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Graveling2015.Pdf This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Hypoglycaemia in children and adults with type 1 diabetes: clinical implications A thesis by Dr Alex J. Graveling MBChB, MRCP (UK) Dissertation presented for the degree of MD (Doctor of Medicine) University of Edinburgh 2015 Page left intentionally blank 2 Declaration 1) This thesis was composed by Alex Graveling 2) Study described in chapter 6 was performed by Dr. Alex Graveling. With the aid of his two supervisors Prof. Brian Frier and Prof. Ian Deary, he wrote the protocol, applied for ethical approval, recruited the participants, executed the glucose clamp procedures, recorded and analysed the data and performed the statistical analysis. Study described in chapter 7 was performed by Dr. Alex Graveling. Dr. Rohana Wright applied for ethical approval and wrote the protocol which was later amended by Dr. Alex Graveling. With the aid of his supervisors Prof. Brian Frier and Prof. Ian Deary he recruited the participants, carried out the initial interviews, collected the subsequent questionnaires and blood glucose diaries, recorded and analysed the data and performed the majority of the statistical analysis. Dr. Mike Allerhand performed the multinomial logistic regression. Study described in chapter 8 was conducted by Dr. Alex Graveling. Prof. Brian Frier supervised the study protocol and advised on the data analysis. Dr. Roderick Warren provided assistance with the statistical analysis and drafted the submitted manuscript for publication. 3) Alex Graveling holds the degree MBChB 4) This thesis has not been submitted for any other degree, diploma or professional qualification. Alex Graveling Signature: __________________ Date: ____________ 3 Lay summary The University of Edinburgh Abstract of Thesis Candidate Name Alex James Graveling Address 70 Blenheim Place, Aberdeen, AB25 2DY Degree MD (Doctor of Medicine) Title Hypoglycaemia in children and adults with type 1 diabetes: clinical implications Total Word Count 85882 4 Lay summary MD Proposal Edinburgh University Student: Doctor Alex J. Graveling Supervisor: Professor Brian M. Frier The proposed thesis will examine three areas of research: (1) the effects of hypoglycaemia on cognitive function in adults with and without T1DM, (2) the symptoms and awareness of hypoglycaemia in children and adolescents with T1DM and (3) hypoglycaemia and driving in people with insulin-treated diabetes: self-treatment and adherence to recommendations for avoidance. (1) Executive cognitive function governs organisation of thoughts, prioritisation of tasks, and time management. This study examined the effect of acute hypoglycaemia on executive function in adults with and without diabetes. Thirty-two adults with and without type 1 diabetes were studied. Two hyperinsulinaemic glucose clamps were performed at least 2 weeks apart in a single-blind, counterbalanced order. Executive functions were assessed with a validated test suite (Delis-Kaplan Executive Function). A general linear model (repeated-measures ANOVA) was used. Compared with euglycaemia, executive functions (with one exception) were significantly impaired during hypoglycaemia; lower test scores were recorded with more time required for completion. Large Cohen d values (>0.8) suggest that hypoglycaemia induces decrements in aspects of executive function with large effect sizes. In some tests, the performance of participants with diabetes was more impaired than those without diabetes. Executive cognitive function, which is necessary to carry out many everyday activities, is impaired during hypoglycaemia in adults with and without type 1 diabetes. (2) In children with type 1 diabetes mellitus (T1DM) the prevalence of impaired awareness of hypoglycaemia (IAH) is uncertain. Questionnaires were completed by 98 children with T1DM (mean age 10.6 years) and their parent(s); hospital admission data for the previous year were collected. 5 Lay summary Awareness of hypoglycaemia was assessed using two questionnaire-based methods that have been validated in adults. For 4 weeks, participants performed routine blood glucose measurements and completed questionnaires after each episode of hypoglycaemia. The ‘Gold’ questionnaire classified a greater proportion of the participants as having IAH than the ‘Clarke’ questionnaire (68.4 vs. 22.4%). Using the ‘Clarke’ method, but not the ‘Gold’ method, children with IAH were younger and more likely to require external assistance or hospital admission. In contrast to adults, behavioural symptoms were the best predictors of awareness status. IAH affects a substantial minority of children and impending hypoglycaemia may be heralded by behavioural symptoms. The ‘Clarke’ method was more effective at identifying those at increased risk. (3) A clinical survey of an outpatient clinic population to ascertain current knowledge and practice among drivers with insulin-treated diabetes. A representative sample of 202 current drivers with insulin-treated diabetes completed a structured questionnaire. A minimum blood glucose level of 4.0 mmol/L or higher was considered necessary for driving by 74.8%, and 87.1% reported always keeping carbohydrate in their vehicle. However, 38.1% reported never carrying a glucose meter when driving, and 59.9% that they never test blood glucose before driving, or test only if symptomatic of hypoglycaemia. Most participants 89% would stop driving to treat hypoglycaemia although only 13.9% would wait longer than 30 min. Compliance with statutory requirements to inform the licensing authority and motor insurer is good. 6 Acknowledgements Acknowledgements I am completely indebted to Professor Brian Frier who was the principal driving force behind all of the work presented in this thesis. His enthusiasm and willingness to share his knowledge was always appreciated despite his busy work commitments. Without his enthusiasm and commitment this thesis would not exist. I am very grateful to Professor Ian Deary who provided such sound advice regarding the cognitive function and paediatric studies. In particular his statistical expertise proved invaluable in the first two studies described within this thesis. I would also like to thank Margaret Boyd with whom I shared an office for 2 years and who provided me with frequent support. Her knowledge and practical suggestions made my life much easier. I would also like to thank Dr. Jacqueline Geddes who supervised my first clamp studies and provided practical assistance. I would also like to thank Dr. Rohana Wright who provided advice and help in designing the paediatric study. I would also like to thank the research nurses in the Wellcome Trust Clinical Research Facility in the Royal Infirmary of Edinburgh. 7 Abbreviations & dedication Abbreviations The below abbreviations are used throughout this thesis: CGM Continuous glucose monitoring IAH Impaired awareness of hypoglycaemia T1DM Type 1 diabetes mellitus T2DM Type 2 diabetes mellitus Dedication For Sylvie & Ruby 8 Contents Table of contents Declaration ........................................................................................................ 3 Abstract of Thesis ............................................................................................. 4 Lay summary of thesis ....................................... Error! Bookmark not defined. Acknowledgements ........................................................................................... 7 Abbreviations .................................................................................................... 8 Dedication .......................................................................................................... 8 Table of contents ............................................................................................... 9 Index of tables and figures ............................................................................. 21 Search strategy ................................................................................................ 26 Chapter 1 ......................................................................................................... 27 1.1 Introduction to hypoglycaemia .................................................... 27 1.2 Historical aspects of hypoglycaemia ........................................... 28 1.3 Definition of hypoglycaemia ....................................................... 30 1.4 Frequency of hypoglycaemia ....................................................... 31 1.41 Frequency of hypoglycaemia in T1DM ........................ 31 1.42 Frequency of hypoglycaemia in the paediatric population with T1DM ............................................................................... 34 1.43 Frequency of hypoglycaemia in T2DM
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