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      Pathophysiology of Type 2 Diabetes Mellitus

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          Abstract

          Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM.

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          PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.

          DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1alpha and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.
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            Global aetiology and epidemiology of type 2 diabetes mellitus and its complications

            Globally, the number of people with diabetes mellitus has quadrupled in the past three decades, and diabetes mellitus is the ninth major cause of death. About 1 in 11 adults worldwide now have diabetes mellitus, 90% of whom have type 2 diabetes mellitus (T2DM). Asia is a major area of the rapidly emerging T2DM global epidemic, with China and India the top two epicentres. Although genetic predisposition partly determines individual susceptibility to T2DM, an unhealthy diet and a sedentary lifestyle are important drivers of the current global epidemic; early developmental factors (such as intrauterine exposures) also have a role in susceptibility to T2DM later in life. Many cases of T2DM could be prevented with lifestyle changes, including maintaining a healthy body weight, consuming a healthy diet, staying physically active, not smoking and drinking alcohol in moderation. Most patients with T2DM have at least one complication, and cardiovascular complications are the leading cause of morbidity and mortality in these patients. This Review provides an updated view of the global epidemiology of T2DM, as well as dietary, lifestyle and other risk factors for T2DM and its complications.
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              ROS function in redox signaling and oxidative stress.

              Oxidative stress refers to elevated intracellular levels of reactive oxygen species (ROS) that cause damage to lipids, proteins and DNA. Oxidative stress has been linked to a myriad of pathologies. However, elevated ROS also act as signaling molecules in the maintenance of physiological functions--a process termed redox biology. In this review we discuss the two faces of ROS--redox biology and oxidative stress--and their contribution to both physiological and pathological conditions. Redox biology involves a small increase in ROS levels that activates signaling pathways to initiate biological processes, while oxidative stress denotes high levels of ROS that result in damage to DNA, protein or lipids. Thus, the response to ROS displays hormesis, given that the opposite effect is observed at low levels compared with that seen at high levels. Here, we argue that redox biology, rather than oxidative stress, underlies physiological and pathological conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                30 August 2020
                September 2020
                : 21
                : 17
                : 6275
                Affiliations
                [1 ]Fundación Biofisika Bizkaia, Barrio Sarriena s/n., 48940 Leioa (Bizkaia), Spain; u.galiciag@ 123456gmail.com (U.G.-G.); asierlarrea@ 123456yahoo.es (A.L.-S.)
                [2 ]Biofisika Institute (UPV/EHU, CSIC), Barrio Sarriena s/n., 48940 Leioa (Bizkaia), Spain; asier.benito@ 123456ehu.eus (A.B.-V.); sjebari001@ 123456ikasle.ehu.eus (S.J.); ofbmaplc@ 123456ehu.es (H.O.)
                [3 ]Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, Apdo. 644, 48080 Bilbao, Spain
                [4 ]Havard Medical School, 25 Shattuck St, Boston, MA 02115, USA; siddiqi.haziq1@ 123456gmail.com
                [5 ]Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramon 182, 20014 Donostia San Sebastián, Spain; kbelloso@ 123456cicbiomagune.es
                Author notes
                [* ]Correspondence: cesar.martin@ 123456ehu.eus ; Tel.: +34-94-601-8052
                Author information
                https://orcid.org/0000-0002-4087-8729
                Article
                ijms-21-06275
                10.3390/ijms21176275
                7503727
                32872570
                15303749-7e4a-4da6-9b72-9ce56fc14ee6
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 August 2020
                : 28 August 2020
                Categories
                Review

                Molecular biology
                type 2 diabetes mellitus,insulin resistance,β-cell,liver,adipocyte,muscle,cardiovascular disease,pathophysiology

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