The Effect of Folate and Vitamin B6 on Endothelial Function in Children with Type 1 Diabetes Dr Karen E MacKenzie The Effect of Folate and Vitamin B6 on Endothelial Function in Children with Type 1 Diabetes Dr Karen Ellen MacKenzie Department of Paediatrics School of Medicine University of Adelaide 2009 A Thesis Submitted for the Degree of Doctor of Philosophy 1 The Effect of Folate and Vitamin B6 on Endothelial Function in Children with Type 1 Diabetes Dr Karen E MacKenzie 2 The Effect of Folate and Vitamin B6 on Endothelial Function in Children with Type 1 Diabetes Dr Karen E MacKenzie Table of Contents Abstract........................................................................................................................11 Introduction....................................................................................................................11 Methods.........................................................................................................................12 Results ..........................................................................................................................12 Conclusions...................................................................................................................13 Acknowledgments.......................................................................................................14 List of Tables ...............................................................................................................15 List of Figures..............................................................................................................17 Abbreviations...............................................................................................................19 Units .............................................................................................................................21 Chapter 1. Introduction ...............................................................................................22 Problem Statement........................................................................................................22 Generation of Hypotheses .............................................................................................24 Aims ..............................................................................................................................25 Research Strategy.........................................................................................................26 Chapter 2. Background ...............................................................................................29 Type 1 Diabetes ...........................................................................................................29 Type 1 Diabetes- Definition and Incidence.....................................................................29 Hypotheses for the Aetiology and Increasing Incidence of T1DM ..................................31 The Hygiene Hypothesis ....................................................................................31 The Accelerator Hypothesis ...............................................................................32 Vitamin D Hypothesis.........................................................................................34 Impact of Type 1 diabetes .............................................................................................35 Type 1 Diabetes- a Historical Perspective .....................................................................36 Endothelium and Atherosclerosis..............................................................................44 Anatomy of the Blood Vessel .............................................................................44 3 The Effect of Folate and Vitamin B6 on Endothelial Function in Children with Type 1 Diabetes Dr Karen E MacKenzie Normal Endothelium...........................................................................................44 The Endothelium and Nitric Oxide......................................................................45 Endothelial Dysfunction......................................................................................47 Endothelial Dysfunction and the Development of Atherosclerosis ......................47 Atherosclerosis in Children ............................................................................................51 Measurement of Endothelial Dysfunction.......................................................................52 Endothelial Dysfunction and Diabetes ...........................................................................54 Endothelial Dysfunction in Children with Type 1 Diabetes .............................................55 Recognised Contributory Factors to Endothelial Dysfunction.........................................56 Diet ....................................................................................................................56 Exercise .............................................................................................................56 Puberty ..............................................................................................................56 Smoking.............................................................................................................57 Insulin ................................................................................................................57 Reversibility of Endothelial Dysfunction..............................................................58 Diabetes and Vascular Disease ..................................................................................59 Macrovascular Complications........................................................................................59 Cardiovascular Disease.................................................................................................59 Cerebrovascular Disease ..............................................................................................61 Microvascular Complications .........................................................................................62 Retinopathy........................................................................................................62 Nephropathy ......................................................................................................62 Neuropathy ........................................................................................................64 Mechanisms underlying Vascular Disease in Diabetes ..................................................65 Polyol Pathway and Aldose Reductase..............................................................67 Advanced Glycation End (AGE) Products ..........................................................68 The Hexosamine Pathway. ................................................................................70 Protein Kinase C and Diacylglycerol ..................................................................70 Reactive Oxygen Species and Oxidative Stress.................................................72 Nitric Oxide ........................................................................................................73 Free Fatty Acids.................................................................................................74 Summary.......................................................................................................................74 Homocyst(e)ine............................................................................................................75 Homocyst(e)ine: The Background..................................................................................75 Metabolism of Homocysteine.........................................................................................76 4 The Effect of Folate and Vitamin B6 on Endothelial Function in Children with Type 1 Diabetes Dr Karen E MacKenzie Pathogenic Mechanism of Hyperhomocyst(e)inaemia ...................................................78 Homocyst(e)ine and Vascular Disease ..........................................................................80 Homocyst(e)ine and Diabetes........................................................................................81 The Controversies .........................................................................................................83 Folate............................................................................................................................85 Folate in the Prevention of Disease. ..............................................................................85 Folate and Homocyst(e)ine............................................................................................86 Folate Status, Homocyst(e)ine and Endothelial Function in Type 1 Diabetes ................87 Folate and Nitric Oxide ..................................................................................................90 Folate and Antioxidant Actions ......................................................................................91 Folate Dose ...................................................................................................................91 Safety Considerations....................................................................................................92 Vitamin B6....................................................................................................................94 Vitamin B6 Metabolism..................................................................................................94