From INSTITUTE OF ENVIRONMENTAL MEDICINE Karolinska Institutet, Stockholm, Sweden EPIDEMIOLOGICAL STUDIES OF FRUCTOSAMINE IN RELATION TO DIABETES, CARDIOVASCULAR DISEASE AND MORTALITY Håkan Malmström Stockholm 2017 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Eprint AB 2017 © HåkanMalmström, 2017 ISBN 978-91-7676-634-7 Epidemiological studies of fructosamine in relation to diabetes, cardiovascular disease and mortality THESIS FOR DOCTORAL DEGREE (Ph.D.) By Håkan Malmström Principal Supervisor: Opponent: Professor Niklas Hammar Professor Markku Peltonen Karolinska Institutet National Institute of Health and Welfare, Finland Institute of Environmental Medicine Department of Public Health Solutions Unit of Epidemiology Chronic Disease Prevention Unit Co-supervisor(s): Examination Board: Professor Göran Walldius Docent Magnus Stenbeck Karolinska Institutet Karolinska institutet Institute of Environmental Medicine Department of Clinical Neuroscience Unit of Cardiovascular Epidemiology Division of Insurance Medicine Docent Sofia Carlsson Docent Bruna Gigante Karolinska Institutet Karolinska institutet Institute of Environmental Medicine Institute of Environmental Medicine Unit of Epidemiology Unit of Cardiovascular Epidemiology Professor Valdemar Grill Professor Fredrik Nyström Norwegian University of Science and Technology Linköping University Department of Cancer Research and Molecular Department of Medical and Health Sciences Medicine Division of Cardiovascular Medicine Table of Contents ABSTRACT ....................................................................................................................................................................... 7 LIST OF SCIENTIFIC PAPERS ............................................................................................................................................ 9 LIST OF ABBREVIATIONS .............................................................................................................................................. 11 INTRODUCTION ............................................................................................................................................................ 13 BACKGROUND .............................................................................................................................................................. 15 DIABETES MELLITUS AND CARDIOVASCULAR DISEASE .................................................................................................................... 15 Types of diabetes ........................................................................................................................................................ 16 BIOCHEMICAL RISK MARKERS FOR DIABETES, CVD AND MORTALITY ............................................................................................... 16 Glycemic exposure ...................................................................................................................................................... 16 Lipids and lipoproteins ................................................................................................................................................ 17 Inflammatory related exposure .................................................................................................................................. 18 RISK FACTORS AND DIAGNOSIS OF TYPE 2 DIABETES ..................................................................................................................... 19 Risk factors for T2D and CVD ...................................................................................................................................... 19 Risk prediction models for T2D ................................................................................................................................... 19 Diagnostic criteria of diabetes .................................................................................................................................... 20 Early identification of type 2 diabetes ........................................................................................................................ 20 FRUCTOSAMINE .................................................................................................................................................................... 21 Historical background ................................................................................................................................................. 21 Biochemical aspect ..................................................................................................................................................... 21 Clinical aspect .............................................................................................................................................................. 21 Research observations in previous studies on fructosamine ..................................................................................... 22 CURRENT KNOWLEDGE GAP .................................................................................................................................................... 24 AIMS OF THE THESIS..................................................................................................................................................... 25 OVERALL AIM ....................................................................................................................................................................... 25 Specific aims ................................................................................................................................................................ 25 MATERIALS & METHODS .............................................................................................................................................. 27 THE AMORIS COHORT ......................................................................................................................................................... 27 Reasons for referral ..................................................................................................................................................... 27 Laboratory analyses .................................................................................................................................................... 28 Associations of fructosamine in the AMORIS population .......................................................................................... 29 REGISTER DATA LINKED TO AMORIS ........................................................................................................................................... 30 National patient register............................................................................................................................................. 31 National cause of death register ................................................................................................................................ 31 National diabetes registry .......................................................................................................................................... 31 Lifestyle ........................................................................................................................................................................ 32 Migration and social factors ....................................................................................................................................... 32 STUDY METHODS .................................................................................................................................................................. 33 RESULTS ........................................................................................................................................................................ 37 STUDY I ............................................................................................................................................................................... 37 STUDY II .............................................................................................................................................................................. 40 STUDY III ............................................................................................................................................................................. 43 STUDY IV ............................................................................................................................................................................. 46 DISCUSSION .................................................................................................................................................................. 49 MAIN FINDINGS .................................................................................................................................................................... 49 METHODOLOGICAL REFLECTIONS ............................................................................................................................................. 50 Selection bias ............................................................................................................................................................... 50 Confounding ...............................................................................................................................................................