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      Relationship between serum bilirubin levels, urinary biopyrrin levels, and retinopathy in patients with diabetes

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          Abstract

          Objective

          Previous reports have indicated that serum bilirubin levels may be associated with diabetic retinopathy. However, the detailed mechanism is not fully understood. In this study, we evaluated the relationship between the severity of diabetic retinopathy and various factors including bilirubin levels and factors influencing bilirubin metabolism.

          Methods

          The study participants consisted of 94 consecutive patients with diabetes mellitus admitted to Kyushu University Hospital from April 2011 to July 2012. The patients were classified into three groups: no retinopathy (NDR), simple retinopathy (SDR), and pre-proliferative or proliferative retinopathy (PDR). The relationship between the severity of retinopathy and various factors was evaluated using univariate and logistic regression analyses. In addition, multivariate regression analysis was performed to evaluate the significant determinants for bilirubin levels.

          Results

          In univariate analysis, a significant difference was found among NDR, SDR and PDR in bilirubin levels, duration of diabetes, systolic blood pressure, and macroalbuminuria. Logistic regression analysis showed that PDR was significantly associated with bilirubin levels, duration of diabetes, and systolic blood pressure (OR 0.737, 95% CI 0.570–0.952, P = 0.012; OR 1.085, 95% CI 1.024–1.149, P = 0.006; OR 1.036, 95% CI 1.011–1.062, P = 0.005, respectively). In turn, multivariate regression analysis showed that bilirubin levels were negatively associated with high-sensitivity C-reactive protein levels and PDR, but positively correlated with urinary biopyrrin levels, oxidized metabolites of bilirubin.

          Conclusion

          PDR was negatively associated with bilirubin levels. This negative association may be due to a decreased production of bilirubin rather than its increased consumption considering the positive association between bilirubin and biopyrrin levels.

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          Most cited references38

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          Diabetic retinopathy.

          Diabetic retinopathy is a common and specific microvascular complication of diabetes, and remains the leading cause of preventable blindness in working-aged people. It is identified in a third of people with diabetes and associated with increased risk of life-threatening systemic vascular complications, including stroke, coronary heart disease, and heart failure. Optimum control of blood glucose, blood pressure, and possibly blood lipids remains the foundation for reduction of risk of retinopathy development and progression. Timely laser therapy is effective for preservation of sight in proliferative retinopathy and macular oedema, but its ability to reverse visual loss is poor. Vitrectomy surgery might occasionally be needed for advanced retinopathy. New therapies, such as intraocular injection of steroids and antivascular endothelial growth-factor agents, are less destructive to the retina than are older therapies, and could be useful in patients who respond poorly to conventional therapy. The outlook for future treatment modalities, such as inhibition of other angiogenic factors, regenerative therapy, and topical therapy, is promising. Copyright 2010 Elsevier Ltd. All rights reserved.
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            Bilirubin is an antioxidant of possible physiological importance

            Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, it is here that bilirubin, at micromolar concentrations in vitro, efficiently scavenges peroxyl radicals generated chemically in either homogeneous solution or multilamellar liposomes. The antioxidant activity of bilirubin increases as the experimental concentration of oxygen is decreased from 20% (that of normal air) to 2% (physiologically relevant concentration). Furthermore, under 2% oxygen, in liposomes, bilirubin suppresses the oxidation more than alpha-tocopherol, which is regarded as the best antioxidant of lipid peroxidation. The data support the idea of a "beneficial" role for bilirubin as a physiological, chain-breaking antioxidant.
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              Molecular understanding of hyperglycemia's adverse effects for diabetic complications.

              Diabetic complications are the major cause of morbidity and mortality in persons with diabetes. Chronic hyperglycemia is a major initiator of diabetic microvascular complications (eg, retinopathy, neuropathy, nephropathy). Glucose processing uses a variety of diverse metabolic pathways; hence, chronic hyperglycemia can induce multiple cellular changes leading to complications. Several predominant well-researched theories have been proposed to explain how hyperglycemia can produce the neural and vascular derangements that are hallmarks of diabetes. These theories can be separated into those that emphasize the toxic effects of hyperglycemia and its pathophysiological derivatives (such as oxidants, hyperosmolarity, or glycation products) on tissues directly and those that ascribe pathophysiological importance to a sustained alteration in cell signaling pathways (such as changes in phospholipids or kinases) induced by the products of glucose metabolism. This article summarizes these theories and the potential therapeutic interventions that may prevent diabetic complications in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Visualization
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SoftwareRole: SupervisionRole: Validation
                Role: ConceptualizationRole: Project administrationRole: SupervisionRole: Validation
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SoftwareRole: SupervisionRole: ValidationRole: Visualization
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                11 February 2021
                2021
                : 16
                : 2
                : e0243407
                Affiliations
                [1 ] Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
                [2 ] Fukuoka City Health Promotion Support Center, Fukuoka City Medical Association, Fukuoka City, Japan
                Medical School, University of Zagreb, CROATIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-0834-2836
                https://orcid.org/0000-0002-7344-6199
                Article
                PONE-D-20-36442
                10.1371/journal.pone.0243407
                7877782
                33571217
                df1701d7-b00c-480c-b627-3b7aaae116b9
                © 2021 Kudo et al

                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
                : 19 November 2020
                : 21 January 2021
                Page count
                Figures: 1, Tables: 3, Pages: 10
                Funding
                Funded by: This work was supported in part by a grant for the Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Funding program “Innovation Center for Medical Redox Navigation”). There was no additional external funding recieved for this study.
                Award Recipient :
                This work was supported in part by a grant for the Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Funding program “Innovation Center for Medical Redox Navigation”). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for the study.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Bile
                Bilirubin
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Bile
                Bilirubin
                Biology and Life Sciences
                Physiology
                Body Fluids
                Bile
                Bilirubin
                Medicine and Health Sciences
                Endocrinology
                Endocrine Disorders
                Diabetes Mellitus
                Medicine and Health Sciences
                Medical Conditions
                Metabolic Disorders
                Diabetes Mellitus
                Medicine and Health Sciences
                Medical Conditions
                Eye Diseases
                Retinal Disorders
                Retinopathy
                Diabetic Retinopathy
                Medicine and Health Sciences
                Ophthalmology
                Eye Diseases
                Retinal Disorders
                Retinopathy
                Diabetic Retinopathy
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Medicine and health sciences
                Diagnostic medicine
                Diabetes diagnosis and management
                HbA1c
                Biology and life sciences
                Biochemistry
                Proteins
                Hemoglobin
                HbA1c
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Regression Analysis
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Regression Analysis
                Biology and Life Sciences
                Cell Biology
                Oxidative Stress
                Biology and Life Sciences
                Biochemistry
                Antioxidants
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

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