diabetic normal. Conclusion: Low grade inflammation and up regulation of inflammatory mediators has been purported to play a significant role in pathogenesis of T2DM. Our findings confirm that positive correlation of TNF-α and IL-6 with T2DM and insulin sensitivity. These can act as early prediction biomarkers of T2DM. Further studies on wider range of pro and anti- inflammatory cytokines i.e. mediators, in association with other biochemical, immunoassay and hematological parameters are needed to help clinicians manage and treat T2DM effectively.
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Affiliation(s)
- Haamid Bashir
- Department of Biochemistry, Govt. Medical College Srinagar, Research CentreUniversity of Kashmir, Srinagar, India
| | | | - Sabhiya Majid
- Department of Biochemistry, Govt. Medical College Srinagar, Research CentreUniversity of Kashmir, Srinagar, India
| | - Rabia Hamid
- Department of Biochemistry , University of Kashmir, Srinagar, India
| | - Rakesh K Koul
- Sheri-Maharaja Hari Singh Hospital (SMHS) & Associated Hospitals Govt. Medical College, Srinagar, Kashmir, India
| | - Muneeb U Rehman
- Department of Biochemistry, Govt. Medical College Srinagar, Research CentreUniversity of Kashmir, Srinagar, India
| | - Insha Din
- Department of Biochemistry, Govt. Medical College Srinagar, Research CentreUniversity of Kashmir, Srinagar, India
| | - Javaid Ahmad Bhat
- Department of Biochemistry, Govt. Medical College Srinagar, Research CentreUniversity of Kashmir, Srinagar, India
| | - Jasiya Qadir
- Department of Biochemistry, Govt. Medical College Srinagar, Research CentreUniversity of Kashmir, Srinagar, India
| | - Akbar Masood
- Department of Biochemistry , University of Kashmir, Srinagar, India
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12
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Stefanaki C, Bacopoulou F, Kandaraki E, Boschiero D, Diamandi-Kandarakis E. Lean Women on Metformin and Oral Contraceptives for Polycystic Ovary Syndrome Demonstrate a Dehydrated Osteosarcopenic Phenotype: A Pilot Study. Nutrients 2019; 11:2055. [PMID: 31480705 PMCID: PMC6769734 DOI: 10.3390/nu11092055] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 08/25/2019] [Accepted: 08/26/2019] [Indexed: 12/19/2022] Open
Abstract
Scarce data exist on the body composition of lean women with polycystic ovary syndrome (PCOS) on treatment with metformin and oral contraceptives (OCs). Thirty-four lean (body mass index 18.5-24.9 kg/m2) women (17 with PCOS on metformin and OCs treatment for six months and 17 controls) aged 18-40 years were assessed for body composition parameters (fat, muscle, glycogen, protein masses, bone masses, and body water compartments) and phase angles. PCOS patients demonstrated lower muscle, glycogen and protein masses (U = 60, p = 0.003), along with a lower bone mineral content and mass (U = 78, p = 0.021; U = 74, p = 0.014) than their healthy counterparts, while total and abdominal fat masses were similar between the two groups. PCOS patients also exhibited increased extracellular body water (U = 10, p < 0.001) and decreased intracellular water, compatible with low-grade inflammation and cellular dehydration. Key differences in body composition between women with PCOS and controls demonstrated an osteosarcopenic body composition phenotype in PCOS patients. A confirmation of these findings in larger studies may render osteosarcopenia management a targeted adjunct therapy in women with PCOS.
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Affiliation(s)
- Charikleia Stefanaki
- Center for Adolescent Medicine and UNESCO Chair on Adolescent Health Care, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, 11527 Athens, Greece.
| | - Flora Bacopoulou
- Center for Adolescent Medicine and UNESCO Chair on Adolescent Health Care, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, 11527 Athens, Greece
| | - Eleni Kandaraki
- Department of Endocrinology, Diabetes and Metabolism, Hygeia Hospital, 15123 Athens, Greece
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Gundala NKV, Das UN. Arachidonic acid-rich ARASCO oil has anti-inflammatory and antidiabetic actions against streptozotocin + high fat diet induced diabetes mellitus in Wistar rats. Nutrition 2019; 66:203-218. [PMID: 31310962 DOI: 10.1016/j.nut.2019.05.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 05/10/2019] [Accepted: 05/27/2019] [Indexed: 10/26/2022]
Abstract
OBJECTIVES The aim of this study was to investigate the effects of arachidonic acid (AA)-rich ARASCO oil on high-fat diet (HFD) + streptozotocin (STZ)-induced diabetes mellitus in male Wistar rats and its possible mechanisms of action. METHODS Male Wistar rats with HFD + STZ-induced diabetes were employed in the present study. ARASCO oil was administered orally for the first 7 d consecutively, followed by once weekly throughout the study (14 wk). At various time points, blood glucose and body weight and oral glucose tolerance tests were measured. At the end of the study, animals were sacrificed to collect plasma and various organs and stored at -80°C. Plasma insulin, tumor necrosis factor-α, interleukin-6, and lipoxin A4 were measured. Expression of the following genes was determined: nuclear factor-κΒ (NF-κB), cyclooxygenase-2 (COX-2), 12-lipoxygenase (12-LOX) in pancreas and lipocalin 2 (LPCLN2) in adipose tissue. Various antioxidants were measured in the plasma and other tissues. Area under the curve and insulin sensitivity index were assessed by computing homeostatic model of assessment for insulin resistance, quantitative insulin check index, Matsuda, and Belfiore indices. RESULTS ARASCO oil treatment decreased hyperglycemia, restored insulin sensitivity, suppressed inflammation, enhanced plasma lipoxin A4 levels, and reversed altered antioxidant status to near normal in animals with HFD + STZ-induced diabetes. CONCLUSION These results suggest that ARASCO, a rich source of AA, can prevent HFD + STZ-induced diabetes in Wistar rats owing to its anti-inflammatory action. It remains to be seen whether ARASCO oil is useful in preventing or postponing the development of type 2 diabetes mellitus in humans.
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Affiliation(s)
- Naveen K V Gundala
- BioScience Research Centre, GVP College of Engineering Campus and Department of Medicine, Gayatri Vidya Parishad Hospital, Visakhapatnam, India
| | - Undurti N Das
- BioScience Research Centre, GVP College of Engineering Campus and Department of Medicine, Gayatri Vidya Parishad Hospital, Visakhapatnam, India; UND Life Sciences, Battle Ground, Washington, USA.
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Zhang L, Qin Q, Liu M, Zhang X, He F, Wang G. Akkermansia muciniphila can reduce the damage of gluco/lipotoxicity, oxidative stress and inflammation, and normalize intestine microbiota in streptozotocin-induced diabetic rats. Pathog Dis 2018; 76:4972761. [PMID: 29668928 DOI: 10.1093/femspd/fty028] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 03/24/2018] [Indexed: 02/06/2023] Open
Abstract
This study aimed to investigate how Akkermansia muciniphila can implicate type 2 diabetes mellitus and the mechanisms underlying the effects A. muciniphila on type 2 diabetes mellitus. Normal and streptozotocin-induced diabetic Sprague-Dawley rats were orally administered with A. muciniphila and solvent. After 4 weeks of treatment, diabetic rats orally administered with live or pasteurized A. muciniphila exhibited significant increase in the blood concentration of high-density lipoprotein, and decrease in the hepatic glycogen, serum plasminogen activator inhibitor-1, tumor necrosis factor-α, lipopolysaccharide, malondialdehyde and total glucagon-like peptide-1. Moreover, diabetic rats orally administered with A. muciniphila showed significantly increased species alpha diversity and gene function in gut microbes. These results indicated that A. muciniphila can improve liver function, reduce gluco/lipotoxicity, alleviate oxidative stress, suppress inflammation and normalize intestine microbiota of the host animal, thereby ameliorating type 2 diabetes mellitus. Akkermansia muciniphila might be considered as one of the ideal new probiotics used in the management of type 2 diabetes mellitus in future.
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Affiliation(s)
- Ling Zhang
- West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qianqian Qin
- West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Manni Liu
- West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiangling Zhang
- West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Fang He
- West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Guoqing Wang
- West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Phosat C, Panprathip P, Chumpathat N, Prangthip P, Chantratita N, Soonthornworasiri N, Puduang S, Kwanbunjan K. Elevated C-reactive protein, interleukin 6, tumor necrosis factor alpha and glycemic load associated with type 2 diabetes mellitus in rural Thais: a cross-sectional study. BMC Endocr Disord 2017; 17:44. [PMID: 28716139 PMCID: PMC5512726 DOI: 10.1186/s12902-017-0189-z] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 06/29/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The elevated levels of inflammatory markers, including C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL6) are supposed to be associated with type 2 diabetes mellitus (T2DM). Frequent high glycemic load (GL) consumption, central obesity, and a lack of physical activity are considered to be T2DM risk factors. This study aimed to determine the difference of these inflammatory markers as well as GL in individuals with versus those without T2DM in rural Thais. METHODS A total of 296 participants aged 35-66 living in Sung Noen District, Nakhon Ratchasima Province, Thailand, were recruited. Blood was collected to evaluate blood glucose levels, lipid profiles, and inflammatory markers. A Semi-food frequency questionnaire was utilized to assess GL followed by socioeconomic and anthropometric assessment. Statistical analysis was subsequently performed. RESULTS Elevated CRP and IL6 levels were associated with increased risk of developing T2DM [OR (95% CI): 7.51 (2.11, 26.74) and 4.95 (1.28, 19.11)], respectively. There was a trend towards increased risk of T2DM with elevated TNF-α levels [OR (95% CI): 1.56 (0.39, 6.14)]. GL correlated significantly with fasting blood glucose (r = 0.289, P = 0.016), suggesting that it is involved in T2DM in this study group. CONCLUSION In this study, CRP, IL6, and TNF-α associated with T2DM. Our findings suggested that these inflammatory markers, especially CRP, may initiate T2DM.
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Affiliation(s)
- Chanchira Phosat
- Department of Tropical Nutrition and Food Science, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Rd, Bangkok, 10400 Thailand
| | - Pornpimol Panprathip
- Department of Tropical Nutrition and Food Science, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Rd, Bangkok, 10400 Thailand
| | - Noppanath Chumpathat
- Faculty of Nursing, Huachiew Chalermprakiet University, 18/18 Bangna-Trad Rd, Samut Prakan, 10540 Thailand
| | - Pattaneeya Prangthip
- Department of Tropical Nutrition and Food Science, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Rd, Bangkok, 10400 Thailand
| | - Narisara Chantratita
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Rd, Bangkok, 10400 Thailand
| | - Ngamphol Soonthornworasiri
- Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Rd, Bangkok, 10400 Thailand
| | - Somchai Puduang
- Department of Tropical Nutrition and Food Science, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Rd, Bangkok, 10400 Thailand
| | - Karunee Kwanbunjan
- Department of Tropical Nutrition and Food Science, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Rd, Bangkok, 10400 Thailand
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Luna GI, da Silva ICR, Sanchez MN. Association between -308G/A TNFA Polymorphism and Susceptibility to Type 2 Diabetes Mellitus: A Systematic Review. J Diabetes Res 2016; 2016:6309484. [PMID: 27822481 PMCID: PMC5086378 DOI: 10.1155/2016/6309484] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 07/12/2016] [Accepted: 09/14/2016] [Indexed: 12/29/2022] Open
Abstract
Diabetes mellitus (DM) is considered to be a worldwide epidemic disease and its type 2 form comprises more than 95% of all cases. Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine. Its dysregulation has been implicated in a variety of human diseases, including type 2 diabetes mellitus (T2DM). The control of expression of this cytokine is associated with insulin resistance and has a strong genetic influence. In order to understand this relationship, the literature from all case-control studies since 2000 to date was reviewed. The genotypes frequency results presented in ten publications with different ethnicities were compared. The correlation between the TNFA promoter genotypes and the risk of developing T2DM remains controversial due to the many discrepancies between the different studies available. Ethnic differences may play a role in these conflicting results, since the distribution of TNFA promoter polymorphisms is distinctive between individuals of dissimilar racial origin. Hence, although the relationship between T2DM incidence and presence of polymorphisms at position -308 of the TNFA gene is not entirely clear, the results of these studies suggest the need for further investigation.
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Affiliation(s)
- Geisa Izetti Luna
- Programa de Pós-Graduação em Saúde Coletiva, Universidade de Brasília, Brasília, DF, Brazil
- *Geisa Izetti Luna:
| | | | - Mauro Niskier Sanchez
- Programa de Pós-Graduação em Saúde Coletiva, Universidade de Brasília, Brasília, DF, Brazil
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Nielsen ST, Janum S, Krogh-Madsen R, Solomon TP, Møller K. The incretin effect in critically ill patients: a case-control study. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2015; 19:402. [PMID: 26567860 PMCID: PMC4645481 DOI: 10.1186/s13054-015-1118-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 10/27/2015] [Indexed: 02/11/2023]
Abstract
Introduction Patients admitted to the intensive care unit often develop hyperglycaemia, but the underlying mechanisms have not been fully described. The incretin effect is reduced in patients with type 2 diabetes. Type 2 diabetes and critical illness have phenotypical similarities, such as hyperglycaemia, insulin resistance and systemic inflammation. Previous studies have shown beneficial effects of exogenous glucagon-like peptide (GLP)-1 on glycaemia in critically ill patients, a phenomenon also seen in patients with type 2 diabetes. In this study, we hypothesised that the incretin effect, which is mediated by the incretin hormones GLP-1 and glucose-dependent insulinotropic peptide (GIP), is impaired in critically ill patients. Methods The incretin effect (i.e., the relative difference between the insulin response to oral and intravenous glucose administration) was investigated in a cross-sectional case–control study. Eight critically ill patients without diabetes admitted to a mixed intensive care unit and eight healthy control subjects without diabetes, matched at group level by age, sex and body mass index, were included in the study. All subjects underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the next day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide and plasma levels of GLP-1, GIP, glucagon and proinflammatory cytokines were measured intermittently. The incretin effect was calculated as the increase in insulin secretion during oral versus intravenous glucose administration in six patients. The groups were compared using either Student’s t test or a mixed model of repeated measurements. Results Blood glucose levels were matched between the OGTT and the IVGI in both groups. Compared with control subjects, proinflammatory cytokines, tumour necrosis factor α and interleukin 6, were higher in patients than in control subjects. The endogenous response of GIP and glucagon, but not GLP-1, to the OGTT was greater in patients. The insulin response to the OGTT did not differ between groups, whereas the insulin response to the IVGI was higher in patients. Consequently, the calculated incretin effect was lower in patients (23 vs. 57 %, p = 0.003). Conclusions In critically ill patients, the incretin effect was reduced. This resembles previous findings in patients with type 2 diabetes. Trial registration ClinicalTrials.gov identifier: NCT01347801. Registered on 2 May 2011. Electronic supplementary material The online version of this article (doi:10.1186/s13054-015-1118-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Signe Tellerup Nielsen
- Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
| | - Susanne Janum
- Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. .,Department of Anaesthesiology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
| | - Rikke Krogh-Madsen
- Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
| | - Thomas P Solomon
- School of Sport, Exercise, and Rehabilitation Sciences, Centre for Endocrinology, Diabetes, and Metabolism, University of Birmingham, Birmingham, UK.
| | - Kirsten Møller
- Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. .,Neurointensive Care Unit, Department of Neuroanaesthesiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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Esser N, Paquot N, Scheen AJ. Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin Investig Drugs 2014; 24:283-307. [PMID: 25345753 DOI: 10.1517/13543784.2015.974804] [Citation(s) in RCA: 187] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION There is a growing body of evidence to suggest that chronic silent inflammation is a key feature in abdominal obesity, metabolic syndrome, type 2 diabetes (T2DM) and cardiovascular disease (CVD). These observations suggest that pharmacological strategies, which reduce inflammation, may be therapeutically useful in treating obesity, type 2 diabetes and associated CVD. AREA COVERED The article covers novel strategies, using either small molecules or monoclonal antibodies. These strategies include: approaches targeting IKK-b-NF-kB (salicylates, salsalate), TNF-α (etanercept, infliximab, adalimumab), IL-1β (anakinra, canakinumab) and IL-6 (tocilizumab), AMP-activated protein kinase activators, sirtuin-1 activators, mammalian target of rapamycin inhibitors and C-C motif chemokine receptor 2 antagonists. EXPERT OPINION The available data supports the concept that targeting inflammation improves insulin sensitivity and β-cell function; it also ameliorates glucose control in insulin-resistant patients with inflammatory rheumatoid diseases as well in patients with metabolic syndrome or T2DM. Although promising, the observed metabolic effects remain rather modest in most clinical trials. The potential use of combined anti-inflammatory agents targeting both insulin resistance and insulin secretion appears appealing but remains unexplored. Large-scale prospective clinical trials are underway to investigate the safety and efficacy of different anti-inflammatory drugs. Further evidence is needed to support the concept that targeting inflammation pathways may represent a valuable option to tackle the cardiometabolic complications of obesity.
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Affiliation(s)
- Nathalie Esser
- University of Liege and Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, Virology and Immunology Unit, GIGA-ST , CHU Liège, Liège , Belgium
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