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  1. 1. Evidence-basedPaediatric andAdolescent DiabetesEdited byJeremy AllgroveBarts and the London NHS TrustRoyal London HospitalLondon, UKPeter G.F. SwiftLeicester Royal InfirmaryChildren’s HospitalLeicester, UKStephen GreeneUniversity of DundeeDepartment of Maternal and Child Health SciencesNinewells HospitalDundee, UK
  2. 2. Evidence-basedPaediatric andAdolescent DiabetesEdited byJeremy AllgroveBarts and the London NHS TrustRoyal London HospitalLondon, UKPeter G.F. SwiftLeicester Royal InfirmaryChildren’s HospitalLeicester, UKStephen GreeneUniversity of DundeeDepartment of Maternal and Child Health SciencesNinewells HospitalDundee, UK
  3. 3. C 2007 by Blackwell PublishingBMJ Books is an imprint of the BMJ Publishing Group Limited, used under licenceBlackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USABlackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UKBlackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, AustraliaThe right of the Author to be identified as the Author of this Work has been asserted inaccordance with the Copyright, Designs and Patents Act 1988.All rights reserved. No part of this publication may be reproduced, stored in a retrievalsystem, or transmitted, in any form or by any means, electronic, mechanical,photocopying, recording or otherwise, except as permitted by the UK Copyright, Designsand Patents Act 1988, without the prior permission of the publisher.First published1 2007Library of Congress Cataloging-in-Publication DataEvidence-based paediatric and adolescent diabetes / edited by Jeremy Allgrove, Peter G.F.Swift, Stephen Greene. p. ; cm. “BMJ books.” Includes bibliographical references. ISBN 978-1-4051-5292-1 (hardback)1. Diabetes in children. 2. Diabetes in adolescence. 3. Evidence-based medicine.I. Allgrove, Jeremy. II. Swift, Peter G. F. III. Greene, Stephen A.[DNLM: 1. Diabetes Mellitus. 2. Adolescent. 3. Child. 4. Evidence-Based Medicine.WK 810 E93 2007]RJ420.D5.E95 2007618.3 646–dc22 2007013626ISBN: 978-1-4051-5292-1A catalogue record for this title is available from the British LibrarySet in 9.5/12 Minion by Aptara Inc., New Delhi, IndiaPrinted and bound in Singapore by Markono Print Media Pte LtdCommissioning Editor: Mary BanksEditorial Assistant: Victoria PittmanDevelopment Editor: Simone DudziakProduction Controller: Rachel EdwardsFor further information on Blackwell Publishing, visit our website:http://www.blackwellpublishing.comThe publisher’s policy is to use permanent paper from mills that operate a sustainableforestry policy, and which has been manufactured from pulp processed using acid-free andelementary chlorine-free practices. Furthermore, the publisher ensures that the text paperand cover board used have met acceptable environmental accreditation standards.Blackwell Publishing makes no representation, express or implied, that the drug dosages inthis book are correct. Readers must therefore always check that any product mentioned inthis publication is used in accordance with the prescribing information prepared by themanufacturers. The author and the publishers do not accept responsibility or legal liabilityfor any errors in the text or for the misuse or misapplication of material in this book.
  4. 4. Contents List of contributors, v Foreword, ix Preface, xi 1 Methodology of evidence-based medicine, 1 Jeremy Allgrove 2 Definition, epidemiology and classification of diabetes and structure of the diabetes team, 9 Maria Craig, Sarah J. Glastras & Kim Donaghue 3 Aetiology of type 1 diabetes mellitus – genetics, autoimmunity and trigger factors, 26 Loredana Marcovecchio, David B. Dunger, Mark Peakman & Keith W. Taylor 4 Type 1 diabetes mellitus – management, 42 Joanne J. Spinks, Julie A. Edge, Krystyna Matyka & Shital Malik 5 Type 1 diabetes mellitus in the very young child, 63 Stuart Brink 6 Adolescence and diabetes: clinical and social science perspectives, 76 Alexandra Greene & Stephen Greene 7 Management of special situations in diabetes, 93 Fergus J. Cameron & Jeremy Allgrove 8 Dietary management: optimising diabetes outcomes, 104 Sheridan Waldron 9 Education in childhood diabetes, 123 Peter G.F. Swift10 Psychological interventions in childhood diabetes, 141 John W. Gregory & Sue Channon11 Screening for associated conditions and prevention of complications, 157 Catherine Peters & Jeremy Allgrove12 Type 2 diabetes mellitus – genetics, diagnosis and management. Polycystic ovarian syndrome, 175 John Porter & Timothy G. Barrett iii
  5. 5. Contents13 Rare forms of diabetes, 197 Julian Shield, Maciej T. Malecki, Nicola A. Bridges & Jeremy Allgrove14 Diabetes and information technology, 221 Kenneth J. Robertson Abbreviations, 228 Index, 232 iv
  6. 6. ContributorsJeremy Allgrove MB BChir, MA, Children’s CentreMD, FRCP, FRCPCH St David’s Hospital CantonConsultant in Paediatric Endocrinology and Cardiff, UK DiabetesBarts and the London NHS Trust Maria Craig, MB BS, PhD, FRACP,Royal London Hospital MMed (ClinEpid)London, UK Paediatric Endocrinologist Institute of Endocrinology and DiabetesTimothy G. Barrett PhD, MB BS, Children’s Hospital WestmeadMRCP, MRCPCH, DCH Westmead, AustraliaProfessor of PaediatricsInstitute of Child Health Kim Donaghue, MB BS, PhD,Birmingham, UK FRACP Associate ProfessorNicola A. Bridges, DM, MRCP, Head of Diabetes ServicesFRCPCH The Children’s Hospital at WestmeadConsultant Paediatric Endocrinologist University of SydneyChelsea and Westminster Hospital Westmead, AustraliaLondon, UK David B. Dunger, MD, FRCPCHStuart Brink, MD Professor of PaediatricsSenior Endocrinologist Department of PaediatricsNew England Diabetes and Endocrinology Addenbrooke’s NHS Trust Center (NEDEC) Cambridge, UKAssociate Clinical Professor of PediatricsTufts University School of MedicineWaltham, USA Julie A. Edge, MD, FRCPCH Consultant in Paediatric DiabetesFergus J. Cameron and EndocrinologyAssociate Professor Department of PaediatricsHead Diabetes Services John Radcliffe HospitalDeputy Director Oxford, UKDepartment of Endocrinology and DiabetesRoyal Children’s Hospital Sarah J. Glastras, MB BS(Hons),Parkville, Australia BSc Psychol(Hons) Junior Medical OfficerSue Channon, BSc D Clin Psych Institute of Endocrinology and DiabetesConsultant Clinical Psychologist The Children’s Hospital at WestmeadChild Psychology Department Westmead, Australia v
  7. 7. ContributorsAlexandra Greene Mark Peakman, BSc, MSc, PhD,Senior Research Fellow MB BS, FRCPathHealth Services Research Centre Professor of Clinical ImmunologyUniversity of Aberdeen Department of ImmunologyScotland, UK King’s College London School of Medicine at Guy’sStephen Greene, MB BS, FRCP, King’s College and St Thomas’ HospitalFRCPCH Guy’s HospitalReader in Child and Adolescent Health London, UKMaternal and Child Health SciencesUniversity of Dundee Catherine Peters, MD, MRCPCHNinewells Hospital SpR Paediatric EndocrinologyDundee, UK Royal London Hospital London, UKJohn W. Gregory, MB ChB, DCH,MD, FRCP, FRCPCH John Porter, BA (Hons), MB BSProfessor of Paediatric Endocrinology Specialist RegistrarDepartment of Child Health Department of EndocrinologyWales College of Medicine Birmingham Children’s HospitalCardiff University Birmingham, UKCardiff, UKMaciej T. Malecki, MD, PhD Kenneth J. Robertson, MB ChB,Senior Lecturer FRCP, FRCPCHDepartment of Metabolic Diseases Consultant PaediatricianJagiellonian University Royal Hospital for Sick ChildrenMedical College Glasgow, UKKrakow, Poland J.P.H. Shield, MD, MRCP, FRCPCHShital Malik, MRCPCH, MD, DCH, Reader in Diabetes and MetabolicDNB EndocrinologyPaediatric Specialist Registrar University of BristolUniversity Hospital Coventry and Bristol Royal Hospital for Children Warwickshire NHS Trust Bristol, UKCoventry, UK Joanne J. Spinks, BSc (Hons), BM,Loredana Marcovecchio MRCPCHResearch Fellow Specialist Registrar Paediatric Diabetes andUniversity of Cambridge EndocrinologyDepartment of Paediatrics John Radcliffe HospitalAddenbrooke’s Hospital Oxford, UKCambridge, UK Peter G.F. Swift, MA, FRCPCH,Krystyna Matyka, MRCP, MD DCHSenior Lecturer in Paediatrics Consultant PaediatricianClinical Sciences Research Institute Leicester Royal InfirmaryUniversity of Warwick Children’s HospitalCoventry, UK Leicester, UK vi
  8. 8. ContributorsKeith W. Taylor, MB, PhD, FRCP Sheridan Waldron, PhDEmeritus Professor Dietetic ManagerBarts and the London Leicestershire Nutrition and DieteticQueen Mary’s School of Medicine and Service Dentistry Leicester Royal InfirmaryLondon, UK Leicester, UK vii
  9. 9. ForewordThere appear to be a number of irrefutable facts about diabetes in childhood: some todo with aetiology and others related to the management of this group of disorders [1].First, type 1 diabetes mellitus (T1DM) accounts for the vast majority of children andyouths with diabetes. T1DM is increasing in incidence worldwide at the rate of 2–5%per year, with immigrant populations relatively quickly assuming the higher incidence intheir new countries. Second, there has been a staggering increase in childhood obesityworldwide, bringing with it a significant increase in earlier onset of T2DM, probably notyet of the epidemic proportions in the youth that many have threatened. Third, molec-ular genetic technologies have helped unravel the mysteries of an increasing number ofmonogenic types of diabetes, both neonatal and childhood/young adult onset. Finally, thedata derived from two sentinel randomised control trials, namely the Diabetes Controland Complications Trial (DCCT) and its extension observation study Epidemiology ofDiabetes Interventions and Complications (EDIC) in T1DM, and the United KingdomProspective Diabetes Study (UKPDS) in T2DM inform the current approach to the controlof hyperglycaemia in order to prevent the onset or slow the progression of diabetes-relatedcomplications. While certain ‘facts’ may seem irrefutable, what is less robust are the data needed to fillin the details about the why’s, when’s, what’s and how-to’s about the cause, course andcomplications of all types of diabetes. This is where a careful distillation of the availableinformation is required and decisions are made based on the most convincing evidence.The discipline of evidence-based medicine has arisen and rapidly evolved as a means ofaccomplishing this as accurately and reproducibly as possible in order to provide the state-of-the-art recommendations for diagnosis, treatment and prognosis of the condition underreview. There are several caveats that warrant attention here. First, the recommendationscan only be as strong as the data that underpin them. Second, there is in the field ofdiabetes in children and the youth a paucity of data on which to make the highest graderecommendations. This is a fact of life in most areas of paediatric medicine. Finally, theevidence changes, and it may do so quite rapidly with the emergence of new therapeuticagents (e.g. insulin analogues and oral hypoglycaemic agents). Hopefully, this means thatas steadily as the evidence accumulates and improves, so does the treatment and outcomeof the condition. A couple of sobering thoughts are in order here. First, a study from the Centers forDisease Control in Atlanta, USA [2], in 2003 reported a loss of almost 20 life years for 10-year-old children diagnosed with diabetes in the year 2000. And Gale from Bristol [3] haspointed out that the majority of children with diabetes worldwide will not achieve levelsof control commensurate with reasonable protection from microvascular complications.Furthermore, ‘the individual and communal legacy of poor glucose control will remain withus for the next thirty years, even if an effective means of preventing new cases of the disease ix
  10. 10. Forewordwere to be introduced tomorrow.’ Gale concluded that ‘the greatest need is for more effectiveimplementation of what is already known’ [3]. In this book, editor Jeremy Allgrove has marshalled the energies and expertise of ahighly qualified and accomplished international group of childhood diabetes specialiststo sift carefully through the evidence (‘what is already known’) and make the best possiblerecommendations for the care of children and the youth with diabetes. The result is anoutstanding addition to the literature in this field. This has been a gargantuan, but highlyworthwhile, task at a number of levels. First, it helps the reader understand just how strong(or not) the evidence is for recommending one approach over another. Then, it highlightsthe areas where the evidence is not based on the type of studies needed to provide high-grade recommendations, but in which there is general consensus as to a most sensibleapproach. In many of these instances, the gold-standard study, a randomised controlledtrial, is unlikely to be performed. Finally, it lays bare the issues that remain inadequatelyaddressed such that no definitive recommendations can be made. Undoubtedly, both the editor and the chapter authors as well as the readers hope thatthe recommendations will soon be out of date with the emergence of ‘newer and better’approaches to diabetes prediction and prevention in both T1DM and T2DM, managementthat facilitates achievement and maintenance of normoglycaemia without the ever-presentthreat of hypoglycaemia and prevention or reversal of complications. Until such time asthese advances become reality, this volume will stand as a wonderful navigator for health-care professionals involved in the care of children with all types of diabetes. My heartiestcongratulations to Dr Allgrove and his contributors for their superb efforts. Denis Daneman Past President, ISPADReferences1 Daneman D. Type 1 diabetes. Lancet 2006; 367: 847–58.2 Narayan KM, Boyle JP, Thompson TJ et al. Lifetime risk for diabetes mellitus in the United States. JAMA 2003; 290: 1884–90.3 Gale EA. Type 1 diabetes in the young: the harvest of sorrow goes on. Diabetologia 2005; 48: 1435–8. x
  11. 11. PrefaceThis book is intended to be part of a series of evidence based publications on a varietyof topics. It is particularly intended as a companion volume to ‘Evidence-Based Diabetes’which will deal in a similar manner with the field of adult diabetes. It is not intended tobe yet another guideline to the treatment of diabetes as several of these have already beenpublished, but rather to concentrate on the evidence that is available in the paediatric fieldto support the development of those guidelines. Whilst we have tried to be as compre-hensive as possible, there are certain topics that have not yet had a significant impact onpaediatric practice and are therefore not covered. These include inhaled insulins, the arti-ficial pancreas and pancreatic cell transplantation. Nevertheless, there are topics covered,not least the chapter on Type 2 Diabetes, which are unlikely to have been included in asimilar publication even five years ago but which are of increasing importance today. It has been an enormous privilege to have been asked to edit this edition of ‘Evidence-Based Paediatric and Adolescent Diabetes’ and a great pleasure to be able to work withmy co-authors, Peter Swift and Stephen Greene, both of them long-standing colleaguesand good friends. I wish to thank them and all of our co-authors for their hard work andeffort in seeing this book through to its final stages. I also wish to thank the publishers,Blackwell’s, for their unstinting support and encouragement in making it possible. Many thanks also to all of the authors who have contributed to the book and for theirefforts in getting manuscripts in on time so that publication can go ahead within thetime frame originally envisaged. Finally I wish to thank my wife, Natalie, for her patienceand understanding in tolerating my slaving over a hot computer when other attractionsbeckoned. When one is responsible for editing a book that is dependent upon evidence, it is, ofcourse, necessary to ensure that the evidence presented is as was originally published,even if the conclusions reached in those papers were dubious. Martin Routh (1755–1854),British academic and President of Magdalen College, Oxford from 1791 until his deathin 1854, was once asked by an admiring student, towards the end of his life, to supply aprecept which might serve as a guiding principle in a young man’s life. ‘I think, sir,’ hereplied, after a moment’s thought, ‘since you come for the advice of an old man, you willfind it a very good practice always to verify your references!’ I hope that all of the referencesquoted here have been verified. Jeremy Allgrove, Editor-in-Chief xi
  12. 12. CHAPTER 1Methodology of evidence-basedmedicineJeremy Allgrove When one admits that nothing is certain one must, I think, also admit that some things are much more nearly certain than others. —Bertrand Russell. ‘Am I an Atheist or an Agnostic?’ 1947 British author, mathematician and philosopher (1872–1970)IntroductionOver the past two decades evidence-based medicine has become increasingly importantin determining the way in which medicine is practised. The medical profession has alwayshad a reputation for questioning its own practices, as demonstrated by the number ofscientific publications that have appeared since medical journals were invented. As a result,considerable advances in health care have been achieved. Nevertheless, it is not always the case that ideas that have developed are necessarilycorrect, and dogmatic statements or assumptions that have been made have sometimesturned out to be false when re-examined more rigorously. Although it has been suggestedthat ‘it is curious, even shocking, that the adjective “evidence-based” is needed’ [1], it isnevertheless the purpose of evidence-based medicine to limit these false assumptions andincorrect dogma so that patients may be treated in the best possible way with the toolsavailable.What is evidence-based health care?The Cochrane library [2] quotes three slightly different definitions of evidence-basedhealth care:r Evidence-based health care is the conscientious use of current best evidence in makingdecisions about the care of individual patients or the delivery of health services. Currentbest evidence is up-to-date information from relevant, valid research about the effects ofdifferent forms of health care, the potential for harm from exposure to particular agents,the accuracy of diagnostic tests and the predictive power of prognostic factors [3].r Evidence-based clinical practice is an approach to decision-making in which the clinicianuses the best evidence available, in consultation with the patient, to decide upon the optionwhich suits that patient best [4].r Evidence-based medicine is the conscientious, explicit and judicious use of currentbest evidence in making decisions about the care of individual patients. The practice 1
  13. 13. Chapter 1of evidence-based medicine means integrating individual clinical expertise with the bestavailable external clinical evidence from systematic research [5]. All of these definitions are very similar but differ slightly in emphasis on such mattersas patient involvement and reliance on diagnostic tests.What constitutes proof?Scientific proof has always depended on probabilities rather than absolute proof and isdetermined by observation and perception. Both of these are open to misinterpretationand can be refuted by other observations that may be made under different circumstances.Statistical analysis is frequently used to ‘verify’ observations and it has become usualpractice to accept that a probability of something being true with 95% certainty ( p < 0.05)means that observation is ‘true’. By definition, it also means that there is a 5% chance thatit will not be true. In contrast, there is a fundamental difference between a scientific proof and a mathe-matical proof [6, pp. 21–2]. In the latter, proof is absolute and remains so forever. If proofis not absolute, i.e. if a flaw can be found in the logic, then proof does not exist. A simpleexample of this is the proof of the well-known formula of Pythagoras:a 2 + b2 = c 2where a, b and c are the values of the sides of a right-angled triangle, c being the hypotenuse.The proof of this theorem is straightforward [6, pp. 333–4] and it can be shown that therelationship is true under all circumstances. Thus, if the values of any two numbers areknown, the third can always be calculated. However, this relationship can be rewritten as:a x + bx = c xwhere the value of x is any whole number greater than 2. The French mathematicianPierre de Fermat (1601–1665) postulated that there is no solution to this equation. Thishas become known as Fermat’s last theorem. He died having claimed that he had founda proof that there is no solution, but the proof was lost and the challenge to rediscover itbecame the most exciting in the field of mathematics for the next 329 years until finallysolved by Andrew Wiles in 1994. Fermat’s last theorem is fiendishly difficult to prove. Initial attempts resulted in proofsthat the postulate is true for values of x = 4 and x = 3. The problem is that even if itis possible to show that for all values between, say, 3 and 1000 the postulate is also true,this does not prove the theorem, as there could still be values greater than 1000 that dosatisfy the equation. This is shown by another conjecture, that of the Swiss mathematicianLeonhard Euler, which states that there are also no solutions to the equation:x 4 + y 4 + z 4 = ω4 Initial attempts to solve it proved fruitless and the lack of a counter-example was takenas proof of its truth until a solution∗ was eventually found in 1988 some two centuries afterit was postulated [6]. Therefore, Euler’s postulate is absolutely not true in mathematical∗ 2,682,4404 + 15,365,6394 + 18,796,7604 = 20,615,6734 2
  14. 14. Methodology of evidence-based medicineterms, although in scientific terms it had been taken to be so. Thus, to obtain an absoluteproof, it is necessary to go back to first mathematical principles and demonstrate that theconditions apply to all numbers. Scientific proof is not so rigorous and only demands that there is a sufficient bodyof evidence to suggest very strongly that a fact is ‘true’. Medicine is no different in thisrespect from other scientific disciplines and, particularly because one is dealing with abiological rather than a physical system, is particularly open to variations in response. Themost rigorous method available to scientists, in the realm of medicine, for determiningthe effectiveness of a treatment is the double-blind, placebo-controlled trial, properlyconducted under clearly defined conditions with sufficient numbers of patients and withremoval of bias. Some treatments have fulfilled these criteria, although others that areregularly used have never been tested under such circumstances. There has, for instance,never been such a trial of the use of insulin in type 1 diabetes mellitus (T1DM). It would,of course, be totally unethical to conduct such a trial now and yet there is little or no doubtthat insulin therapy is effective in treating T1DM. The statement ‘insulin is an effectivetreatment of T1DM’ is taken to be true. Evidence-based medicine depends upon scientificobservation rather than mathematical proof and is always open to some degree of doubt,however small. It is therefore necessary to have some means of gauging how reliable a pieceof evidence is in scientific terms.Grading of evidenceSeveral methods of grading evidence have been used and different guideline developmentgroups (GDGs) have used different methods of classifying evidence. The classificationused by the Scottish Intercollegiate Guideline Network (SIGN) is the most detailed [7].The ‘levels of evidence’ are then converted into ‘grades of recommendation’ (A–D). Inaddition, they list ‘good practice points’ (GPPs). The National Institute for Clinical Excellence (NICE), an independent body set up bythe UK Department of Health, uses a similar, though not quite so detailed, classification[8]. It gives grades A–D and GPPs, and also recommendations from NICE technologyappraisals. The American Diabetes Association (ADA) has the simplest classification. This doesnot describe a level of evidence which is then converted into a grade but assigns a gradedirectly to a study [9]. The classification is shown in Table 1.1. All of these grading methods are similar but, since this book is not designed to beanother guideline but rather to present the evidence, we have chosen to use the ADAclassification which does not include any GPPs, etc. The new International Society forPediatric and Adolescent Diabetes (ISPAD) guidelines also use the same gradings. Whererelevant, gradings have been assigned to references within the text.GuidelinesSince the beginning of the 1990s there has been a move away from professional consensustowards more rigorous scientific methods, such as systematic reviews and meta-analyses[10]. This has usually been done in the context of creating guidelines, although the qualityof these guidelines has varied depending on how rigorously the methodology has beenapplied. In 2003, Burgers et al. published a study, on behalf of the Appraisal of Guidelines, 3
  15. 15. Chapter 1Table 1.1 ADA evidence grading system for clinical practice recommendationsLevel DescriptionA Clear evidence from well-conducted, generalisable, randomised controlled trials that are adequately powered, including: r evidence from a well-conducted multicentre trial r evidence from a meta-analysis that incorporated quality ratings in the analysis r compelling non-experimental evidence, i.e. ‘all-or-none’ rule developed by Centre for Evidence-Based Medicine at Oxford Supportive evidence from well-conducted randomised controlled trials that are adequately powered, including: r evidence from a well-conducted trial at one or more institutions r evidence from a meta-analysis that incorporated quality ratings in the analysisB Supportive evidence from well-conducted cohort studies: r evidence from a well-conducted prospective cohort study or registry r evidence from a well-conducted meta-analysis of cohort studies r supportive evidence from a well-conducted case-control studyC Supportive evidence from poorly controlled or uncontrolled studies: r evidence from randomised clinical trials with one or more major or three or more minor methodological flaws that could invalidate the results r evidence from observational studies with high potential for bias (such as case series with comparison to historical controls) r evidence from case series or case reports Conflicting evidence with the weight of evidence supporting the recommendationE Expert consensus or clinical experienceNote: There is no Grade D.Research and Evaluation for Europe (AGREE) study group [11], in which they describedthe structures and working methods of 18 national GDGs from 13 different countriesworldwide. These did not include guideline development by NICE since this organisationwas formed only in 1999 and produced its first report in 2002. They concluded that‘principles of evidence-based medicine dominate current guideline programs’. As a result,it can be concluded that most of the current guidelines that have been developed arereasonably well evidence based and well referenced. However, this is not always the case. For instance, the Consensus Guidelines for theManagement of Type 1 Diabetes in Children and Adolescents published by ISPAD in 2000contained no references. It raises the question of how truly evidence-based they were andhow much they depended on the views and opinions of the guideline development team.Having said that, they have proved invaluable as a resource. The situation is due to berectified with the publication of the new ISPAD Clinical Practice Consensus Guidelines2006/2007, which are heavily referenced. The first two chapters were published in 2006 (E)[12, 13], with the rest due to be published in 2007. Bertrand Russell is quoted as saying [14], ‘The fact that an opinion has been widely held isno evidence whatever that it is not utterly absurd; indeed in view of the silliness of the majorityof mankind, a widespread belief is more likely to be foolish than sensible’. Although he wasreferring to marriage, he could as easily have been referring to clinical guidelines. That isnot to say that guidelines should not be followed, but it must be understood that, whilst 4
  16. 16. Methodology of evidence-based medicinethey are usually well researched, there are often aspects of the guidelines that are basedsolely on the personal opinions of those drawing them up with little or no hard evidenceto support them and there may be individual circumstances where they do not necessarilyapply. There may also be a tendency, in some instances, for recommendations to be ‘transferred’from one guideline to another by default. Let us examine, as an example, the statementmade in all of the major national and international guidelines for the treatment of diabeticketoacidosis (DKA) in children that the dose of insulin should be ‘0.1 unit per kilogrambody weight per hour’ (E) [8, 15–18]. The British Society for Paediatric Endocrinology andDiabetes (BSPED) guidelines (E) [16] state that ‘Modifications (to their previous guideline)have been made in the light of the guidelines produced by the International Society for Pediatricand Adolescent Diabetes (2000) and the recent ESPE/LWPES consensus statement on diabeticketoacidosis in children and adolescents’, and the NICE guidelines (E) [8] say that ‘Thecurrent guidelines take account of recently published consensus statements developed by theEuropean Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric EndocrineSociety. The guidelines highlight the need for further research to investigate the effectivenessof different concentrations of rehydration fluid, the rate of rehydration and the concentrationof insulin infusion in the management of diabetic ketoacidosis’. The implication of thesetwo statements is that they are merely following previous recommendations and have notre-examined the evidence. Despite claims to the contrary [15], the evidence for the stated dose of insulin is weak. TheLawson Wilkins Pediatric Endocrine Society/British Society of Paediatric Endocrinologyand Diabetes (LWPES/BSPED) guidelines state that ‘Physiologic studies indicate that IVinsulin at a dose of 0.1 unit/kg per hour, which achieves steady state plasma insulin levels of∼100 to 200 μU/mL within 60 minutes, is effective’. However, as stated by Edge and Spinksin Chapter 4 of this book, ‘there is a body of opinion that a dose of 0.05 units/kg/hour issufficient to reverse the metabolic abnormalities and overcome any insulin resistance whilstreducing the blood glucose at a steadier rate’, and many units in the UK ignore the nationaland international guidelines and routinely use this lower dose. The statement, which is given an A grading, is based on a study conducted in six adultswith established diabetes who were rendered ketotic by the administration of two doses ofdexamethasone and cessation of insulin in the 24 hours prior to the study [19]. They werethen given insulin infusions at varying rates (0.01, 0.1 and 1 U/kg/h) in random order.Steady-state levels of insulin were measured and the rates of fall of glucose and ketones, asmeasured by β-hydroxybutyric acid and acetoacetate, observed with the different doses.The principal conclusions were as follows:1 An infusion rate of 0.1 U/kg/h achieves a steady-state insulin concentration between100 and 200 μU/mL (an increase between 90 and 112 μU/mL over baseline).2 Logarithmic increases in infusion rates resulted in logarithmic increases in insulin con-centration.3 The effect of insulin on reducing ketones was maximal at 0.1 U/kg/h but the effect onreducing blood glucose had no such plateau effect; i.e. the rate of fall of blood glucosecontinues to increase with larger doses of insulin. Unfortunately, an infusion rate of 0.05 U/kg/h was not tested but it can be deducedfrom the above that this lower rate of infusion would be likely to result in a steady-state concentration of insulin of ∼55 μU/mL, which may well be sufficient to switch offketogenesis (the principal aim of insulin therapy in the treatment of DKA) whilst reducing 5
  17. 17. Chapter 1the rate of fall of blood glucose. This is supported by another study, also conducted inadults [20], and also quoted in the LWPES/BSPED guidelines, in which patients withnewly diagnosed diabetes were admitted with DKA and treated with insulin at a rate of1 mU/kg/min (≡0.06 U/kg/h). This resulted in a steady fall in blood glucose at an acceptablerate of 3.3 mmol/L/h and correction of the acidosis. In some units it is considered important to control the rate of fall of blood glucosewith the use of systems that involve the use of solutions of different strengths of dextrose,used at different rates depending upon circumstances, a situation that arguably increasesthe risk of error. Even so, in one such study [21], which was conducted in children, therecommended dose of 0.1 U/kg/h was used and the blood glucose fell initially, when noglucose was being infused, by approximately 33 mmol/L in the first 5 hours (6.6 mmol/h),a rate which is now regarded as being too rapid. Although there is little evidence to supportit, a maximum of 5 mmol/L/h is recommended by the ISPAD guidelines (E) [17]. It is therefore clear that the evidence for the recommended dose of insulin is weakand has never been properly tested in children. It is possible that this dose is correct(although it may be different at different ages) but, as stated in the NICE guidelines, ‘furtherresearch to investigate the effectiveness of different concentrations of . . . insulin infusion in themanagement of diabetic ketoacidosis’ is required (see above). Evidence-based medicineshould ultimately be able to provide an answer. Guidelines are widely quoted throughout this book and in many instances, the recom-mendations are clearly evidence based and have a high degree of validity. Nevertheless, inview of the fact that they are all consensus documents, they are always given an E grading.Whilst there is clearly a hierarchy of validity between A and C, an E grading does notnecessarily mean that this is the lowest level since consensus documents do often containsystematic reviews or meta-analyses, which, under other circumstances, might be rated A.Having said that, some C-graded articles, particularly those that are case reports, may stillcarry quite a lot of weight if they contain, for instance, convincing genetic data.Sources of dataElectronic databases, such as MEDLINE, have proved enormously helpful in searching forrelevant studies. Not only do they make the searches much faster than previously, but theyare inevitably more thorough. We have made use of all the available databases including:r Allied & Complementary Medicine – 1985 to dater British Nursing Index – 1994 to dater CINAHL (R) – 1982 to dater DH-DATA – 1983 to dater EMBASE – 1974 to dater King’s Fund – 1979 to dater MEDLINE – 1950 to dater PsycINFO – 1806 to date. These have all been available either via KA24, the National Health Service (NHS)portal available to NHS employees (accessible via http://www.hilo.nhs.uk/ to registeredpersonnel) [22], or via PUBMED, a service of the National Library of Medicine andthe National Institutes of Health (accessible via http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Pager&DB=pubmed). 6
  18. 18. Methodology of evidence-based medicine In addition, the relevant Cochrane databases have been examined. These are a se-ries of systematic reviews based on available publications and are also available viahttp://www.hilo.nhs.uk/ [22]. (This requires no special permissions.) Cochrane describesa systematic review as follows:r To help identify which forms of health-care work, which do not and which are evenharmful, Results from similar randomised trials need to be brought together. Trials needto be assessed and those that are good enough can be combined to produce both a morestatistically reliable result and one that can be more easily applied in other settings. Thiscombination of trials needs to be done in as reliable a way as possible. It needs to besystematic. A systematic review uses a predefined, explicit methodology. The methodsused include steps to minimise bias in all parts of the process: identifying relevant studies,selecting them for inclusion and collecting and combining their data. Studies should besought regardless of their results.r A systematic review does not need to contain a statistical synthesis of the results from theincluded studies. This might be impossible if the designs of the studies are too differentfor an averaging of their results to be meaningful or if the outcomes measured are notsufficiently similar. If the results of the individual studies are combined to produce anoverall statistic, this is usually called a meta-analysis. A meta-analysis can also be donewithout a systematic review, simply by combining the results from more than one trial.However, although such a meta-analysis will have greater mathematical precision thanan analysis of any one of the component trials, it will be subject to any biases that arisefrom the study-selection process and may produce a mathematically precise, but clinicallymisleading, result. The Cochrane databases deal mainly with adult practice and have little relevance topaediatrics. There is only one systematic review relating directly to children listed ontheir website [23]. Nevertheless, the principles of systematic reviews and meta-analysesare important and apply equally to children as to adults.Summary and conclusionsEvidence-based medicine is becoming increasingly important in determining how bestpatients should be treated. There is an element of cost-effectiveness built into the systembut this is not the principal aim of the process. Unfortunately, in paediatric practice, thereis a certain paucity of studies in many areas and it has been necessary to rely on studies inadults which are then extrapolated into paediatrics. Whilst this is valid in some areas, itmay not be so in others and one has to retain a certain degree of scepticism in doing so.The aim of this book is to present the data that are available in the hope that they will shedsome light on why paediatricians treat their patients as they do and to highlight some ofthe areas where knowledge is lacking and which require further research.References 1 Dickersin K, Straus SE, Bero LA. Increasing, not dictating, choice. BMJ 2007; 334(Supplement Medical Milestones): s10. 2 The Cochrane Library. Evidence for healthcare decision-making. Available at: http://www3.interscience. wiley.com/cgi-bin/mrwhome/106568753/WhatAreSystematicReviews.html. 3 National Institute of Public Health. First Annual Nordic Workshop on how to critically appraise and use evidence in decisions about healthcare. Oslo, Norway, 1996. 7
  19. 19. Chapter 1 4 Muir-Gray JA. Evidence-Based Healthcare: How to Make Health Policy and Management Decisions. Churchill Livingstone, London, 1997. 5 Sackett DL, Rosenberg WM, Gray JA et al. Evidence based medicine: what it is and what it isn’t. BMJ 1996; 312: 71–2. 6 Singh S. Fermat’s Last Theorem. Clays Ltd., St Ives, UK, 1997. 7 Scottish Intercollegiate Guideline Network. SIGN 50: A Guideline Developers’ Handbook Sec- tion 6: Forming Guideline Recommendations. Available at: http://www.sign.ac.uk/guidelines/fulltext/50/ section6.html 8 NICE. Type 1 Diabetes in Children and Young People: Full Guideline 2004. Available at: http://www.nice. org.uk/page.aspx?o=CG015childfullguideline 9 American Diabetes Association. Summary of revisions for the 2007 clinical practice recommendations. Diabetes Care 2007; 30(suppl 1): S3.10 Grimshaw J, Russell I. Achieving health gain through clinical guidelines. I: developing scientifically valid guidelines. Qual Health Care 1993; 2: 243–8.11 Burgers JS, Grol R, Klazinga NS et al. Towards evidence-based clinical practice: an international survey of 18 clinical guideline programs. Int J Qual Health Care 2003; 15: 31–45.12 Craig ME, Hattersley A, Donaghue K. ISPAD Clinical Practice Consensus Guidelines 2006–2007: defi- nition, epidemiology and classification. Pediatr Diabetes 2006; 7: 343–51.13 Hattersley A, Bruining J, Shield J et al. ISPAD Clinical Practice Consensus Guidelines 2006–2007: the diagnosis and management of monogenic diabetes in children. Pediatr Diabetes 2006; 7: 352–60.14 Russell B. Marriage and Morals. George Allen & Unwin, London, 1929.15 Dunger DB, Sperling MA, Acerini CL et al. European Society for Paediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society consensus statement on diabetic ketoacidosis in children and adolescents. Pediatrics 2004; 113: e133–40.16 Edge JA. BSPED Recommended DKA Guidelines. Available at: http://www.bsped.org.uk/professional/ guidelines/docs/BSPEDDKAApr04.pdf17 Wolfsdorf J, Craig ME, Daneman D et al. ISPAD Clinical Practice Consensus Guidelines 2006–2007: Diabetic Ketoacidosis. Pediatr Diabetes 2007; 8: 28–43.18 NHMRC. The Australian Clinical Practice Guidelines on the Management of Type 1 Diabetes in Children and Adolescents 2005. Available at: http://www.chw.edu.au/prof/services/endocrinology/ apeg/apeg handbook final.pdf19 Schade DS, Eaton RP. Dose response to insulin in man: differential effects on glucose and ketone body regulation. J Clin Endocrinol Metab 1977; 44: 1038–53.20 Luzi L, Barrett EJ, Groop LC et al. Metabolic effects of low-dose insulin therapy on glucose metabolism in diabetic ketoacidosis. Diabetes 1988; 37: 1470–7.21 Grimberg A, Cerri RW, Satin-Smith M et al. The ‘two bag system’ for variable intravenous dextrose and fluid administration: benefits in diabetic ketoacidosis management. J Pediatr 1999; 134: 376–8.22 HILO (Health Information for London Online). KA24: Knowledge Access 24 hours. KA24. Available at: http://www.hilo.nhs.uk/23 Clar C, Waugh N, Thomas S. Routine hospital admission versus out-patient or home care in children at diagnosis of type 1 diabetes mellitus. Cochrane Database Syst Rev 2003; Issue 3: Art no CD004099. 8
  20. 20. CHAPTER 2Definition, epidemiology andclassification of diabetes and structureof the diabetes teamMaria Craig, Sarah J Glastras & Kim Donaghue Accurate knowledge is the basis of correct opinions; the want of it makes the opinions of most people of little value. —Charles Simmons, American Writer (1924–)Definition, epidemiology and classificationDiabetes mellitus is a group of metabolic diseases characterised by chronic hyperglycaemiaresulting from defects in insulin secretion, insulin action, or both. The abnormalities incarbohydrate, fat and protein metabolism that are found in diabetes are due to deficientaction of insulin on target tissues. If ketones are present in blood or urine, treatment isurgent, because ketoacidosis can evolve rapidly.Diagnostic criteria for diabetes in childhood and adolescenceDiabetes in children usually presents with the characteristic symptoms of polyuria, poly-dipsia and weight loss, in association with glycosuria and ketonuria. In its most severeform ketoacidosis or, rarely, a non-ketotic hyperosmolar state may develop and lead tostupor, coma and, without treatment, death. The diagnosis is usually confirmed quicklyby measurement of a markedly elevated blood glucose level. If ketones are also present inblood or urine, treatment is urgent. Waiting another day to confirm the hyperglycaemiais dangerous as ketoacidosis can evolve rapidly (E). In the presence of mild symptoms, the diagnosis of diabetes should never be madeon the basis of a single abnormal blood glucose value. Diagnosis may require continuedobservation with fasting and/or 2-hour postprandial blood glucose levels and/or an oralglucose tolerance test (OGTT) (E) [1, 2] (Table 2.1). In the absence of symptoms ofdiabetes, hyperglycaemia detected incidentally or under conditions of acute infection,trauma, circulation or other stress may be transitory and should not in itself be regardedas diagnostic of diabetes. An OGTT should not be performed if diabetes can be diagnosed using fasting and ran-dom or postprandial criteria, as excessive hyperglycaemia can result. It is rarely indicatedin making the diagnosis of type 1 diabetes mellitus (T1DM) in childhood and adolescence(E) [1]. If doubt remains, periodic retesting should be undertaken until the diagnosis is 9
  21. 21. Chapter 2Table 2.1 Criteria for the diagnosis of diabetes mellitus (E) [1, 2]r Symptoms of diabetes plus casual plasma glucose concentration ≥11.1 mmol/L (200 mg/dL)* (Casual is defined as any time of day without regard to time since last meal.) orr Fasting plasma glucose ≥7.0 mmol/L (≥126 mg/dL) (Fasting is defined as no caloric intake for at least 8 h.) orr Two-hour post-load glucose ≥11.1 mmol/L (≥200 mg/dL) during an OGTTThe test should be performed as described by WHO [1], using a glucose load containing the equivalentof 75 g anhydrous glucose dissolved in water or 1.75 g/kg of body weight to a maximum of 75 g.∗ Corresponding values (mmol/L) are ≥10.0 for venous whole blood and ≥11.1 for capillary whole bloodand ≥6.1 for both venous and capillary whole blood.established. In the absence of unequivocal hyperglycaemia with acute metabolic decom-pensation, these criteria should be confirmed by repeat testing on a different day.Impaired glucose tolerance and impaired fasting glycaemiaImpaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) are intermedi-ate stages in the natural history of disordered carbohydrate metabolism between normalglucose homeostasis and diabetes (E) [1, 2]. IFG and IGT are not interchangeable andrepresent different abnormalities of glucose regulation; IFG is a measure of disturbedcarbohydrate metabolism in the basal state, whilst the IGT is a dynamic measure of car-bohydrate intolerance after a standardised glucose load. Patients with IFG and/or IGT are now referred to as having ‘pre-diabetes’, indicating theirrelatively high risk for development of diabetes (A) [3, 4]. Pre-diabetes can be observed asan intermediate stage in any of the disease processes given in Table 2.2. IFG and IGT maybe associated with the metabolic syndrome, which includes obesity (especially abdom-inal or visceral obesity), dyslipidaemia of the high-triglyceride and/or low-high-densitylipoprotein type and hypertension (E) [5]. Individuals who meet criteria for IGT or IFG may be euglycaemic in their daily lives asshown by normal or near-normal glycated haemoglobin levels, and those with IGT maymanifest hyperglycaemia only when challenged with an OGTT. Recently, the EuropeanDiabetes Epidemiology Group has recommended revising the lower cut-off for IFG backto 6.1 mmol/L from the current value of 5.6 mmol/L due to the two- to fivefold increase inprevalence of IFG across the world (E) [6] but the American Diabetes Association (ADA)continues to recommend 5.6 mmol/L as the cut-off point for normal FPG [2]. Categories of fasting plasma glucose (FPG) are defined as follows [2]:r FPG <5.6 mmol/L (100 mg/dL) = normal fasting glucoser FPG 5.6–6.9 mmol/L (100–125 mg/dL) = IFGr FPG ≥7.0 mmol/L (126 mg/dL) = provisional diagnosis of diabetes (The diagnosis mustbe confirmed, as described above in the section Diagnostic criteria.) The corresponding categories for stimulated plasma glucose when the OGTT is usedare as follows:r 2-hour post-load glucose <7.8 mmol/L (140 mg/dL) = normal glucose tolerancer 2-hour post-load glucose 7.8–11.1 mmol/L (140–199 mg/dL) = IGTr 2-hour post-load glucose ≥11.1 mmol/L (200 mg/dL) = provisional diagnosis of diabetes(The diagnosis must be confirmed, as described above.) 10
  22. 22. Diabetes and diabetes teamTable 2.2 Aetiological classification of disorders of glycaemiaI Type 1 Beta-cell destruction, usually leading to absolute insulin deficiency Autoimmune IdiopathicII Type 2 It may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistanceIII Other specific types(a) Genetic defects of beta-cell development or function Chromosome 12, HNF-1α (MODY3) Chromosome 7, glucokinase (MODY2) Chromosome 20, HNF-4α (MODY1) Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4) Chromosome 17, HNF-1ß (MODY5) Chromosome 2, NeuroD1 (MODY6) carboxyl exter lipase (CEL) gene (MODY7) Mitochondrial DNA mutation DIDMOAD (Wolfram) Chromosome 11 PNDM Chromosome 11 PNDM/TNDM Chromosome 6 TNDM Chromosome 2 Wolcott—Rallison Chromosome X IPEX Chromosome 10 PNDM and cerebellar agenesis Others(b) Genetic defects in insulin action Type A insulin resistance Leprechaunism Rabson–Mendenhall syndrome Lipoatrophic diabetes Others(c) Diseases of the exocrine pancreas Pancreatitis Trauma/pancreatectomy Neoplasia Cystic fibrosis Haemochromatosis Fibrocalculous pancreatopathy Others(d) Endocrinopathies Acromegaly Cushing syndrome Glucagonoma Phaeochromocytoma Hyperthyroidism Somatostatinoma Aldosteronoma Others(e) Drug or chemical induced Vacor Pentamidine Nicotinic acid Glucocorticoids Thyroid hormone Continued 11
  23. 23. Chapter 2Table 2.2 Continued Diazoxide β-adrenergic agonists Thiazides Dilantin Interferon alpha Others(f) Infections Congenital rubella Enterovirus Cytomegalovirus Others(g) Uncommon forms of immune-mediated diabetes ‘Stiff-man’ syndrome Anti-insulin receptor antibodies Autoimmune polyendocrine syndromes (APS) I and II Others(h) Other genetic syndromes sometimes associated with diabetes Down syndrome Klinefelter syndrome Turner syndrome DIDMOAD (Wolfram) syndrome Friedreich ataxia Huntington chorea Laurence–Moon–Biedl syndrome Myotonic dystrophy Porphyria Prader–Willi syndrome OthersIV Gestational diabetesDIDMOAD, Diabetes insipidus, diabetes mellitus, optic atrophy and deafness; PNDM, permanentneonatal diabetes mellitus; TNDM, transient neonatal diabetes mellitus; IPEX, immune dysregulation,polyendocrinopathy, enteropathy X-linked syndrome.Epidemiology of T1DMApproximately 50–60% of individuals with T1DM are diagnosed before the age of 15years (B) [7]. In most Western countries, T1DM accounts for over 90% of childhood andadolescent diabetes. However, T2DM is becoming more common and it accounts for asignificant proportion of youth-onset diabetes in certain at-risk populations (B) [8, 9]. T1DM incidence varies greatly between different countries, within countries, and be-tween different ethnic populations (B) [10]. Epidemiological incidence studies define the‘onset of T1DM’ by the date of the first insulin injection because of the variable timebetween the onset of symptoms and diagnosis (B) [10]. Annual incidence rates for child-hood T1DM (0–14 yr age group) comparing different countries of the world are shown inFigure 2.1 (0.1–43.9/100,000) [10–13]. Gender differences in incidence are found in some,but not all, populations (B) [10, 14–17]. Incidence rates show a close correlation with the frequency of human leucocyte antigen(HLA) susceptibility genes in the general population of white Caucasian ancestry; thislocus confers approximately 50% of the genetic susceptibility to T1DM (B) [18–20] (seeChapter 3 for a more detailed discussion of this). In countries where the incidence of T1DM 12
  24. 24. Finland Sardinia Canada (Newfoundland) Sweden UK (Scotland) New Zealand Kuwait Australia UK (Nth Ireland) Norway Canada (Calgary) UK (Oxford) USA (White) USA (African American) Puerto Rico (USA) Denmark Spain Malta Germany Iceland Netherlands Italy (Liguria) Belgium Estonia USA (Hispanic) Luxembourg Cyprus Bulgaria Greece Austria Czech Republic Slovak Republic Hungary Portugal Libya Slovenia Algeria France Italy (Peninsular) Sudan Lithuania Poland Latvia Brazil Russia Croatia Argentina Israel Romania China (Wuhan) Chile Macedonia Cuba Japan Korea Hong Kong China (H.K.) Paraguay Pakistan Columbia Thailand China (Zunyi) Fiji 0 5 10 15 20 25 30 35 40 4513 Diabetes and diabetes team Figure 2.1 Annual incidence rates for T1DM (0–14 yr age group) comparing different countries in the world. (Modified from IDF Atlas 2003 [10, 11].)
  25. 25. Chapter 2is extremely low, HLA associations are different from those in white Caucasians [21]. Inaddition, a unique, slowly progressive form of T1DM is found in Japan (B) [22, 23]. Migrating populations may exhibit diabetes incidence rates closer to those of their newcountry compared with their country of origin [24, 25], although this is not universallythe case [26], suggesting that the interplay between genetics and environmental factors isvariable. A well-documented rise in the incidence has been noted in many countries. From 1960to 1996, there was a significant increase in 65% of countries and an upward trend in32% (B) [27]. From 1995 to 1999, the average annual increase was 3.4% [10]. In Europethe average increase was 3.2% (95% CI 2.7–3.7) from 1989 to 1999, in keeping with theincreases reported in other parts of the world (B) [10, 28, 29]. In some reports there hasbeen a disproportionately greater increase in those under the age of 5 years (B) [10, 27,30, 31]. The rising incidence is unlikely to have a strong genetic basis, as it has occurredover too short a time period [32]. Possible explanations include increased exposure toinfections and wealth-related factors, such as lifestyle and nutrition [28, 33–35]. A seasonal variation in the presentation of new cases is well described, with the peakbeing in the autumn and winter months (B) [17, 30, 36]. Seasonality of birth has also beendescribed in some countries, suggesting a perinatal environmental trigger [37, 38]. Higherincidence rates have been found in countries with colder climates (B) [10] and in colderareas of large nations, such as China [39]. Despite familial aggregation, there is no recognisable pattern of Mendelian inheritance.The risk of diabetes to an identical twin of a patient with T1DM is about 36% (B) [40]and for a sibling the risk is approximately 4% by age 20 years (B) [41, 42] and 9.6% byage 60 years (B) [43], compared with 0.5% for the general population. The risk is higherin siblings of probands diagnosed at younger age (B) [42, 44]. T1DM is two to three timesmore common in the offspring of diabetic men (3.6–8.5%) compared with diabetic women(1.3–3.6%) (B) [42, 44–49]. The age of onset of T1DM has decreased in many countries (B) [31, 50]. This has beenaccompanied by increased weight and linear growth prior to the onset of diabetes and theobservation that children with T1DM are heavier and taller than their peers [34, 51]. Theseepidemiological findings suggest that insulin resistance is responsible for overloading thebeta cell (‘the accelerator hypothesis’) (B, C) [33, 34, 51–53], although this hypothesisremains to be proven and is not universally accepted. When the clinical presentation is typical of T1DM (often associated with diabetic ke-toacidosis) but antibodies are absent, then the diabetes is classified as type 1B (idiopathic)[54]. This represents approximately 5% of T1DM in white populations but is more com-mon in other parts of the world, such as Japan [22].ClassificationThe aetiological classification recommended by the ADA (E) [2] and the WHO expertcommittee on the classification and diagnosis of diabetes (E) [1] is shown in Table 2.2 withminor modification.Classifying types of diabetesThe differentiation between T1DM, T2DM and monogenic diabetes has important impli-cations for both therapeutic decisions and educational approaches. Regardless of the typeof diabetes, however, the child who presents with severe fasting hyperglycaemia, metabolic 14
  26. 26. Diabetes and diabetes teamderangements and ketonaemia will require insulin therapy initially to reverse the metabolicabnormalities [55]. Measurement of diabetes-associated autoantibody markers, for example ICA, GAD,IA2, IAA and/or HbA1c, may be helpful in some situations. However, there is currentlyinsufficient evidence to support the routine use of HbA1c for the diagnosis of diabetes(E) [54]. Measurement of fasting insulin or C-peptide may be useful in the diagnosis of T2DM inchildren. Fasting insulin and C-peptide levels are usually normal or elevated, although notas elevated as might be expected for the degree of hyperglycaemia (E) [56]. If patients areinsulin treated, measuring C-peptide when the glucose is sufficiently high (>8 mmol/L)to stimulate C-peptide will detect if endogenous insulin secretion is still occurring. Thisis rare outside the honeymoon period (2–3 yr) in children with T1DM (E). The possibility of other types of diabetes should be considered in:r the antibody-negative child who has a family history of diabetes consistent with autoso-mal dominant inheritancer associated conditions such as deafness, optic atrophy or syndromic featuresr marked insulin resistancer those requiring little or no insulin outside the partial remission phaser a history of exposure to drugs that are known to be toxic to beta cells or that cause insulinresistance. The characteristic features of T1DM with T2DM and monogenic diabetes are comparedin Table 2.3.Type 2 diabetes mellitusT2DM is rapidly increasing in children and adolescents (B, E) [8, 57]. There may be pre-dominantly insulin resistance with relative insulin deficiency or a predominantly secretorydefect (non-autoimmune mediated) with or without insulin resistance. The possibility of T2DM should be considered in children and adolescents who areobese, have a strong family history of T2DM, come from an ethnic background at highrisk for diabetes, produce little or no ketonuria and manifest signs of insulin resistance(acanthosis nigricans or polycystic ovarian syndrome) (Table 2.3). The rising incidence of T2DM is associated with the epidemic of obesity. Lifestyle factorssuch as little exercise and overeating leading to obesity have profound effects. Whilst manyindigenous ethnic groups are especially prone to T2DM (e.g. Pima Indians in Arizona,Cree–Ojibwe Indians in Canada, Pacific islanders, Australian Aborigines, Torres Straitislanders), the increased risk is now being seen in many populations (e.g. Indian, Pakistaniand Bangladeshi communities originating from South Asia, Chinese, Africans, African-Americans, African-Caribbeans, Arabs and Hispanic-Americans) (B) [8]. T2DM is often asymptomatic but may present with ketosis and even mild-to-moderateketoacidosis (B) [57]. It may be the underlying cause of hyperglycaemia associated withinfections and severe illness in some patients (see section Stress hyperglycaemia below). The long-term microvascular complications of diabetes occur at least as frequently asin T1DM (B) [58] and the onset may be earlier (C) [59, 60]. The risk of nephropathyappears to be greater in patients with early onset of T2DM (<20 yr of age) comparedwith adult-onset T2DM. However, based on limited data, the risk of retinopathy does notappear to be increased in youth-onset T2DM [58]. Abnormalities of liver function arefound in up to half of youth with T2DM [61, 62]. Because T2DM may have a prolonged 15
  27. 27. Chapter 2Table 2.3 Clinical characteristics of T1DM, T2DM and monogenic diabetes in children andadolescentsCharacteristic Type 1 Type 2 MonogenicGenetics Polygenic Polygenic MonogenicAge Throughout Usually pubertal (or later) Often postpubertal childhood except MODY2 and neonatal diabetesOnset Most often Variable; from slow, mild Variable acute, rapid (often insidious) to severeAssociationsAutoimmunity Yes No NoKetosis Common Rare Rare in MODY, common in neonatal diabetesObesity Reflects the Very common Reflects the background background risk riskAcanthosis No Yes NonigricansFrequency(percentage of Usually 90%+ Most countries < 10% ?1–3%all diabetes in (Japan 60–80%)young people)Parent with 2–4% 80% 90%diabetesasymptomatic phase, screening for complications should start at diagnosis or soon after(E) [63, 64]. The risks for macrovascular complications are also increased and reflect theunderlying metabolic syndrome in T2DM.Screening for T2DMPopulation screening for T2DM in children and adolescents cannot be justified in somecountries because of the low prevalence. In countries with higher incidence, such as Japanand Taiwan, annual school glycosuria screening programmes are in place [9, 65]. Targetedscreening of youths is recommended at the point of medical contact if they are overweightand have any two risk factors listed below (E) [66, 67]. Testing may also be considered inother high-risk patients who have any of the risk factors (Table 2.4). Testing of high-risksubjects should be undertaken starting at age 10 years or at onset of puberty, whichever isearlier, and every 2 years thereafter (E) [56]. 16
  28. 28. Diabetes and diabetes team Table 2.4 Risk factors for T2DM – screening is recommended if any two risk factors are present Overweight defined as either: BMI > 85th percentile for age and sex Weight for height > 85th percentile Weight > 120% of ideal (50th percentile) for height A family history of T2DM in first- or second-degree relatives An at-risk ethnic group: Native Americans African-Americans Hispanic-Americans Asians South Pacific islanders Signs of insulin resistance or conditions associated with insulin resistance: Acanthosis nigricans Hypertension Dyslipidaemia Polycystic ovarian syndrome BMI, body mass index.Maturity-onset diabetes of the youngMaturity-onset diabetes of the young (MODY) was described as a disorder with the fol-lowing characteristics: onset before 25 years of age, autosomal dominant inheritance andnon-ketotic diabetes mellitus [68, 69]. These classical definitions given to MODY are nolonger very helpful, as T2DM diabetes occurs in children and will often meet all thesecriteria (B, C) [63]. In addition, defining the molecular genetics has shown that there aremarked differences between genetic subgroups within these old, broad categories makingit much more appropriate to use the genetic subgroups, an approach that has been sup-ported by the ADA and WHO in their guidelines on classification (E) (Table 2.2). Thereis great variation in the degree of hyperglycaemia, need for insulin and risk for futurecomplications (B) [70] (see Chapter 13 for more details).Stress hyperglycaemiaStress hyperglycaemia has been reported in up to 5% of children presenting to an emergencydepartment with acute illness or injury. Traumatic injuries, febrile seizures and elevatedbody temperature (>39 ◦ C) were identified as the most common associated features [71].The reported incidence of progression to overt diabetes varies from 0 to 32% (B, C) [72–77]. Children with incidental hyperglycaemia without a serious concomitant illness weremore likely to develop diabetes than those with a serious illness [73]. Islet cell antibodiesand insulin autoantibody testing had a high positive and negative predictive value forT1DM in children with stress hyperglycaemia [73].Structure of the diabetes management teamConsensus guidelines on the management of diabetes in childhood and adolescence rec-ommend that children and adolescents with diabetes should have frequent access to careby a multidisciplinary team (E) [55, 78–80]. The diabetes management team includes the 17
  29. 29. Chapter 2child or adolescent, his or her family, paediatric endocrinologist or physician with spe-cialist training in childhood diabetes, diabetes educator, dietitian and social worker orpsychologist (Table 2.5). The aims of the diabetes management team are to provide edu-cation, initiate insulin replacement and blood glucose monitoring and provide nutritionalplanning and psychological support. There have been no conclusive evidence-based studies validating the multidisciplinaryteam approach to diabetes management, as opposed to care provided by individual disci-plines. However, many studies have demonstrated that a team approach improves diabetesoutcomes. The largest study to date, the Diabetes Control and Complications Trial (DCCT),was a prospective, randomised multicentred clinical trial which convincingly showed thatstrict glycaemic control could be achieved by individualised treatment provided by a teamof highly trained diabetes doctors, nurses, educators and dietitians (A) [87]. Their strate-gies included frequent contact via outpatient visits as well as regular telephone contact.The investigators aimed to educate patients and parents and empower them in diabetesmanagement. The effectiveness of the diabetes management team in assisting patients toimprove glycaemic control and preventing or delaying onset of diabetes complications inthe DCCT has been the motivating factor in establishing the diabetes management teamas a necessary component of diabetes care (B, E) [55, 79, 80, 87]. In the paediatric popula-tion, a multidisciplinary team approach to intensive management of T1DM has also beenshown to improve glycaemic control (A, B) [88–91]. Involvement by the diabetes management team should begin at initial diagnosis ofdiabetes (E). This multidisciplinary approach has been shown to reduce hospital lengthof stay, as compared with management by an endocrinologist or general physician alone(B) [92]. Management by the multidisciplinary team at diagnosis may reduce the riskof microvascular disease at follow-up [84]. Many children and adolescents with newlydiagnosed diabetes can be managed from diagnosis at home rather than in hospital (A)[93, 94] (Table 2.6). Initial ambulatory management does not lead to any disadvantagesin terms of metabolic control, diabetes complications and subsequent hospitalisations orpsychosocial adjustments. However, children who present with diabetic ketoacidosis atdiagnosis must of necessity be managed in hospital until stabilisation (E) [55, 79, 80]. Ongoing review by the diabetes management team should be carried out regularly af-ter diagnosis. More frequent visits to a multidisciplinary diabetes clinic were associatedwith lower HbA1c levels (three to four visits compared with one to two visits) (B) [89,95]. Provision of a mobile diabetes education and care team to a rural area in Germanywas associated with lower HbA1c levels, fewer hospitalisations and better quality of life inchildren with T1DM (B) [96]. Current guidelines suggest that there should be at least onemajor annual review where growth, blood pressure, puberty, associated conditions, nutri-tion and complications are assessed and managed (E) [78, 79]. Availability of a patient’sHbA1c result at the time of the clinic visit improved glycaemic control (A) [97]. Diabetesmanagement via telemedicine may provide a more time-effective way of delivering care topatient with diabetes. Telemedicine may offer the advantage of more frequent contact andresult in improvement of glycaemic control, decreased insulin requirements and reducednumber of hypoglycaemic events (A, B) [98–102] (see Chapter 14 for a more detailed dis-cussion of this). However, regular phone contact with adolescents does not always improveglycaemic control (B) [103, 104]. Current guidelines recommend that the diabetes management team should be speciallytrained in the management of diabetes in children and adolescents [55, 78–80]. A child’s 18
  30. 30. Diabetes and diabetes teamTable 2.5 Evidence for the role of the diabetes management teamTeam Level ofmember Role Evidence for effectiveness evidenceDiabetes To provide (a) Specialist care was associated with (B) [81]specialist high-level medical higher levels of participation in diabetes care self-care practices and better glycaemic control. (b) There was a higher incidence of neuropathy, overt nephropathy and coronary artery disease in those who did not receive ongoing care from an endocrinologist, diabetologist or diabetes clinic after diagnosis of T1DM in childhood.Diabetes To teach and (a) Clinic attendance, hospital admission (A) [82, 83]educator support children and glycaemic control were improved in and families to 154 children after institution of a manage the diabetes educator. diabetes regimen (b) There was a 50% reduction in length and to become of hospitalisation at diagnosis 2 yr after independent employment of an educator and A1c levels were lower 1 and 3 yr after using a primary nurse managed in the team.Dietitian To provide specific (a) Dietitians have special training in (C) diabetes-related applying and teaching about appropriate dietary advice and food choices and exercise. education (b) Their expertise is utilised by 86% of consultant paediatric services caring for young people with diabetes in the UK.Social To support child (a) Appropriate emotional support (B, C) [80,worker and family and should be offered at diagnosis to all 84, 85] provide financial children with diabetes. and community (b) Intensive psychosocial support as required education/support in the month following diagnosis led to better adherence to therapy, better family relations and better sociability. (c) Consultation with a social worker at diagnosis reduced retinopathy 6 yr later.Psychologist To provide (a) There was an improvement in (C) [86] psychological glycaemic control from referral to assessment and psychologist and next clinic appointment managementCase To encourage (a) Their involvement increased visits (A) [82]ambassador families to seek made to the diabetes clinic. medical advice and (b) When written material regarding remind or specific issues pertaining to diabetes reschedule clinic care was provided, there was also a appointments significant reduction in hospital use and hypoglycaemic events. 19
  31. 31. 20 Chapter 2 Table 2.6 Evidence for stabilisation in ambulatory versus in-hospital care Evidence Study Population Intervention Comparator Outcome level Clar 2003 Six studies involving children Home-based Inpatient stabilisation No significant difference in Cochrane with newly diagnosed T1DM. management at diagnosis glycaemic control, admission to systematic Total of 237 patients in the at diagnosis hospital in first 2 yr, acute review outpatient/home-care group complications and cost (A) [93] (mean age 10–13 yr) Srinivasan All children newly diagnosed with Diabetes Inpatient stabilisation Children receiving ambulatory (B) [94] 2004 T1DM (n = 61) after introduction day-care at diagnosis stabilisation via a DCCP had a of programme compared with a programme shorter initial stay in hospital and pre-intervention cohort (n = 49) suffered no adverse events McEvilly 400 children with diabetes Diabetes 20-yr comparison Reduced readmission rates to Historical 2005 home-care between outpatient hospital, HbA1c after comparison service care now and inpatient stabilisation, diabetic (C) [91] care before (∼1980) ketoacidosis and cost
  32. 32. Diabetes and diabetes teamage and stage of development affect management priorities such as age-specific glycaemicgoals as well as issues in self-management. Glycaemic goals in very young children shouldtake into account the unique risks of hypoglycaemia (see Chapter 5 for a more detaileddiscussion of this). The family unit is always an integral part of the management team.Whereas young children rely heavily on their families for diabetes care, middle- and high-school students should be expected to provide some of their own diabetes care whilemaintaining close supervision by their parents [55]. To date, there is a limited evidence baseto support these recommendations regarding age-specific management and education.ConclusionChildhood diabetes is predominantly due to T1DM that needs prompt treatment to pre-vent the development of ketoacidosis. Other forms of diabetes are also found and maybe more common than T1DM diabetes in certain populations. The incidence of T1DMvaries significantly worldwide and is increasing by approximately 3% per year globally.The rising incidence is likely to have a multifactorial basis, with recent evidence suggestingthat nutritional and lifestyle factors are important. Initial and ongoing care by a multidis-ciplinary diabetes team forms the standard for management of diabetes in children andadolescents.References 1 Alberti K, Aschner P, Assal J-P et al. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva, 1999. Available at: http://www.staff.ncl.ac.uk/philip.home/who dmc.htm#Authors 2 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2007; 30(suppl 1): S42–7. 3 Harris R, Donahue K, Rathore SS et al. Screening adults for type 2 diabetes: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2003; 138: 215–29. 4 Hoerger TJ, Harris R, Hicks KA et al. Screening for type 2 diabetes mellitus: a cost-effectiveness analysis. Ann Intern Med 2004; 140: 689–99. 5 Alberti KG, Zimmet P, Shaw J. The metabolic syndrome – a new worldwide definition. Lancet 2005; 366: 1059–62. 6 Forouhi NG, Balkau B, Borch-Johnsen K et al. The threshold for diagnosing impaired fasting glucose: a position statement by the European Diabetes Epidemiology Group. Diabetologia 2006; 49: 822–7. 7 Vandewalle CL, Coeckelberghs MI, De Leeuw IH et al. Epidemiology, clinical aspects, and biology of IDDM patients under age 40 years. Comparison of data from Antwerp with complete ascertainment with data from Belgium with 40% ascertainment. The Belgian Diabetes Registry. Diabetes Care 1997; 20: 1556–61. 8 Pinhas-Hamiel O, Zeitler P. The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr 2005; 146: 693–700. 9 Wei JN, Sung FC, Lin CC et al. National surveillance for type 2 diabetes mellitus in Taiwanese children. JAMA 2003; 290: 1345–50. 10 The DIAMOND Project Group. Incidence and trends of childhood Type 1 diabetes worldwide 1990– 1999. Diabet Med 2006; 23: 857–66. 11 International Diabetes Federation. Diabetes Atlas, 2nd edn. International Diabetes Federation, Brussels, 2003. 12 Green A, Patterson CC. Trends in the incidence of childhood-onset diabetes in Europe 1989–1998. Diabetologia 2001; 44(suppl 3): B3–8. 13 Karvonen M, Viik-Kajander M, Moltchanova E et al. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 2000; 23: 1516–26. 21
  33. 33. Chapter 214 Cucca F, Goy JV, Kawaguchi Y et al. A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients. Nat Genet 1998; 19: 301–2.15 Gale EA, Gillespie KM. Diabetes and gender. Diabetologia 2001; 44: 3–15.16 Karvonen M, Pitkaniemi M, Pitkaniemi J et al. Sex difference in the incidence of insulin-dependent di- abetes mellitus: an analysis of the recent epidemiological data. World Health Organization DIAMOND Project Group. Diabetes Metab Rev 1997; 13: 275–91.17 Weets I, Kaufman L, Van der AB et al. Seasonality in clinical onset of type 1 diabetes in Belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence. Diabetologia 2004; 47: 614–21.18 Barker JM. Clinical review: type 1 diabetes-associated autoimmunity: natural history, genetic associ- ations, and screening. J Clin Endocrinol Metab 2006; 91: 1210–17.19 Gillespie KM, Bain SC, Barnett AH et al. The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes. Lancet 2004; 364: 1699–1700.20 Kukko M, Virtanen SM, Toivonen A et al. Geographical variation in risk HLA-DQB1 genotypes for type 1 diabetes and signs of beta-cell autoimmunity in a high-incidence country. Diabetes Care 2004; 27: 676–81.21 Sugihara S, Sakamaki T, Konda S et al. Association of HLA-DR, DQ genotype with different beta-cell functions at IDDM diagnosis in Japanese children. Diabetes 1997; 46: 1893–7.22 Kawasaki E, Matsuura N, Eguchi K. Type 1 diabetes in Japan. Diabetologia 2006; 49: 828–36.23 Ohtsu S, Takubo N, Kazahari M et al. Slowly progressing form of type 1 diabetes mellitus in children: genetic analysis compared with other forms of diabetes mellitus in Japanese children. Pediatr Diabetes 2005; 6: 221–9.24 Raymond NT, Jones JR, Swift PG et al. Comparative incidence of Type I diabetes in children aged under 15 years from South Asian and White or Other ethnic backgrounds in Leicestershire, UK, 1989 to 1998. Diabetologia 2001; 44(suppl 3): B32–6.25 Shamis I, Gordon O, Albag Y et al. Ethnic differences in the incidence of childhood IDDM in Is- rael (1965–1993). Marked increase since 1985, especially in Yemenite Jews. Diabetes Care 1997; 20: 504–8.26 Neu A, Willasch A, Ehehalt S et al. Diabetes incidence in children of different nationalities: an epi- demiological approach to the pathogenesis of diabetes. Diabetologia 2001; 44(suppl 3): B21–6.27 Onkamo P, Vaananen S, Karvonen M et al. Worldwide increase in incidence of Type I diabetes – the analysis of the data on published incidence trends. Diabetologia 1999; 42: 1395–1403.28 Haynes A, Bulsara MK, Bower C et al. Independent effects of socioeconomic status and place of residence on the incidence of childhood type 1 diabetes in Western Australia. Pediatr Diabetes 2006; 7: 94–100.29 Taplin CE, Craig ME, Lloyd M et al. The rising incidence of childhood type 1 diabetes in New South Wales, 1990–2002. Med J Aust 2005; 183: 243–6.30 EURODIABS ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. EURODIAB ACE Study Group. Lancet 2000; 355: 873–6.31 Karvonen M, Pitkaniemi J, Tuomilehto J. The onset age of type 1 diabetes in Finnish children has become younger. The Finnish Childhood Diabetes Registry Group. Diabetes Care 1999; 22: 1066–70.32 Viskari HR, Koskela P, Lonnrot M et al. Can enterovirus infections explain the increasing incidence of type 1 diabetes? Diabetes Care 2000; 23: 414–16.33 Betts P, Mulligan J, Ward P et al. Increasing body weight predicts the earlier onset of insulin-dependant diabetes in childhood: testing the ‘accelerator hypothesis’ (2). Diabet Med 2005; 22: 144–51.34 EURODIABS Study Group. Rapid early growth is associated with increased risk of childhood type 1 diabetes in various European populations. Diabetes Care 2002; 25: 1755–60.35 Patterson CC, Dahlquist G, Soltesz G et al. Is childhood-onset type I diabetes a wealth-related disease? An ecological analysis of European incidence rates. Diabetologia 2001; 44(suppl 3): B9–16.36 Levy-Marchal C, Patterson C, Green A. Variation by age group and seasonality at diagnosis of childhood IDDM in Europe. The EURODIAB ACE Study Group. Diabetologia 1995; 38: 823–30.37 Laron Z, Lewy H, Wilderman I et al. Seasonality of month of birth of children and adolescents with type 1 diabetes mellitus in homogenous and heterogeneous populations. Isr Med Assoc J 2005; 7: 381–4.38 Rothwell PM, Gutnikov SA, McKinney PA et al. Seasonality of birth in children with diabetes in Europe: multicentre cohort study. European Diabetes Study Group. BMJ 1999; 319: 887–8.39 Yang Z, Long X, Shen J et al. Epidemics of type 1 diabetes in China. Pediatr Diabetes 2005; 6: 122–8.22
  34. 34. Diabetes and diabetes team40 Olmos P, A’Hern R, Heaton DA et al. The significance of the concordance rate for type 1 (insulin- dependent) diabetes in identical twins. Diabetologia 1988; 31: 747–50.41 Harjutsalo V, Podar T, Tuomilehto J. Cumulative incidence of type 1 diabetes in 10,168 siblings of Finnish young-onset type 1 diabetic patients. Diabetes 2005; 54: 563–9.42 Steck AK, Barriga KJ, Emery LM et al. Secondary attack rate of type 1 diabetes in Colorado families. Diabetes Care 2005; 28: 296–300.43 Lorenzen T, Pociot F, Hougaard P et al. Long-term risk of IDDM in first-degree relatives of patients with IDDM. Diabetologia 1994; 37: 321–7.44 Gillespie KM, Gale EA, Bingley PJ. High familial risk and genetic susceptibility in early onset childhood diabetes. Diabetes 2002; 51: 210–14.45 Dorman JS, Steenkiste AR, O’Leary LA et al. Type 1 diabetes in offspring of parents with type 1 diabetes: the tip of an autoimmune iceberg? Pediatr Diabetes 2000; 1: 17–22.46 el Hashimy M, Angelico MC, Martin BC et al. Factors modifying the risk of IDDM in offspring of an IDDM parent. Diabetes 1995; 44: 295–9.47 EURODIABS ACE Study Group. Familial risk of type I diabetes in European children. The Eurodiab Ace Study Group and The Eurodiab Ace Substudy 2 Study Group. Diabetologia 1998; 41: 1151–6.48 Lorenzen T, Pociot F, Stilgren L et al. Predictors of IDDM recurrence risk in offspring of Danish IDDM patients. Danish IDDM Epidemiology and Genetics Group. Diabetologia 1998; 41: 666–73.49 Warram JH, Krolewski AS, Gottlieb MS et al. Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. N Engl J Med 1984; 311: 149–52.50 Dahlquist G, Mustonen L. Analysis of 20 years of prospective registration of childhood onset diabetes time trends and birth cohort effects. Swedish Childhood Diabetes Study Group. Acta Paediatr 2000; 89: 1231–7.51 Hypponen E, Virtanen SM, Kenward MG et al. Obesity, increased linear growth, and risk of type 1 diabetes in children. Diabetes Care 2000; 23: 1755–60.52 Clarke SL, Craig ME, Garnett SP et al. Increased adiposity at diagnosis in younger children with type 1 diabetes does not persist. Diabetes Care 2006; 29: 1651–3.53 Kordonouri O, Hartmann R. Higher body weight is associated with earlier onset of Type 1 diabetes in children: confirming the ‘Accelerator Hypothesis’. Diabet Med 2005; 22: 1783–4.54 World Health Organization. Diagnosis and classification of diabetes mellitus. Diabetes Care 2006; 29(suppl 1): S43–8.55 Silverstein J, Klingensmith G, Copeland K et al. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care 2005; 28: 186–212.56 American Diabetes Association. Type 2 diabetes in children and adolescents. American Diabetes As- sociation. Pediatrics 2000; 105: 671–80.57 Pinhas-Hamiel O, Dolan LM, Zeitler PS. Diabetic ketoacidosis among obese African-American ado- lescents with NIDDM. Diabetes Care 1997; 20: 484–6.58 Krakoff J, Lindsay RS, Looker HC et al. Incidence of retinopathy and nephropathy in youth-onset compared with adult-onset type 2 diabetes. Diabetes Care 2003; 26: 76–81.59 Eppens MC, Craig ME, Cusumano J et al. Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care 2006; 29: 1300–6.60 Pavkov ME, Bennett PH, Knowler WC et al. Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians. JAMA 2006; 296: 421–6.61 Nadeau KJ, Klingensmith G, Zeitler P. Type 2 diabetes in children is frequently associated with elevated alanine aminotransferase. J Pediatr Gastroenterol Nutr 2005; 41: 94–98.62 Roberts EA. Non-alcoholic fatty liver disease (NAFLD) in children. Front Biosci 2005; 10: 2306–18.63 American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000; 23: 381–9.64 American Diabetes Association. Screening for type 2 diabetes. Diabetes Care 2004; 27(suppl 1): S11–14.65 Urakami T, Kubota S, Nitadori Y et al. Annual incidence and clinical characteristics of type 2 diabetes in children as detected by urine glucose screening in the Tokyo metropolitan area. Diabetes Care 2005; 28: 1876–81.66 Alberti G, Zimmet P, Shaw J et al. Type 2 diabetes in the young: the evolving epidemic: the international diabetes federation consensus workshop. Diabetes Care 2004; 27: 1798–1811. 23