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Association between insulin resistance and the development of cardiovascular disease

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      Abstract

      For many years, cardiovascular disease (CVD) has been the leading cause of death around the world. Often associated with CVD are comorbidities such as obesity, abnormal lipid profiles and insulin resistance. Insulin is a key hormone that functions as a regulator of cellular metabolism in many tissues in the human body. Insulin resistance is defined as a decrease in tissue response to insulin stimulation thus insulin resistance is characterized by defects in uptake and oxidation of glucose, a decrease in glycogen synthesis, and, to a lesser extent, the ability to suppress lipid oxidation. Literature widely suggests that free fatty acids are the predominant substrate used in the adult myocardium for ATP production, however, the cardiac metabolic network is highly flexible and can use other substrates, such as glucose, lactate or amino acids. During insulin resistance, several metabolic alterations induce the development of cardiovascular disease. For instance, insulin resistance can induce an imbalance in glucose metabolism that generates chronic hyperglycemia, which in turn triggers oxidative stress and causes an inflammatory response that leads to cell damage. Insulin resistance can also alter systemic lipid metabolism which then leads to the development of dyslipidemia and the well-known lipid triad: (1) high levels of plasma triglycerides, (2) low levels of high-density lipoprotein, and (3) the appearance of small dense low-density lipoproteins. This triad, along with endothelial dysfunction, which can also be induced by aberrant insulin signaling, contribute to atherosclerotic plaque formation. Regarding the systemic consequences associated with insulin resistance and the metabolic cardiac alterations, it can be concluded that insulin resistance in the myocardium generates damage by at least three different mechanisms: (1) signal transduction alteration, (2) impaired regulation of substrate metabolism, and (3) altered delivery of substrates to the myocardium. The aim of this review is to discuss the mechanisms associated with insulin resistance and the development of CVD. New therapies focused on decreasing insulin resistance may contribute to a decrease in both CVD and atherosclerotic plaque generation.

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      Global and societal implications of the diabetes epidemic.

      Changes in human behaviour and lifestyle over the last century have resulted in a dramatic increase in the incidence of diabetes worldwide. The epidemic is chiefly of type 2 diabetes and also the associated conditions known as 'diabesity' and 'metabolic syndrome'. In conjunction with genetic susceptibility, particularly in certain ethnic groups, type 2 diabetes is brought on by environmental and behavioural factors such as a sedentary lifestyle, overly rich nutrition and obesity. The prevention of diabetes and control of its micro- and macrovascular complications will require an integrated, international approach if we are to see significant reduction in the huge premature morbidity and mortality it causes.
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        The metabolic syndrome.

        The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated. A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and cardiovascular disease risk reduction.
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          Oxidative stress and diabetic complications.

          Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized ("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.
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            Author and article information

            Affiliations
            [1 ]ISNI 0000 0001 2298 9663, GRID grid.5380.e, Faculty of Biological Sciences, Pharmacology Department, , University of Concepcion, ; Concepción, Chile
            [2 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine + Biomedical Sciences, , The University of Queensland, ; Brisbane, Australia
            [3 ]ISNI 0000 0001 2298 9663, GRID grid.5380.e, Faculty of Pharmacy, Department of Clinical Biochemistry and Immunology, , University of Concepcion, ; Concepción, Chile
            [4 ]Department of Obstetrics and Gynecology, Ochsner Baptist Hospital, New Orleans, Louisiana USA
            Contributors
            vormazabal@udec.cl
            s.nair@uq.edu.au
            S4337714@student.uq.edu.au
            caguayo@udec.cl
            ORCID: http://orcid.org/0000-0003-4474-0046, +61 7 33465500 , c.salomongallo@uq.edu.au
            fzuniga@udec.cl
            Journal
            Cardiovasc Diabetol
            Cardiovasc Diabetol
            Cardiovascular Diabetology
            BioMed Central (London )
            1475-2840
            31 August 2018
            31 August 2018
            2018
            : 17
            30170598 6119242 762 10.1186/s12933-018-0762-4
            © The Author(s) 2018

            Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

            Funding
            Funded by: FundRef http://dx.doi.org/10.13039/501100002850, Fondo Nacional de Desarrollo Científico y Tecnológico;
            Award ID: 1170809
            Award Recipient :
            Funded by: Lions Medical Research Foundation
            Funded by: FundRef http://dx.doi.org/10.13039/501100000971, Diabetes Australia;
            Categories
            Review
            Custom metadata
            © The Author(s) 2018

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