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      Associations of the Inflammatory Marker YKL-40 with Measures of Obesity and Dyslipidaemia in Individuals at High Risk of Type 2 Diabetes

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          Abstract

          Introduction

          Circulating levels of the inflammatory marker YKL-40 are elevated in cardiovascular disease and obesity-related type 2 diabetes (T2D), and serum YKL-40 levels are related to elements of dyslipidaemia.

          Objective

          We aimed to investigate the associations between serum YKL-40 and obesity-related traits in a Danish sample of non-diabetic relatives to T2D patients and, furthermore, to estimate the heritability of YKL-40.

          Research Design and Methods

          324 non-diabetic individuals with family relation to a T2D patient were included in the study. The participants underwent oral- and intravenous glucose tolerance tests for estimation of glucose tolerance and surrogate measures of insulin sensitivity. Anthropometric measures were retrieved and biochemical measures of the plasma lipid profile and serum YKL-40 levels were obtained. Association-analyses between serum YKL-40 and obesity-related traits and estimates of the narrow sense heritability of YKL-40 were based on a polygenic variance component model.

          Results

          Fasting serum levels of YKL-40 were positively associated with waist-hip-ratio (p<0.001) and fasting plasma triglyceride levels (p<0.001). None of the insulin sensitivity indexes were significantly associated with YKL-40. According to the AE model, the familiality-estimate h 2 of YKL-40 was 0.45 (SE 0.13). When the ACE-model was applied, the heritability-estimate h 2 of YKL-40 did not reach statistical significance.

          Conclusions

          Our results suggest a role of serum YKL-40 in obesity-related low grade inflammation, but do not indicate that YKL-40 is directly involved in the development of T2D.

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          Most cited references29

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          Adipose tissue dysfunction in obesity, diabetes, and vascular diseases.

          The classical perception of adipose tissue as a storage place of fatty acids has been replaced over the last years by the notion that adipose tissue has a central role in lipid and glucose metabolism and produces a large number of hormones and cytokines, e.g. tumour necrosis factor-alpha, interleukin-6, adiponectin, leptin, and plasminogen activator inhibitor-1. The increased prevalence of excessive visceral obesity and obesity-related cardiovascular risk factors is closely associated with the rising incidence of cardiovascular diseases and type 2 diabetes mellitus. This clustering of vascular risk factors in (visceral) obesity is often referred to as metabolic syndrome. The close relationship between an increased quantity of visceral fat, metabolic disturbances, including low-grade inflammation, and cardiovascular diseases and the unique anatomical relation to the hepatic portal circulation has led to an intense endeavour to unravel the specific endocrine functions of this visceral fat depot. The objective of this paper is to describe adipose tissue dysfunction, delineate the relation between adipose tissue dysfunction and obesity and to describe how adipose tissue dysfunction is involved in the development of diabetes mellitus type 2 and atherosclerotic vascular diseases. First, normal physiology of adipocytes and adipose tissue will be described.
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            Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes.

            There is increasing evidence that an ongoing cytokine-induced acute-phase response (sometimes called low-grade inflammation, but part of a widespread activation of the innate immune system) is closely involved in the pathogenesis of type 2 diabetes and associated complications such as dyslipidemia and atherosclerosis. Elevated circulating inflammatory markers such as C-reactive protein and interleukin-6 predict the development of type 2 diabetes, and several drugs with anti-inflammatory properties lower both acute-phase reactants and glycemia (aspirin and thiazolidinediones) and possibly decrease the risk of developing type 2 diabetes (statins). Among the risk factors for type 2 diabetes, which are also known to be associated with activated innate immunity, are age, inactivity, certain dietary components, smoking, psychological stress, and low birth weight. Activated immunity may be the common antecedent of both type 2 diabetes and atherosclerosis, which probably develop in parallel. Other features of type 2 diabetes, such as fatigue, sleep disturbance, and depression, are likely to be at least partly due to hypercytokinemia and activated innate immunity. Further research is needed to confirm and clarify the role of innate immunity in type 2 diabetes, particularly the extent to which inflammation in type 2 diabetes is a primary abnormality or partly secondary to hyperglycemia, obesity, atherosclerosis, or other common features of the disease.
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              Obesity, insulin resistance and free fatty acids.

              To describe the role of free fatty acid (FFA) as a cause for insulin resistance in obese people. Elevated plasma FFA levels can account for a large part of insulin resistance in obese patients with type 2 diabetes. Insulin resistance is clinically important because it is closely associated with several diseases including type 2 diabetes, hypertension, dyslipidemia and abnormalities in blood coagulation and fibrinolysis. These disorders are all independent risk factors for cardiovascular disease (heart attacks, strokes and peripheral arterial disease). The mechanisms by which FFA can cause insulin resistance, although not completely known, include generation of lipid metabolites (diacylglycerol), proinflammatory cytokines (TNF-α, IL-1β, IL-6, MCP1) and cellular stress including oxidative and endoplasmic reticulum stress. Increased plasma FFA levels are an important cause of obesity-associated insulin resistance and cardiovascular disease. Therapeutic application of this knowledge is hampered by the lack of readily accessible methods to measure FFA and by the lack of medications to lower plasma FFA levels.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                21 July 2015
                2015
                : 10
                : 7
                : e0133672
                Affiliations
                [1 ]Section of Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [2 ]Center of Endocrinology and Metabolism, Department of Medicine, Copenhagen University Hospital, Herlev, Denmark
                [3 ]Biostatistics, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [4 ]Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [5 ]Section of Molecular Diabetes & Metabolism, Institute of Clinical Research & Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
                [6 ]Institute of Biomedical Science, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [7 ]Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
                Sapienza University of Rome, ITALY
                Author notes

                Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: TH and OP hold personal shares in Novo Nordisk A/S. The remaining authors declare that there is no competing interest associated with this manuscript. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: HE TH OP. Performed the experiments: HE TH OP. Analyzed the data: APG CTE SBT. Contributed reagents/materials/analysis tools: OP HV. Wrote the paper: SBT APG CNR CTE HE TH OP HV. Conceived the idea for the paper: SBT APG CNR TH OP HV.

                Article
                PONE-D-15-11905
                10.1371/journal.pone.0133672
                4510434
                26197239
                17f90b0e-40dc-4b97-a822-6341dda4439d
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 22 March 2015
                : 30 June 2015
                Page count
                Figures: 0, Tables: 3, Pages: 10
                Funding
                The study was supported by grants from The Novo Nordisk Foundation, The Research Foundation of Copenhagen University Hospital Herlev, The Jacobsen Foundation and The A.P. Moeller and wife Chastine McKinney Moeller Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                The authors confirm that, for approved ethical reasons, some restrictions apply to the data underlying the findings. Data are available upon request from the Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics. The authors may be contacted at henrik.vestergaard@ 123456sund.ku.dk or torben.hansen@ 123456sund.ku.dk .

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