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Heritability of Type 2 Diabetes and Related Traits

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Heritability of Type 2 Diabetes and Related Traits Department of Public Health and Finnish Institute for Molecular Medicine, University of Helsinki, Finland HERITABILITY OF TYPE 2 DIABETES AND RELATED TRAITS Mikko Lehtovirta ACADEMIC DISSERTATION To be presented, with the permission of the Faculty of Medicine at the University of Helsinki, for public examination in the Biomedicum 1 lecture hall 1, Helsinki on January 24th 2014, at 12 noon. Helsinki 2014 Publications of Public Health M220:2014 Supervisors Professor Jaakko Kaprio Department of Public Health Hjelt-institute, University of Helsinki Finnish Institute of Molecular Medicine (FIMM), University of Helsinki National Institute for Health and Welfare (THL), Helsinki Professor Leif Groop Finnish Academy FiDiPro-professor Finnish Institute of Molecular Medicine (FiMM), University of Helsinki Department of Clinical Science Malmö, Diabetes & Endocrinology, Lund University Reviewed by Docent Leo Niskanen, MD, PhD University of Eastern Finland, Kuopio, Finland Associate Professor Sofia Carlsson, PhD Karolinska Institute, Stockholm, Sweden Opponent Docent Heikki Koistinen, MD, PhD Department of Medicine, Division of Endocrinology Helsinki University Central Hospital ISSN 0355-7979 ISBN 978-952-10-6605-4 (paperback) ISBN 978-952-10-9654-9 (PDF) ethesis.helsinki.fi Unigrafia Helsinki 2014 I dedicate this work to my father, medical counsellor Erkki Lehtovirta, MD, PhD, who is an exceptional colleague. What more, he is a monozygotic twin, has participated in the Finnish Twin Cohort Study and wrote his doctoral thesis about obesity and glucose tolerance. TABLE OF Contents 1. LIST OF ORIGINAL PUBLICATIONS .........................................................5 1.1 PUBLICATIONS NOT INCLUDED IN THE DOCTORAL THESIS ....6 2. ABBREVIATIONS ........................................................................................8 3. LIST OF TABLES ........................................................................................12 4. LIST OF FIGURES .....................................................................................13 5. LIST OF EQUATIONS ................................................................................14 6. ABSTRACT ................................................................................................. 17 7. INTRODUCTION .......................................................................................21 8. REVIEW OF THE LITERATURE ..............................................................25 8.1 TYPE 2 DIABETES MELLITUS AND RELATED METABOLIC DISTURBANCES ................................................................................25 8.1.1 OBESITY................................................................................25 Definition and diagnosis of obesity .......................................25 Assessment of obesity ............................................................25 Genetics of obesity .................................................................27 8.1.2. TYPE 2 DIABETES MELLITUS .......................................... 28 Definition and diagnosis of type 2 diabetes ......................... 28 Epidemiology of type 2 diabetes ...........................................29 Genetics of type 2 diabetes ....................................................29 8.1.3 INSULIN SECRETION ........................................................ 30 Physiology of insulin secretion ..............................................31 Genetics of insulin secretion .................................................32 Assessment of insulin secretion ............................................32 Fasting values and indices .....................................................33 Non-steady-state methods ....................................................34 1 LEHTOVIRTA – Heritability of Type 2 Diabetes and Related Traits Steady-state methods: hyperglycaemic clamp ......................37 Minimal model and approaches to insulin secretion using C-peptide kinetics ........................................................37 Measurement of pulsatile insulin secretion ..........................42 8.1.4 INSULIN ACTION ................................................................43 Insulin sensitivity and insulin resistance ..............................44 History of insulin resistance ..................................................44 Definition of insulin resistance .............................................45 Genetics of insulin resistance ................................................46 Assessment of insulin sensitivity or insulin resistance ........47 Fasting values and indices .................................................... 48 Non-steady-state methods ....................................................49 Steady-state methods ............................................................55 Limb balance techniques .......................................................57 Combined methods................................................................58 8.1.5 REPRODUCIBILITY OF ASSESSMENT METHODS .........59 8.2 METHODOLOGY FOR THE STUDY OF VARIABILITY AMONG INDIVIDUALS ................................................................... 60 8.2.1 HISTORY OF QUANTITATIVE GENETICS ....................... 60 8.2.2 TWIN STUDIES ....................................................................62 8.2.3 HERITABILITY .....................................................................63 Definition of the statistics of similarity .................................64 Genotypes and population frequencies .................................65 Decomposition of variances ..................................................66 Bivariate model ......................................................................67 Heritability .............................................................................69 Intraclass correlations and concordances .............................69 8.2.4 STATISTICAL METHODS ....................................................70 Structural equation modelling and path analysis .................70 2 8.3 GENETICS OF COMPLEX DISORDERS ..........................................72 9. AIMS OF THE STUDY ...............................................................................76 10. MATERIALS AND METHODS ..................................................................77 10.1 STUDY SUBJECTS .............................................................................77 10.1.1 THE FINNISH TWIN COHORT STUDY .............................77 10.1.2 THE BOTNIA STUDY ...........................................................77 10.1.3 DATA COMPILATION .........................................................78 Studies I to III ........................................................................78 Study IV .................................................................................78 Study V ...................................................................................79 10.2 METHODS ......................................................................................... 80 10.2.1 ANTHROPOMETRIC, BODY COMPOSITION AND BLOOD PRESSURE MEASUREMENTS ............................. 80 10.2.2 ASSESSMENT OF INSULIN SECRETION AND GLUCOSE METABOLISM ................................................... 80 OGTT: studies II, III and V .................................................. 80 IVGTT and clamp tests ..........................................................81 IVGTT: studies I and II .........................................................81 Clamp tests: studies I and II..................................................81 Botnia clamp ..........................................................................81 10.2.3 LABORATORY ASSAYS ....................................................... 82 10.2.4 CALCULATIONS .................................................................. 82 Beta cell function .................................................................. 82 Insulin sensitivity ................................................................. 83 10.2.5 STATISTICAL METHODS ................................................... 83 Twin correlations and variance components in studies I to IV ........................................................................ 84 Heritability of type 2 diabetes and quantitative traits in the Botnia Study, study V ........................................85 11. RESULTS ....................................................................................................87 3 LEHTOVIRTA – Heritability of Type 2 Diabetes and Related Traits 11.1 CLINICAL CHARACTERISTICS ........................................................87 11.2 PHENOTYPIC CORRELATIONS ...................................................... 89 11.3 BMI AND THE RISK OF DEVELOPING TYPE 2 DIABETES MELLITUS (STUDY IV) .................................................................... 89 11.4 TWIN CORRELATIONS ................................................................... 89 11.5 HERITABILITY OF TYPE 2 DIABETES AND ASSOCIATED TRAITS .......................................................................91 11.5.1 DIRECT ESTIMATES OF HERITABILITY .......................... 91 11.5.2 INDIRECT ESTIMATES OF HERITABILITY ......................92 11.5.3 BIVARIATE ANALYSIS ........................................................93 12. DISCUSSION ..............................................................................................95 13. SUMMARY AND CONCLUSIONS .............................................................99 14. ACKNOWLEDGEMENTS .......................................................................
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