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      Mechanisms of muscle insulin resistance and the cross‐talk with liver and adipose tissue

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          Abstract

          Insulin resistance is a metabolic disorder affecting multiple tissues and is a precursor event to type 2 diabetes (T2D). As T2D affects over 425 million people globally, there is an imperative need for research into insulin resistance to better understand the underlying mechanisms. The proposed mechanisms involved in insulin resistance include both whole body aspects, such as inflammation and metabolic inflexibility; as well as cellular phenomena, such as lipotoxicity, ER stress, and mitochondrial dysfunction. Despite numerous studies emphasizing the role of lipotoxicity in the pathogenesis of insulin resistance, an understanding of the interplay between tissues and these proposed mechanisms is still emerging. Furthermore, the tissue‐specific and unique responses each of the three major insulin target tissues and how each interconnect to regulate the whole body insulin response has become a new priority in metabolic research. With an emphasis on skeletal muscle, this mini‐review highlights key similarities and differences in insulin signaling and resistance between different target‐tissues, and presents the latest findings related to how these tissues communicate to control whole body metabolism.

          Abstract

          Overview of insulin resistance mechanisms: the ability of the mitochondria to respond to metabolic disruptions is essential for healthy cellular bioenergetics, and interference with this process may prompt unregulated mitochondrial biogenesis and mitophagy, thus contributing to insulin resistance in major insulin target tissues.

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          Mechanisms of Insulin Action and Insulin Resistance

          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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            Mechanisms of mitophagy in cellular homeostasis, physiology and pathology

            Mitophagy is an evolutionarily conserved cellular process to remove dysfunctional or superfluous mitochondria, thus fine-tuning mitochondrial number and preserving energy metabolism. In this Review, we survey recent advances towards elucidating the molecular mechanisms that mediate mitochondrial elimination and the signalling pathways that govern mitophagy. We consider the contributions of mitophagy in physiological and pathological contexts and discuss emerging findings, highlighting the potential value of mitophagy modulation in therapeutic intervention.
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              Cytokines in Inflammatory Disease

              This review aims to briefly discuss a short list of a broad variety of inflammatory cytokines. Numerous studies have implicated that inflammatory cytokines exert important effects with regard to various inflammatory diseases, yet the reports on their specific roles are not always consistent. They can be used as biomarkers to indicate or monitor disease or its progress, and also may serve as clinically applicable parameters for therapies. Yet, their precise role is not always clearly defined. Thus, in this review, we focus on the existing literature dealing with the biology of cytokines interleukin (IL)-6, IL-1, IL-33, tumor necrosis factor-alpha (TNF-α), IL-10, and IL-8. We will briefly focus on the correlations and role of these inflammatory mediators in the genesis of inflammatory impacts (e.g., shock, trauma, immune dysregulation, osteoporosis, and/or critical illness).
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                Author and article information

                Contributors
                dasilvas@myumanitoba.ca
                joseph.gordon@umanitoba.ca
                Journal
                Physiol Rep
                Physiol Rep
                10.1002/(ISSN)2051-817X
                PHY2
                physreports
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                2051-817X
                10 October 2020
                October 2020
                : 8
                : 19 ( doiID: 10.1002/phy2.v8.19 )
                : e14607
                Affiliations
                [ 1 ] Department of Human Anatomy and Cell Science University of Manitoba Winnipeg Canada
                [ 2 ] The Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme University of Manitoba Winnipeg Canada
                [ 3 ] Children’s Hospital Research Institute of Manitoba (CHRIM) University of Manitoba Winnipeg Canada
                [ 4 ] College of Nursing University of Manitoba Winnipeg Canada
                Author notes
                [*] [* ] Correspondence

                Simone C. da Silva Rosa, Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Children’s Hospital Research Institute of Manitoba, University of Manitoba, 715 McDermot Avenue, Winnipeg, MB, Canada.

                Email: dasilvas@ 123456myumanitoba.ca

                Joseph Gordon, Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, College of Nursing, Children’s Hospital Research Institute of Manitoba, University of Manitoba, 715 McDermot Avenue, Winnipeg, MB, Canada.

                Email: joseph.gordon@ 123456umanitoba.ca

                Author information
                https://orcid.org/0000-0002-3732-3781
                https://orcid.org/0000-0002-0061-2168
                Article
                PHY214607
                10.14814/phy2.14607
                7547588
                33038072
                e246ef04-a71b-4290-aad6-14f949f589f1
                © 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 August 2020
                : 18 September 2020
                : 19 September 2020
                Page count
                Figures: 2, Tables: 2, Pages: 24, Words: 19271
                Funding
                Funded by: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada , open-funder-registry 10.13039/501100002790;
                Funded by: Children's Hospital Research Institute of Manitoba , open-funder-registry 10.13039/100012854;
                Funded by: Diabetes Research Envisioned and Accomplished in Manitoba Theme
                Funded by: Natural Sciences and Engineering Research Council of Canada , open-funder-registry 10.13039/501100000038;
                Funded by: Heart and Stroke Foundation of Canada , open-funder-registry 10.13039/100004411;
                Funded by: Research Manitoba , open-funder-registry 10.13039/100008794;
                Funded by: University of Manitoba , open-funder-registry 10.13039/100010318;
                Categories
                Short Review
                Short Review
                Custom metadata
                2.0
                October 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.2 mode:remove_FC converted:10.10.2020

                adipose tissue,insulin resistance,lipotoxicity,liver,mitochondrial dysfunction,skeletal muscle

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