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Sixth Edition
Textbook of
Diabetes
Edited by Richard ..
I G Holt * Allan Flyvbjerg
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WlLEY Blackwell
Textbook of Diabetes

We dedicate this book to all people living with diabetes and the healthcare professionals
who look after them. We would also like to dedicate this book to our families, without
whose support and encouragement the book would never have been finished.
Textbook of
Diabetes
EDITED BY
RICHARD I.G. HOLT MA, MB BChir, PhD, FRCP, FHEA

Professor in Diabetes & Endocrinology
Human Development and Health
Faculty of Medicine, University of Southampton
Southampton, UK
Honorary Consultant Physician
Southampton National Institute for Health Research Biomedical Research Centre
University Hospital Southampton NHS Foundation Trust
Southampton, UK
ALLAN FLYVBJERG MD, DMSc

Former CEO at Steno Diabetes Center Copenhagen (SDCC)
The Capital Region of Denmark
Professor of Clinical Endocrinology
Faculty of Health and Medical Sciences
University of Copenhagen
Copenhagen, Denmark
SIXTH EDITION
This sixth edition first published 2024
© 2024 John Wiley & Sons Ltd.
Edition History
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Library of Congress Cataloging-in-Publication Data
Names: Holt, Richard I. G., editor. |Flyvbjerg, Allan, editor.

Title: Textbook of diabetes / edited by Richard I.G. Holt, Allan Flyvbjerg.
Other titles: Textbook of diabetes (Pickup)
Description: Sixth edition. | Hoboken, NJ : Wiley-Blackwell 2024. |
Includes bibliographical references and index.
Identifiers: LCCN 2022049550 (print) | LCCN 2022049551 (ebook) | ISBN
9781119697428 (hardback) | ISBN 9781119697435 (adobe pdf) | ISBN
9781119697411 (epub)
Subjects: MESH: Diabetes Mellitus
Classification: LCC RC660.4 (print) | LCC RC660.4 (ebook) | NLM WK 810 |
DDC 616.4/62–dc23/eng/20230125
LC record available at https://lccn.loc.gov/2022049550
LC ebook record available at https://lccn.loc.gov/2022049551
Cover Design: Wiley

Cover Images: Courtesy of Olaniru, Jones & Persaud, King’s College London
Set in 9.25/11pt MinionPro by Straive, Pondicherry, India

Contents
List of Contributors, viii Part 3 Pathogenesis of Diabetes

Preface, xv
12 The Genetics of Diabetes, 157
List of Abbreviations, xvi Rashmi B. Prasad
13 Genetics of Obesity, 197
Part 1 Diabetes in its Historical and Social I. Sadaf Farooqi
Context
14 Autoimmune Type 1 Diabetes, 203
Omar Akel and Åke Lernmark
1 The History of Diabetes Mellitus, 3
Robert B. Tattersall and David R. Matthews 15 Other Disorders with Type 1 Diabetes and Atypical
Phenotypes, 216
2 Classification and Diagnosis of Diabetes, 22 Alice P.S. Kong, Elaine Y.K. Chow, Andrea O.Y. Luk,
Ambady Ramachandran, Chamukuttan Snehalatha, and Juliana C.N. Chan
Arun Raghavan, and Arun Nanditha
16 Abnormalities of Insulin Secretion and β-Cell Defects in Type 2
3 The Global Burden of Diabetes, 28 Diabetes, 225
Jessica L. Harding, Mary Beth Weber, and Jonathan E. Shaw Stefano Del Prato, Cristina Bianchi, and Giuseppe Daniele
4 Epidemiology of Type 1 Diabetes, 41 17 Insulin Resistance in Type 2 Diabetes, 238
Lars C. Stene and Jaakko Tuomilehto Michael Roden, Kitt Falk Petersen, and Gerald I. Shulman
5 Epidemiology of Type 2 Diabetes, 55 18 Obesity and Diabetes, 250
Ronald C.W. Ma and Peter C.Y. Tong Nick Finer
19 The Microbiome and Diabetes, 261
Part 2 Normal Physiology Amanda J. Cox, Nicholas P. West, and Allan W. Cripps
6 Overview of Glucose Metabolism, 77

Richard I.G. Holt Part 4 Other Types of Diabetes
7 Islet Function and Insulin Secretion, 84
Peter M. Jones and Shanta J. Persaud 20 Monogenic Causes of Diabetes, 275
Brittany L. Resnick, Maggie H. Shepherd, and
8 Glucagon in Islet and Metabolic Regulation, 99
Andrew T. Hattersley
Jonathan E. Campbell and David A. D’Alessio
21 Drug-Induced Diabetes, 295
9 Mechanism of Insulin Action, 111
Charles D. Ponte and Devra K. Dang
Morris F. White
22 Diabetes in Hypersecreting Endocrine Disorders, 304
10 Central Control of Glucose Homeostasis, 128
Allan A. Vaag, Neil A. Hanley, and Caroline M. Kistorp
Kimberly M. Alonge, Kendra L. Francis, Nicole E. Richardson,
and Michael W. Schwartz 23 Pancreatic Disease and Diabetes, 319
Ranjit Unnikrishnan and Viswanathan Mohan
11 Control of Body Weight: How and Why Do We Gain Weight
Easier Than We Lose It?, 142 24 Clinical Presentations of Diabetes, 330
Janine Makaronidis and Rachel L. Batterham Ee Lin Lim and Roy Taylor
v
Contents
Part 5 Managing the Person with Diabetes 44 Diabetic Nephropathy, 640

Peter Rossing and Allan Flyvbjerg
25 The Aims of Diabetes Care, 343 45 Diabetic Neuropathy, 655
Katharine D. Barnard-Kelly and Richard I.G. Holt Shazli Azmi, Uazman Alam, and Rayaz A. Malik
26 Education to Empower the Person with Diabetes, 354
Ingrid Willaing and Michael Vallis
Part 8 Macrovascular Complications
27 Dietary Management of Diabetes, 368
Nicola Guess
in Diabetes
28 Physical Activities and Diabetes, 382 46 Pathogenesis of Macrovascular Complications in Diabetes, 681
Emma J. Cockcroft and Robert C. Andrews Jakob A. Østergaard, Tomasz J. Block, Sophia Dahm,
29 Monitoring Diabetes, 404 Waheed Khan, and Karin A.M. Jandeleit-Dahm
Emma English 47 Hypertension and Diabetes, 700
30 Biomarkers and Precision Medicine in Diabetes, 414 Peter M. Nilsson
Sok Cin Tye, Michele Provenzano, and Hiddo J.L. Heerspink 48 Dyslipidaemia and Diabetes, 713
Adie Viljoen, Ahmed Handhle, and Anthony S. Wierzbicki
Part 6 Treatment of Diabetes 49 Ischaemic Heart Disease in Diabetes, 724
Michael Lehrke and Nikolaus Marx
31 Insulin and Insulin Treatment, 431
Roman Vangoitsenhoven, Parth Narendran, 50 Heart Failure and Diabetes, 732
and Chantal Mathieu Ambarish Pandey, Kershaw V. Patel, and Subodh Verma
32 New Technologies for Glucose Monitoring, 444 51 Cerebrovascular Disease and Diabetes, 745
Thomas Danne and Olga Kordonouri Colum F. Amory, Jesse Weinberger, and Travis S. Smith
33 New Technologies for Insulin Administration, 459 52 Peripheral Vascular Disease, 755
Hannah Forde and Pratik Choudhary Henrik H. Sillesen
34 Whole Pancreas and Islet Cell Transplantation, 473

Braulio A. Marfil-Garza, Peter A. Senior,
and A.M. James Shapiro Part 9 Other Complications of Diabetes
35 Oral Glucose-Lowering Agents, 492 53 Foot Problems in People with Diabetes, 771
Clifford J. Bailey and Andrew J. Krentz Frank L. Bowling, Keeley J. Foley, and Andrew J.M. Boulton
36 Non-insulin Parenteral Therapies, 520 54 Sexual Function in Men and Women with Diabetes, 780
Tina Vilsbøll, Mikkel Christensen, Andreas Andersen, Kirsty Winkley, Camilla Kristensen, Jackie Fosbury,
and Filip K. Knop and David Price
37 How to Use Type 2 Diabetes Treatments in Clinical Practice, 534 55 Gastrointestinal Manifestations of Diabetes, 796
Thomas Karagiannis, Aris Liakos, and Apostolos Tsapas Michael Camilleri and Adil E. Bharucha
38 Weight Management and Metabolic Surgery, 551 56 Diabetes and Oral Health, 810
Alexis Sudlow, Dimitri J. Pournaras, and Carel W. le Roux Palle Holmstrup, Christian Damgaard, and Allan Flyvbjerg
39 In-Hospital Treatment and Surgery in People with Diabetes, 559 57 Diabetes and Non-alcoholic Fatty Liver Disease, 820
Ketan Dhatariya, Philip Newland-Jones, and Mayank Patel Alessandro Mantovani, Giovanni Targher, and
40 Hypoglycaemia in Diabetes, 579 Christopher D. Byrne
Ahmed Iqbal, Elaine Y.K. Chow, Timothy W. Jones, 58 The Skin in Diabetes, 838
and Simon R. Heller Paul Devakar Yesudian
41 Acute Metabolic Complications of Diabetes: Diabetic Ketoacidosis 59 Bone and Rheumatic Disorders in Diabetes, 853
and the Hyperosmolar Hyperglycaemic State in Adults, 602 Andrew Grey and Nicola Dalbeth
Philip Newland-Jones, Mayank Patel, and Ketan Dhatariya
60 Diabetes and Cancer: Risk, Outcomes, and Clinical
Implications, 867
Part 7 Microvascular Complications in Diabetes
Ellena Badrick, Emily J. Gallagher, and Andrew G. Renehan
42 Pathogenesis of Microvascular Complications, 615 61 Diabetes and Infections, 878
Allan Flyvbjerg Andrea O.Y. Luk and Clive S. Cockram
43 Diabetic Retinopathy, 629 62 Sleep and Diabetes, 897
Toke Bek Sonya Deschênes, Amy McInerney, and Norbert Schmitz
vi
Contents
Part 10 Psychosocial Aspects of Diabetes 72 Diabetes in Old Age, 1072

Ahmed H. Abdelhafiz and Alan J. Sinclair
63 Psychosocial and Behavioural Aspects of Diabetes, 907 73 Diabetes at the End of Life, 1085
Frans Pouwer and Jane Speight Trisha Dunning and June James
64 Role of Cognitive Function in Managing People
with Diabetes, 922 Part 12 Delivery and Organization of
Tamsin Santos, Chelsea Baird, Sally Eastwood, Kerrie Shiell, Diabetes Care
and Joseph E. Ibrahim
65 Mental Disorders and Diabetes, 933 74 The Role of the Multidisciplinary Team across Primary
Najma Siddiqi, Marietta Stadler, and Richard I.G. Holt and Secondary Care, 1097
Samuel Seidu and Kamlesh Khunti
66 Social Aspects of Diabetes, 956
Brian M. Frier and Mark W.J. Strachan 75 Models of Diabetes Care in Low-and Middle-Income
Countries, 1107
67 Social Determinants of Diabetes, 973 David Beran, Sigiriya Aebischer Perone,
Keri F. Kirk, Gerald McKinley, Briana Mezuk, and Erica Spears and Maria Lazo-Porras
Part 11 Diabetes in Special Groups Part 13 Future Directions
68 Ethnic, Cultural, and Religious Aspects to the Management 76 Immunotherapies for Type 1 Diabetes, 1125
of Diabetes, 987 Jesper Johannesen and Flemming Pociot
Wasim Hanif, Sarah N. Ali, and Vinod Patel 77 Stem Cell Therapy in Diabetes, 1137
69 Diabetes in Childhood, 999 Angelo Avogaro and Gian Paolo Fadini
Jennifer M. Ikle, Ananta Addala, and David M. Maahs 78 Gene Therapy for Diabetes, 1144
70 Adolescence and Emerging Adulthood: Diabetes Veronica Jimenez and Fatima Bosch
in Transition, 1019 79 Future Drug Treatments for Type 2 Diabetes, 1154
Charlotte W. Chen and Lori M.B. Laffel Clifford J. Bailey
71 Diabetes in Pregnancy, 1034
David R. McCance and Laura Cassidy Index, 1167
vii
List of Contributors
Ahmed H. Abdelhafiz Angelo Avogaro David Beran

Department of Elderly Medicine Department of Medicine Division of Tropical and Humanitarian Medicine
Rotherham General Hospital University of Padova University of Geneva and Geneva University
Rotherham, UK Padua, Italy Hospitals
Faculty Diabetes Centre, Faculty of Medicine
Ananta Addala Shazli Azmi University of Geneva
Faculty of Biology, Medicine and Health Geneva, Switzerland
Division of Endocrinology, Department of Pediatrics
University of Manchester
Stanford University
Manchester, UK
Stanford, CA, USA Adil E. Bharucha
Clinical Enteric Neuroscience Translational and
Ellena Badrick
Omar Akel Epidemiological Research (CENTER)
Division of Cancer Sciences
Department of Clinical Sciences, Lund University CRC Division of Gastroenterology and Hepatology, Mayo
Skåne University Hospital Clinic
Manchester, UK
Malmö, Sweden Rochester, MN, USA
Clifford J. Bailey
Uazman Alam School of Life and Health Sciences Cristina Bianchi
Department of Cardiovascular and Metabolic Aston University Department of Clinical and Experimental Medicine
Medicine, Institute of Life Course and Medical Birmingham, UK University of Pisa
Sciences, University of Liverpool, Liverpool, UK Pisa, Italy
Chelsea Baird
Sarah N. Ali Queen Elizabeth Centre, Ballarat Health Service and
Tomasz J. Block
Department of Diabetes and Endocrinology Department of Forensic Medicine, Monash
Department of Diabetes, Central Clinical School
Royal Free London NHS Foundation Trust University
Monash University
London, UK Melbourne, Australia
Melbourne, Australia
Kimberly M. Alonge Katharine D. Barnard-Kelly

Southern Health NHS Foundation Trust Fatima Bosch
UW Medicine Diabetes Institute, Department of
Southampton, UK Center of Animal Biotechnology and Gene Therapy,
Medicine
Department of Biochemistry and Molecular
University of Washington
Biology
Seattle, WA, USA Rachel L. Batterham
University Autònoma de Barcelona
Centre for Obesity Research, Rayne Institute
Barcelona, Spain
Department of Medicine, University College London
Colum F. Amory Centro de Investigación Biomédica en Red de
University College London Hospital (UCLH)
Albany Medical College Diabetes y Enfermedades Metabólicas Asociadas
Bariatric Centre for Weight Management and
Albany, NY, USA (CIBERDEM)
Metabolic Surgery
Madrid, Spain
National Institute of Health Research, UCLH
Andreas Andersen Biomedical Research Centre
University of Copenhagen London, UK Andrew J.M. Boulton
Copenhagen, Denmark
Department of Medicine, University of
Toke Bek Manchester and
Robert C. Andrews Department of Ophthalmology Manchester Royal Infirmary
Faculty of Health & Life Science, Clinical and Aarhus University Hospital Manchester, UK
Biomedical Sciences, University of Exeter, Exeter, UK Department of Clinical Medicine, Faculty of Health Miller School of Medicine
Department of Diabetes, Taunton and Somerset Aarhus University University of Miami
NHS Foundation Trust, Taunton, UK Aarhus, Denmark Miami, FL, USA
viii
Frank L. Bowling Mikkel Christensen Stefano Del Prato

Department of Medicine, University of University of Copenhagen Department of Clinical and Experimental Medicine
Manchester and Copenhagen, Denmark University of Pisa
Manchester Royal Infirmary Pisa, Italy
Manchester, UK
Emma J. Cockcroft
Miller School of Medicine
Faculty of Health & Life Science Sonya Deschênes
University of Miami
Department of Health and Community Sciences School of Psychology
Miami, FL, USA
University of Exeter University College Dublin
Exeter, UK Dublin, Ireland
Christopher D. Byrne
Nutrition and Metabolism, Faculty of Medicine Clive S. Cockram Ketan Dhatariya
University of Southampton The Chinese University of Hong Kong Norfolk and Norwich University Hospitals NHS
Southampton National Institute for Health and Care Hong Kong SAR, China Foundation Trust
Research Biomedical Research Centre University of East Anglia
University Hospital Southampton, Southampton Norwich, UK
Amanda J. Cox
General Hospital
Menzies Health Institute Queensland and School of
Southampton, UK
Pharmacy and Medical Sciences Trisha Dunning
Griffith University Formerly of Deakin University
Michael Camilleri Southport, QLD, Australia Geelong, Victoria, Australia
Clinical Enteric Neuroscience Translational and
Epidemiological Research (CENTER) Allan W. Cripps Sally Eastwood
Division of Gastroenterology and Hepatology, Menzies Health Institute Queensland and School of Queen Elizabeth Centre, Ballarat Health
Mayo Clinic Medicine Service and
Rochester, MN, USA Griffith University Department of Forensic Medicine, Monash
Southport, QLD, Australia University
Melbourne, Australia
Jonathan E. Campbell
Department of Medicine, Division of Nicola Dalbeth
Endocrinology Department of Primary Care Health Sciences Emma English
Duke University University of Oxford Faculty of Medicine and Health
Durham, NC, USA Oxford, UK University of East Anglia
Department of Clinical Biochemistry
Norfolk and Norwich University Hospital Trust
Laura Cassidy David A. D’Alessio Norwich, UK
Regional Centre for Endocrinology and Diabetes Department of Medicine, Division of
Royal Victoria Hospital Endocrinology
Gian Paolo Fadini
Belfast, Northern Ireland Duke University
Department of Medicine
Durham, NC, USA
University of Padova
Juliana C.N. Chan Padova, Italy
Department of Medicine and Therapeutics Sophia Dahm
Hong Kong Institute of Diabetes and Obesity Sadaf Farooqi
Li Ka Shing Institute of Health Sciences Monash University
Wellcome-MRC Institute of Metabolic Science
The Chinese University of Hong Kong Melbourne, Victoria, Australia
Addenbrooke’s Hospital
Prince of Wales Hospital Cambridge, UK
Hong Kong, SAR, China Christian Damgaard
Department of Odontology, Faculty of Health and Nick Finer
Medical Sciences National Centre for Cardiovascular Prevention and
Charlotte W. Chen University of Copenhagen Outcomes
Pediatric, Adolescent and Youth Adult Section Copenhagen, Denmark UCL Institute of Cardiovascular Science
Joslin Diabetes Center, and Harvard Medical School
London, UK
Boston, MA, USA
Devra K. Dang
University of Connecticut School of Pharmacy Allan Flyvbjerg
Pratik Choudhary Storrs, CT, USA Steno Diabetes Center Copenhagen and
Leicester Diabetes Centre Department of Clinical Medicine, Faculty of Health
Leicester, UK Giuseppe Daniele and Medical Sciences, University of Copenhagen
Department of Clinical and Experimental Medicine Copenhagen, Denmark
Elaine Y.K. Chow University of Pisa
Department of Medicine and Therapeutics Pisa, Italy Keeley J. Foley
Hong Kong Institute of Diabetes and Obesity Department of Medicine, University of Manchester
Li Ka Shing Institute of Health Sciences Thomas Danne Manchester Royal Infirmary
Phase 1 Clinical Trial Centre Diabetes Center, Children’s Hospital AUF DER Manchester, UK
The Chinese University of Hong Kong BULT Miller School of Medicine
Prince of Wales Hospital Hannover Medical School University of Miami
Hong Kong, SAR, China Hannover, Germany Miami, FL, USA
ix
Hannah Forde Andrew T. Hattersley University Autònoma de Barcelona

Leicester Diabetes Centre Institute of Biomedical and Clinical Science Barcelona, Spain
Leicester, UK University of Exeter Medical School Centro de Investigación Biomédica en Red de
Exeter, UK Diabetes y Enfermedades Metabólicas Asociadas
(CIBERDEM)
Jackie Fosbury Madrid, Spain
Hiddo J.L. Heerspink
Sussex Community NHS Foundation Trust
Department of Clinical Pharmacy and
Brighton, UK
Pharmacology, University of Groningen Jesper Johannesen
University Medical Center Groningen Department of Paediatrics and Adolescent
Kendra L. Francis Groningen, The Netherlands Medicine
UW Medicine Diabetes Institute, Department of Herlev and Gentofte Hospital
Medicine Simon R. Heller Steno Diabetes Center Copenhagen
University of Washington Department of Oncology and Metabolism, Department of Clinical Medicine, Faculty of Health
Seattle, WA, USA The Medical School and Medical Sciences
University of Sheffield University of Copenhagen
Sheffield, UK Copenhagen, Denmark
Brian M. Frier
Centre for Cardiovascular Science, The Queen’s Peter M. Jones
Palle Holmstrup
Medical Research Institute Department of Diabetes
Department of Odontology, Faculty of Health
University of Edinburgh King’s College London
and Medical Sciences
Edinburgh, UK London, UK
Copenhagen, Denmark
Emily J. Gallagher Timothy W. Jones
Division of Endocrinology, Department Richard I.G. Holt Department of Endocrinology and Diabetes
of Medicine Professor in Diabetes & Endocrinology, Perth Children’s Hospital and Telethon Kids Institute
Icahn School of Medicine at Mount Sinai Human Development and Health, University of Perth, Western Australia, Australia
New York, NY, USA Southampton, Faculty of Medicine and
Honorary Consultant Physician, Southampton Thomas Karagiannis
National Institute for Health Research Biomedical Diabetes Centre and Clinical Research and
Andrew Grey Research Centre, University Hospital Southampton Evidence-Based Medicine Unit
Department of Medicine NHS Foundation Trust, Southampton, UK Second Medical Department, Aristotle University of
University of Auckland
Thessaloniki
Auckland, New Zealand Joseph E. Ibrahim Thessaloniki, Greece
Queen Elizabeth Centre, Ballarat Health Service
Nicola Guess Department of Forensic Medicine, Monash University
Waheed Khan
Department of Primary Care Health Sciences Melbourne, Australia
University of Oxford Monash University
Oxford, UK Jennifer M. Ikle Melbourne, Victoria, Australia
Division of Endocrinology, Department of Pediatrics
Stanford University
Ahmed Handhle Stanford, CA, USA
Kamlesh Khunti
East Hertfordshire Hospitals Trust Diabetes Research Centre, University of Leicester,
Lister Hospital Leicester General Hospital, Leicester, UK
Ahmed Iqbal
Stevenage, UK Department of Oncology and Metabolism, The
Department of Clinical Biochemistry Medical School Keri F. Kirk
Addenbrooke’s Hospital University of Sheffield Department of Family Medicine and Psychiatry,
Cambridge, UK Sheffield, UK Georgetown University School of Medicine
MedStar-Georgetown University Hospital
Washington, DC, USA
Wasim Hanif June James
University Hospitals Birmingham NHS Foundation Leicester Diabetes Centre
Trust Leicester, UK Caroline M. Kistorp
Birmingham, UK Steno Diabetes Center Copenhagen
Karin A.M. Jandeleit-Dahm Rigshospitalet
Department of Diabetes, Central Clinical School Copenhagen, Denmark
Neil A. Hanley
Monash University
Centre for Endocrinology and Diabetes
Melbourne, Victoria, Australia Filip K. Knop
German Diabetes Centre (DDZ) University of Copenhagen
Manchester, UK
Institute for Clinical Diabetology Copenhagen, Denmark
Leibniz Centre for Diabetes Research at Heinrich
Jessica L. Harding Heine University Alice P.S. Kong
Departments of Medicine and Surgery, School of Düsseldorf, Germany Department of Medicine and Therapeutics
Medicine Hong Kong Institute of Diabetes and Obesity
Department of Epidemiology, Rollins School of Veronica Jimenez Li Ka Shing Institute of Health Sciences
Public Health Center of Animal Biotechnology and Gene The Chinese University of Hong Kong
Emory University Therapy, Department of Biochemistry and Prince of Wales Hospital
Atlanta, GA, USA Molecular Biology Hong Kong, SAR, China
x
Olga Kordonouri Andrea O.Y. Luk David R. Matthews

Diabetes Center, Children’s Hospital AUF DER Department of Medicine and Therapeutics University of Oxford
BULT Hong Kong Institute of Diabetes and Obesity Oxford, UK
Hannover Medical School Li Ka Shing Institute of Health Sciences
Hannover, Germany Phase 1 Clinical Trial Centre
David R. McCance
The Chinese University of Hong Kong
Regional Centre for Endocrinology and Diabetes
Prince of Wales Hospital
Andrew J. Krentz Royal Victoria Hospital
Hong Kong, SAR, China
Institute for Cardiovascular and Metabolic Belfast, Northern Ireland
Research
University of Reading Ronald C.W. Ma Dayna E. McGill
Reading, UK Division of Endocrinology and Diabetes,
Boston Children’s Hospital, Division of
Department of Population Health Sciences Department of Medicine and Therapeutics
Endocrinology
King’s College London Li Ka Shing Institute of Health Sciences
Mass General Hospital for Children, Boston and
London, UK Hong Kong Institute of Diabetes and Obesity
Harvard Medical School
The Chinese University of Hong Kong
Boston, MA, USA
Prince of Wales Hospital
Camilla Kristensen
Hong Kong, SAR, China
King’s College London
Amy McInerney
London, UK
School of Psychology
David M. Maahs University College Dublin
Division of Endocrinology, Department of
Lori M.B. Laffel Dublin, Ireland
Pediatrics
Boston Children’s Hospital, Division of
Stanford University
Endocrinology
Stanford, CA, USA Gerald McKinley
Mass General Hospital for Children, Boston and
Department of Pathology and Laboratory Medicine,
Harvard Medical School
Schulich Interfaculty Program in Public Health
Boston, MA, USA Janine Makaronidis Schulich School of Medicine and Dentistry,
Centre for Obesity Research, Rayne Institute
Western University
Department of Medicine, University College
Maria Lazo-Porras London, ON, Canada
London
Division of Tropical and Humanitarian Medicine
University College London Hospital (UCLH)
University of Geneva
Bariatric Centre for Weight Management and Briana Mezuk
Geneva, Switzerland
Metabolic Surgery Center for Social Epidemiology and Population
CRONICAS Centre of Excellence in Chronic
National Institute of Health Research, UCLH Health
Diseases
Biomedical Research Centre University of Michigan School of Public Health
Universidad Peruana Cayetano Heredia
London, UK Ann Arbor, MI, USA
Lima, Peru
Rayaz A. Malik Viswanathan Mohan

Michael Lehrke Dr. Mohan’s Diabetes Specialities Centre
Department of Medicine
Department of Internal Medicine I (Cardiology),
Weill Cornell Medicine-Qatar IDF Centre of Excellence in Diabetes Care
University Hospital
Doha, Qatar Madras Diabetes Research Foundation
RWTH Aachen University
ICMR Center for Advanced Research on Diabetes
Aachen, Germany
Alessandro Mantovani Chennai, India
Section of Endocrinology, Diabetes and
Åke Lernmark Metabolism, Department of Medicine Arun Nanditha
Department of Clinical Sciences, Lund University University of Verona Dr. A. Ramachandran’s Diabetes Hospitals
CRC Verona, Italy India Diabetes Research Foundation
Skåne University Hospital Chennai, India
Malmö, Sweden
Braulio A. Marfil-Garza
Department of Surgery Parth Narendran
Carel W. le Roux University of Alberta Institute of Biomedical Research, The Medical
Diabetes Complications Research Centre Edmonton, Alberta, Canada School
University College Dublin University of Birmingham and The Queen Elizabeth
Dublin, Ireland Nikolaus Marx Hospital
Department of Internal Medicine I (Cardiology), Birmingham, UK
Aris Liakos University Hospital
Diabetes Centre and Clinical Research and RWTH Aachen University Philip Newland-Jones
Evidence-Based Medicine Unit Aachen, Germany University Hospitals Southampton NHS Foundation
Second Medical Department, Aristotle University of Trust
Thessaloniki Chantal Mathieu Southampton, UK
Thessaloniki, Greece Clinical and Experimental Endocrinology,
Department of Chronic Diseases Peter M. Nilsson
Ee Lin Lim and Metabolism Lund University
Royal Preston Hospital KU Leuven and University Hospitals Skåne University Hospital
Preston, UK Leuven, Belgium Malmö, Sweden
xi
Jakob A. Østergaard Dimitri J. Pournaras Michael Roden

Department of Diabetes, Central Clinical School Department of Bariatric Surgery Department of Endocrinology and Diabetology,
Monash University Southmead Hospital Medical Faculty and University Hospital
Melbourne, Victoria, Australia Bristol, UK Institute for Clinical Diabetology, German
Steno Diabetes Center Diabetes Center, Leibniz Center for Diabetes
Aarhus and Department of Endocrinology & Research
Internal Medicine, Aarhus University Hospital
Frans Pouwer Heinrich-Heine University Düsseldorf
Department of Psychology, University of Southern
Aarhus, Denmark Düsseldorf, Germany
Denmark and
German Center for Diabetes Research,
Steno Diabetes Center Odense (SDCO)
Ambarish Pandey Partner Düsseldorf
Odense, Denmark
Division of Cardiology, Department of Internal München-Neuherberg, Germany
School of Psychology, Deakin University
Medicine
Geelong, Victoria, Australia
UT Southwestern Medical Center
Dallas, TX, USA Peter Rossing
Rashmi B. Prasad Steno Diabetes Center Copenhagen
Kershaw V. Patel Lund University Diabetes Centre, Department of Department of Clinical Medicine,
Department of Cardiology Clinical Sciences, Diabetes and Endocrinology, Faculty of Health and Medical Sciences
Houston Methodist DeBakey Heart and Lund University University of Copenhagen
Vascular Center Malmö, Sweden Copenhagen, Denmark
Houston, Texas, USA Institute for Molecular Medicine Finland (FIMM)
Helsinki University
Mayank Patel Helsinki, Finland Tamsin Santos
University Hospitals Southampton NHS Queen Elizabeth Centre, Ballarat Health
Foundation Trust Service and
David Price Department of Forensic Medicine,
Southampton, UK
Morriston Hospital Monash University
Swansea, UK Melbourne, VIC, Australia
Vinod Patel
Warwick Medical School
University of Warwick Michele Provenzano
Coventry, UK Nephrology, Dialysis and Renal Transplant Unit
Norbert Schmitz
Acute Medicine, Medical Obstetrics, Diabetes and Department of Psychiatry, McGill University
S’Orsola Hospital - IRCCS - Alma Mater Studiorum
Endocrinology Centre, George Eliot Hospital NHS Douglas Mental Health University Institute
University of Bologna, Italy
Trust, Nuneaton, UK Montreal, Canada
Department of Population-Based Medicine
Arun Raghavan University of Tübingen
Sigiriya Aebischer Perone
Dr. A. Ramachandran’s Diabetes Hospitals Tübingen, Germany
Division of Tropical and Humanitarian Medicine
Geneva University Hospitals India Diabetes Research Foundation
Geneva, Switzerland Chennai, India
Michael W. Schwartz
UW Medicine Diabetes Institute,
Shanta J. Persaud Ambady Ramachandran Department of Medicine
Department of Diabetes
Dr. A. Ramachandran’s Diabetes Hospitals University of Washington
King’s College London
India Diabetes Research Foundation Seattle, WA, USA
London, UK
Chennai, India
Kitt Falk Petersen

Department of Internal Medicine and Yale Diabetes Andrew G. Renehan Samuel Seidu
Division of Cancer Sciences Diabetes Research Centre
Research Center
University of Manchester University of Leicester, Leicester General Hospital
Yale School of Medicine
Manchester, UK Leicester, UK
New Haven, CT, USA
Flemming Pociot
Brittany L. Resnick Peter A. Senior
Steno Diabetes Center Copenhagen
Exeter NIHR Clinical Research Facility Department of Medicine and Clinical Islet
Department of Clinical Medicine, Faculty of Health
Royal Devon University Healthcare NHS Transplant Program
and Medical Sciences
Foundation Trust University of Alberta
Exeter, UK Edmonton, Alberta, Canada
Copenhagen, Denmark
Charles D. Ponte Nicole E. Richardson A.M. James Shapiro

Robert C. Byrd Health Sciences Center, West UW Medicine Diabetes Institute, Department of Medicine
Virginia University – Schools of Pharmacy and Department of Medicine University of Alberta
Medicine, One Medical Center Drive, Morgantown, University of Washington Edmonton, Alberta, Canada
WV, USA Seattle, WA, USA
xii
Jonathan E. Shaw Jane Speight Second Medical Department, Aristotle University of

Clinical and Population Health, Baker Institute Department of Psychology, University of Southern Thessaloniki
School of Life Sciences, La Trobe University Denmark, Odense, Denmark Thessaloniki, Greece
School of Public Health and Preventive Medicine, Department of Medical Psychology Harris Manchester College
Monash University Amsterdam UMC, Amsterdam, The Netherlands University of Oxford
Melbourne, Australia Australian Centre for Behavioural Research in Oxford, UK
Diabetes, Diabetes Victoria
Melbourne, Victoria, Australia
Maggie H. Shepherd Jaakko Tuomilehto
Exeter NIHR Clinical Research Facility, Department of Public Health, University of Helsinki
Royal Devon and Exeter NHS Foundation Trust Marietta Stadler Helsinki, Finland
Institute of Biomedical and Clinical Science, Department of Diabetes, School of Cardiovascular National School of Public Health
University of Exeter Medical School and Metabolic Medicine and Sciences Madrid, Spain
Exeter, UK Faculty of Live Sciences and Medicine Diabetes Research Group, King Abdulaziz University
King’s College London Jeddah, Saudi Arabia
London, UK
Kerrie Shiell
Queen Elizabeth Centre, Ballarat Health Service Sok Cin Tye
Department of Forensic Medicine, Monash Lars C. Stene
Department of Clinical Pharmacy and
University Department of Chronic Diseases, Norwegian
Pharmacology, University of Groningen
Melbourne, Australia Institute of Public Health
University Medical Center Groningen
Oslo Diabetes Research Centre, Oslo University
Groningen, The Netherlands
Hospital
Gerald I. Shulman Oslo, Norway
Departments of Internal Medicine and Cellular &
Ranjit Unnikrishnan
Molecular Physiology, and Yale Diabetes Research
Mark W.J. Strachan Dr. Mohan’s Diabetes Specialities Centre
Center
Metabolic Unit IDF Centre of Excellence in Diabetes Care
Yale School of Medicine
Western General Hospital Madras Diabetes Research Foundation
New Haven, CT, USA
Edinburgh, UK ICMR Center for Advanced Research on Diabetes
Chennai, India
Najma Siddiqi
Department of Health Sciences Alexis Sudlow
University of York and Hull York Medical School Department of Bariatric Surgery Allan A. Vaag
York, UK Southmead Hospital Steno Diabetes Center Copenhagen
Bradford District Care NHS Foundation Trust Bristol, UK Rigshospitalet
Bradford, UK Copenhagen, Denmark
Giovanni Targher
Henrik H. Sillesen Section of Endocrinology, Diabetes and Metabolism, Michael Vallis
Department of Vascular Surgery, Rigshospitalet Department of Medicine Department of Family Medicine
University of Copenhagen University of Verona Dalhousie University
Copenhagen, Denmark Verona, Italy Halifax, NS, Canada
Robert B. Tattersall Roman Vangoitsenhoven

Alan J. Sinclair
University of Nottingham Clinical and Experimental Endocrinology,
Foundation for Diabetes Research in Older People
Nottingham, UK Department of Chronic Diseases and
(DROP)
King’s College London Metabolism
London, UK Roy Taylor KU Leuven and University Hospitals
Diabetes Research Group, Institute of Translational Leuven, Belgium
and Clinical Research
Travis S. Smith Newcastle University
Albany Medical College Subodh Verma
Newcastle upon Tyne, UK Division of Cardiac Surgery, St Michael’s Hospital
Albany, NY, USA
University of Toronto
Peter C.Y. Tong Toronto, ON, Canada
Chamukuttan Snehalatha The Jockey Club School of Public Health and
Dr. A. Ramachandran’s Diabetes Hospitals Primary Care
India Diabetes Research Foundation The Chinese University of Hong Kong
Adie Viljoen
Chennai, India East Hertfordshire Hospitals Trust
Hong Kong SAR, China
Lister Hospital
Stevenage, UK
Erica Spears Apostolos Tsapas Department of Clinical Biochemistry
Louisiana Public Health Institute Diabetes Centre and Clinical Research and Addenbrooke’s Hospital
New Orleans, LA, USA Evidence-Based Medicine Unit Cambridge, UK
xiii
Tina Vilsbøll Morris F. White Kirsty Winkley

University of Copenhagen Division of Endocrinology, Children’s Hospital Boston King’s College London
Copenhagen, Denmark Harvard Medical School London, UK
Boston, MA, USA
Mary Beth Weber
Global Diabetes Research Center and Hubert Paul Devakar Yesudian
Anthony S. Wierzbicki
Department of Global Health Department of Dermatology,
Guy’s & St Thomas Hospitals
Rollins School of Public Health Wrexham Maelor Hospital
London, UK
Emory University Betsi Cadwaladr University Health Board
Atlanta, GA, USA Wrexham, UK
Ingrid Willaing
Jesse Weinberger Steno Diabetes Center Copenhagan
Mount Sinai School of Medicine Copenhagen, Denmark and Department of Health
New York, NY, USA Services Research, Institute of Public Health
Nicholas P. West Copenhagen, Denmark
Menzies Health Institute Queensland
and School of Pharmacy and Medical Sciences
Griffith University
Southport, QLD, Australia
xiv
Preface
It is nearly seven years since the last edition of the Textbook of iabetes technology has necessitated a split into separate chapters
d
Diabetes was published, during which time there have been many on glucose monitoring and insulin delivery. Transplantation has
exciting developments in our understanding of diabetes and novel moved from future treatments to current management to acknowl-
treatments that have improved the lives of those living with diabetes. edge its current place in clinical care. In the macrovascular section,
Despite our ability to alleviate the risk of its long-term complica- we have added a new chapter on heart failure, which has come to
tions, the global burden of diabetes continues to rise as the preva- the fore as a result of the sodium–glucose cotransporter 2 (SGLT-2)
lence inexorably increases. According to the International Diabetes inhibitor cardiovascular outcome trials. Oral health and sleep are
Federation, diabetes now affects 537 million adults, compared with added to the list of other areas of diabetes complications, while the
415 million when the last edition was published. Over three-quarters importance of social determinants of health and ethnicity, culture,
of people with diabetes live in low-and middle-income countries and religion is now included in the psychosocial aspects of diabetes
and diabetes causes 6.7 million deaths a year, approximately one section. The final new chapter describes managing diabetes in low-
every five seconds. The cost of treating diabetes has reached almost to middle-income countries, where the majority of people with
US$1 trillion per annum, a threefold increase over the last 15 years. diabetes live.
The need for accurate and up-to-date information to help healthcare As editors, we are only too aware of the hard work that goes into
professionals support people with diabetes has never been greater. the production of a comprehensive and up-to-date book such as
Ironically, as the volume of information and diversity of digital this. For this edition the pressures of the Covid-19 pandemic added
resources have increased, many are finding it overwhelming to keep to the challenges of bringing the book to fruition. Our thanks go to
abreast of the new advances. It is particularly challenging to deter- each and every chapter author who, despite busy academic, clinical,
mine the validity of many source materials. In this textbook we aim and professional lives, was prepared to devote the time, energy, and
to bring together a series of chapters from internationally leading expertise to provide their essential contributions to the text. Thank
diabetes experts who provide accurate and clinically relevant infor- you for your forbearance of our nagging e-mails!
mation to both academic and practising diabetes healthcare We are also grateful for the support we have received from our
professionals. publisher, Wiley- Blackwell. Our commissioning editor Jennifer
We have retained the structure from the previous edition, with a Seward, who took over from Priyanka Gibbons during the book’s
similar length and number of chapters. The centenary of the discov- development, has provided guidance and encouragement. Our
ery of insulin has just passed and the book begins with a history of thanks also go to Rajalaxmi Rajendrasingh, Sally Osborn, and the
diabetes that provides many valuable insights from the past. We rest of the Wiley-Blackwell team. The book looks even better than
then move through the epidemiology of diabetes, the physiology of the last edition! We would like to pay tribute to Clive Cockram and
glucose metabolism, and the pathogenesis of diabetes, before sec- Barry Goldstein, our editing colleagues for the fourth and fifth
tions on clinical management. A discussion of the microvascular editions. You were missed this time round.
and macrovascular complications then follows, after which there We hope you enjoy reading the book, whether it be dipping in or
are sections on the psychosocial aspects of diabetes, the manage- reading from cover to cover, as much as we did editing it. We have
ment of diabetes in special groups, and models of care, before a final taken away useful, novel information that will aid in our daily pro-
section to glimpse into the future. New chapters include an over- fessional lives and hope that this book will help you to support the
view of glucose homeostasis and the central control of glucose people with diabetes you know in the widest sense of this meaning.
metabolism, as well as chapters on the genetics and management of
obesity to recognize the close relationship between obesity and type Richard I.G. Holt
2 diabetes. There is a new chapter on the emerging topic of Allan Flyvbjerg
biomarkers and precision medicine, while the rapid advance in February 2023
xv
List of Abbreviations
AACE American Association of Clinical Endocrinologists CML carboxymethyllysine

AAV adeno-associated vectors CNS central nervous system
ABP ankle blood pressure COC combination oral contraceptive
ACCORD Action to Control Cardiovascular Risk in Diabetes COX cyclooxygenase
ACE angiotensin-converting enzyme CPC cardiac progenitor cell
ACHOIS Australian Carbohydrate Intolerance Study in CRP C-reactive protein
Pregnant Women CSII continuous subcutaneous insulin infusion
ACR albumin : creatinine ratio CT computed tomography
ADA American Diabetes Association CV coefficient of variation
ADP adenosine diphosphate CVD cardiovascular disease
AICAR 5-aminoimidazole-4-carboxamide-1β-d- DAWN Diabetes Attitudes, Wishes, and Needs study
ribofuranoside DCCT Diabetes Control and Complications Trial
AMDCC Animal Models for Diabetes Complications DKA diabetic ketoacidosis
Consortium DPP dipeptidyl peptidase
AMP adenosine monophosphate DSN diabetes specialist nurse
Apo apolipoprotein DVLA Driver and Vehicle Licensing Agency
aPWV aortic pulse wave velocity EASD European Association for the Study of Diabetes
Arx aristaless-related homeobox ECG electrocardiography/electrocardiogram
ATP adenosine triphosphate eGFR estimated glomerular filtration rate
AUC area under the curve EMA European Medicines Agency
BCAA branched-chain amino acid ER endoplasmic reticulum
BMD bone mineral density ERCP endoscopic retrograde cholangiopancreatography
BMI body mass index ERK extracellular signal-regulated kinase
BM-MNC mononuclear bone marrow-derived stem cell ERM ezrin–radixin–moesin
BPH benign prostatic hyperplasia ESC embryonic stem cell
bpm beats per minute ESRD end-stage renal disease
BTX-A botulinum toxin type A ESRF end-stage renal failure
CABG coronary artery bypass grafting FDA Food and Drug Administration (USA)
CA-MRSA community-associated methicillin-resistant FDC fixed-dose combination
Staphylococcus aureus FDKP fumaryldiketopiperazine
CAPD continuous ambulatory peritoneal dialysis FFA free fatty acid
CBG capillary blood glucose FGF fibroblast growth factor
CBT cognitive–behavioral therapy FHWA Federal Highways Administration
CCM corneal confocal microscopy FMD flow-mediated endothelium-dependent arterial dilation
CDA Canadian Diabetes Association FOXO forkhead box O
CDC cardiosphere-derived stem cell FXR farnesoid-X receptor
CDC Centers for Disease Control and Prevention G6P glucose-6-phosphatase
CDE Certified Diabetes Educator G-6-P glucose-6-phosphate
CEMACH Confidential Enquiry into Maternal and Child Health G6PD glucose-6-phosphate dehydrogenase
CETP cholesteryl ester transfer protein GAD glutamine acid decarboxylase
CGM continuous glucose monitoring GCGR glucagon receptor
CI confidence interval GCK glucokinase
CKD chronic kidney disease G-CSF granulocyte colony-stimulating factor
xvi
GDF growth differentiation factor LV left ventricular

GDM gestational diabetes mellitus LVEF left ventricular ejection fraction
CF cystic fibrosis MAOI monoamine oxidase inhibitor
GI gastrointestinal MDI multiple daily injection
GLO glyoxalase MDRD Modification of Diet in Renal Disease
GLP-1RA GLP-1 receptor agonist MG53 mitsugumin 53
GLUT glucose transporter mGDP mitochondrial glycerolphosphate dehydrogenase
GPR G-protein-coupled receptor MGO methylglyoxal
GRPP glicentin-related pancreatic polypeptide MI myocardial infarction
GWA genome-wide association MIBG m-iodobenzylguanidine
GWAS genome-wide association studies MIRKO muscle-specific InsR knockout
HAPO Hyperglycemia and Adverse Pregnancy Outcomes MODY maturity-onset diabetes of the young
HbA1c hemoglobin A1c MPGF major proglucagon fragment
HBV hepatitis B virus MPO myeloperoxidase
HCV hepatitis C virus MRI magnetic resonance imaging
HDL high-density lipoprotein MSC mesenchymal stem cell
HGF hepatocyte growth factor MS mass spectrometry
hGH human recombinant growth hormone mTOR mammalian or mechanistic target of rapamycin
HHS hyperosmolar non-ketotic hyperglycemic state mTORC1 mechanistic target of rapamycin complex 1
HR hazard ratio MTPI microsomal transfer protein inhibitor
HRT hormone replacement therapy NAD nicotinamide adenine dinucleotide
HRV heart rate variability NaDIA National Diabetes Inpatient Audit
HSC hematopoietic stem cell NAFLD non-alcoholic fatty liver disease
hsCRP high-sensitivity C-reactive protein NANC non-adrenergic, non-cholinergic
IADPSG International Association of Diabetes Pregnancy NCV nerve conduction velocity
Study Groups NEFA non-esterified fatty acid
IAsp insulin aspart MFMU Maternal–Fetal Medicine Units Network
IAUC incremental area under the blood glucose curve NEP neutral endopeptidase
ICA islet cell antibody NFκB nuclear factor κB
ICU intensive care unit Ngn3 neurogenin 3
i.d. intradermal NHANES National Health and Nutrition Examination
IDDM insulin-dependent diabetes mellitus Survey
IDeg insulin degludec NHS National Health Service
IDF International Diabetes Federation NICE National Institute for Health and Care Excellence
IDL intermediate-density lipoprotein NIDDM non-insulin-dependent diabetes mellitus
IDRS Indian Diabetes Risk Score NIH National Institutes of Health
IgG immunoglobulin G NMU neuromedin U
IGR impaired glucose regulation Nox NAD(P)H oxidase
IGT impaired glucose tolerance NOD non-obese diabetic
IKKβ inhibitor κB kinase-β NPH neutral protamine Hagedorn
IL interleukin NRTI nucleoside reverse-transcriptase inhibitor
IMT intima-media thickness NSAID non-steroidal anti-inflammatory drug
InsR insulin receptor NT-3 neurotrophin-3
IRMA intraretinal microvascular abnormality NT-proBNP N-terminal pro-brain-type natriuretic peptide
ISPAD International Society for Pediatric and OCP oral contraceptive pill
Adolescent Diabetes OGIS oral glucose insulin sensitivity
IT information technology OGTT oral glucose tolerance test(ing)
IVUS intravascular ultrasound OR odds ratio
IWGDF International Working Group on the Diabetic Foot oxLDL oxidation of low-density lipoprotein
JBDS Joint British Diabetes Societies PAS periodic acid–Schiff
KDIGO Kidney Disease: Improving Global Outcomes PBA phenylboronic acid
Km Michaelis constant PC prohormone convertase
LADA latent autoimmune diabetes in adults PCB polychlorinated biphenyl
LDL low-density lipoprotein PCI percutaneous coronary intervention
LDL-C low-density lipoprotein cholesterol PCR polymerase chain reaction
LDLR low-density lipoprotein receptor PCSK-9 proprotein convertase subtilisin kexin type 9
LGA large-for-gestational age PDH pyruvate dehydrogenase
LIRKO liver-specific InsR knockout Pdx1 pancreatic duodenal homeobox 1
LPS lipopolysaccharide PGF placental growth factor
Lst limostatin PI protease inhibitor
xvii
PI3K phosphatidylinositol 3-kinase SGA second-generation antipsychotics

PID proportional integral derivative SHP short heterodimer protein
P/KX combined pancreas/kidney transplantation SMBG self-monitoring of blood glucose
PNDM permanent neonatal diabetes mellitus SMI severe mental illness
PPAR peroxisome proliferator-activated receptor SNP sub-basal nerve plexus
PROactive Prospective Pioglitazone Clinical Trial in SSRI selective serotonin reuptake inhibitor
Macrovascular Events T1DM type 1 diabetes mellitus
PTDM post-transplantation diabetes mellitus T2DM type 2 diabetes mellitus
PTP1B protein tyrosine phosphatase 1B TAG triacylglyceride
PYY polypeptide YY TB tuberculosis
QoL quality of life TCF7L2 transcription factor 7 like 2
RA receptor agonist TE transient elastography
RAMP receptor activity-modifying protein TIND treatment-induced neuropathy in diabetes
RCT randomized controlled trial TLR toll-like receptor
RDN renal denervation TNDM transient neonatal diabetes mellitus
RECORD Rosiglitazone Evaluated for Cardiac Outcomes and TNFα tumor necrosis factor alpha
Regulation of Glycemia in Diabetes Treg regulatory T cell
REMS Risk Evaluation and Mitigation Strategy TSH thyroid-stimulating hormone
rHuPH20 recombinant human hyaluronidase TZD thiazolidinedione
RMR resting metabolic rate UKPDS UK Prospective Diabetes Study
ROS reactive oxygen species US ultrasound
RR relative risk UT University of Texas
RR risk ratio VEGF vascular endothelial growth factor
RT-PCR reverse transcriptase polymerase chain reaction VLCD very low calorie diet
SCFA short-chain fatty acid VLDL very low-density lipoprotein
s.c. subcutaneous VRIII variable-rate intravenous insulin infusion
sdHDL small, dense high-density lipoprotein WGS whole-genome sequencing
sdLDL small, dense low-density lipoprotein WHO World Health Organization
SDS-PAGE sodium dodecyl sulfate polyacrylamide gel XO xanthine oxidase
electrophoresis YY1 Yin Yang 1
xviii
1 Diabetes in its Historical
and Social Context
1 The History of Diabetes Mellitus
Robert B. Tattersall1 and David R. Matthews2
1 University of Nottingham, Nottingham, UK
2 University of Oxford, Oxford, UK
Key points
• Polyuric diseases have been described for over 3500 years. The name insulin in 1956. The presence of insulin receptors was deduced in 1971 by
diabetes comes from the Greek word for a syphon; the sweet taste of Freychet, and the receptor protein was isolated in 1972 by Cuatrecasas.
diabetic urine was recognized at the beginning of the first millennium, • The various types of diabetic retinopathy were described in the second
but the adjective mellitus (honeyed) was added by Rollo only in the late half of the nineteenth century, as were the symptoms of neuropathy.
eighteenth century. Albuminuria was noted as a common abnormality in people with diabetes
• The sugar in diabetic urine was identified as glucose by Chevreul in 1815. in the nineteenth century and a unique type of kidney disease was
In the 1840s, Bernard showed that glucose was normally present in described in 1936 by Kimmelstiel and Wilson. The concept of a specific
blood, and that it was stored in the liver (as glycogen) for secretion into diabetic angiopathy was developed by Lundbæk in the early 1950s.
the bloodstream during fasting. • Milestones in insulin pharmacology have included the invention of delayed-
• In 1889, Minkowski and von Mering reported that pancreatectomy action preparations in the 1930s and 1940s, synthetic human insulin in 1979,
caused severe diabetes in the dog. In 1893, Laguesse suggested that the and in the 1990s novel insulin analogues by recombinant DNA technology.
pancreatic islets described by Langerhans in 1869 produced an internal • The first sulfonylurea carbutamide was introduced in 1955, followed
secretion that regulated glucose metabolism. by tolbutamide in 1957 and chlorpropamide in 1960. The biguanide
• Insulin was discovered in 1921 by Banting, Best, Macleod, and Collip phenformin became available in 1959 and metformin in 1960.
in acid-ethanol extracts of pancreas. It was first used for treatment in • That improved glucose management in both type 1 diabetes and
January 1922. type 2 diabetes was beneficial was proved by the Diabetes Control and
• Diabetes was subdivided on clinical grounds into diabète maigre Complications Trial (DCCT) in 1993 and the UK Prospective Diabetes
(lean people) and diabète gras (obese people) by Lancereaux in 1880, Study (UKPDS) in 1998.
and during the 1930s by Falta and Himsworth into insulin-sensitive and • Landmarks in the treatment of complications include photocoagulation for
insulin-insensitive types. These classifications were the forerunners of the retinopathy, first described by Meyer-Schwickerath; the importance of blood
aetiological classification into type 1 (insulin-dependent) diabetes and pressure management to slow the progression of nephropathy, demon-
type 2 (non-insulin-dependent) diabetes. strated by Mogensen and Parving; the introduction of low-dose insulin in
• Insulin resistance and β-cell failure, the fundamental characteristics of the treatment of diabetic ketoacidosis in the 1970s; improvements in the
type 2 diabetes, have been investigated by many researchers. The insulin care of pregnant women with diabetes pioneered by White and Pedersen;
clamp method devised by Andres and DeFronzo was the first accurate and the emergence of heart failure as a common and treatable pathology.
technique for measuring insulin action. • The understanding of the complex physiology of type 2 diabetes improved
• Maturity-onset diabetes of the young was described as a distinct variant at the beginning of the twenty-first century with clarification of the roles
of type 2 diabetes by Tattersall in 1974. of fat metabolism and signalling; the gut as an endocrine organ; the
• Lymphocytic infiltration of the islets (insulitis) was described as early as signals of satiety to the brain; and the role of glucagon as an important
1901 and highlighted in 1965 by Gepts, who suggested that it might be a homeostatic signal.
marker of autoimmunity. Islet cell antibodies were discovered by Doniach • The many therapeutic breakthroughs of the twenty-first century include
and Bottazzo in 1979. the discovery of peroxisome proliferator-activated receptor γ (PPAR-γ)
• The primary sequence of insulin was reported in 1955 by Sanger and the activation as a therapy for insulin resistance; the activation of the incretin
three-dimensional structure by Hodgkin in 1969. Proinsulin was discov- axis by glucagon-like peptide 1 (GLP-1) receptor agonists and the dipep-
ered by Steiner in 1967, and the sequence of the human insulin gene tidyl peptidase 4 (DPP-4) inhibitors; and the blocking of the renal glucose
by Bell in 1980. Yalow and Berson invented the radioimmunoassay for transporter channels by sodium-glucose cotransporter 2 (SGLT-2) inhibitors.
Professor Robert Tattersall died on 23 November 2020. This historical text is largely his work. Professor David R. Matthews has updated and revised the chapter.
Textbook of Diabetes, Sixth Edition. Edited by Richard I.G. Holt and Allan Flyvbjerg.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
3
Part 1 Diabetes in its Historical and Social Context
Ancient times
Diseases with the cardinal features of diabetes mellitus were

recognized in antiquity (Table 1.1). A polyuric state was described
in an Egyptian papyrus dating from c. 1550 bce, discovered by
Georg Ebers (Figure 1.1), and a clearly recognizable description of
what would now be called type 1 diabetes was given by Aretaeus of
Cappadocia in the second century ce (Figure 1.2a). Aretaeus was
the first to use the term diabetes, from the Greek word for a syphon,
‘because the fluid does not remain in the body, but uses the man’s
body as a channel whereby to leave it’. His graphic account of the
disease highlighted the incessant flow of urine, unquenchable
thirst, the ‘melting down of the flesh and limbs into urine’, and
short survival.
The Hindu physicians Charak and Sushrut, who wrote between
400 and 500 bce, were probably the first to recognize the sweetness
of diabetic urine (Figure 1.2b). Indeed, the diagnosis was made by
tasting the urine or seeing that ants congregated round it. Charak
and Sushrut noted that the disease was most prevalent in those who
Table 1.1 Milestones in the clinical descriptions of diabetes and its

complications.
Figure 1.1 The Ebers papyrus. Source: Courtesy of the Wellcome Library, London.
Clinical features of diabetes
Ebers papyrus (Egypt, 1500 bce) Polyuric state
Sushrut and Charak (India, fifth Sugary urine; thin individuals and
century bce) those with obesity distinguished were indolent, overweight, and gluttonous, and who indulged in
Aretaeus (Cappadocia, second Polyuric state named diabetes sweet and fatty foods. Physical exercise and liberal quantities of
century ce) vegetables were the mainstays of treatment in people with obesity,
Chen Chuan (China, seventh Sugary urine while lean people, in whom the disease was regarded as more seri-
century ce)
ous, were given a nourishing diet. The crucial fact that diabetic
Avicenna (Arabia, tenth century ce) Sugary urine; gangrene and
impotence as complications
urine tasted sweet was also emphasized by Arabic medical texts
from the ninth to eleventh centuries ce, notably in the medical
Diabetic ketoacidosis encyclopaedia written by Avicenna (980–1037).
William Prout (England, 1810–1820) Diabetic coma
Adolf Kussmaul (Germany, 1874) Acidotic breathing
Hyperlipidaemia Seventeenth and eighteenth centuries

Albert Heyl (Philadelphia, 1880) Lipaemia retinalis
Retinopathy In Europe, diabetes was neglected until Thomas Willis (1621–1675)

Eduard von Jaeger (Germany, 1855) General features wrote Diabetes, or the Pissing Evil [1]. According to him, ‘diabetes
Stephen Mackenzie and Edward Microaneurysms was a disease so rare among the ancients that many famous physi-
Nettleship (England, 1879) cians made no mention of it . . . but in our age, given to good fellow-
Edward Nettleship (England, 1888) New vessels, beading of retinal veins ship and guzzling down of unallayed wine, we meet with examples
Julius Hirschberg (Germany, 1890) Classification of lesions; specific and instances enough, I may say daily, of this disease’. He described
to diabetes the urine as being ‘wonderfully sweet like sugar or honey’, but did
Neuropathy and foot disease not consider that this might be because it contained sugar.
John Rollo (England, 1797) Neuropathic symptoms The first description of hyperglycaemia was in a paper published
Marchal de Calvi (France, 1864) Neuropathy is a complication in 1776 by Matthew Dobson (1735–1784) of Liverpool (Figure 1.3
of diabetes and Table 1.2) [2]. He found that the serum as well as the urine of
William Ogle (England, 1866) Ocular nerve palsies in diabetes his patient Peter Dickonson (who passed 28 pints of urine a day)
Frederick Pavy (England, 1885) Peripheral neuropathy tasted sweet. Moreover, he evaporated the urine to ‘a white cake
Julius Althaus (Germany, 1890) Mononeuropathy [which] smelled sweet like brown sugar, neither could it by the taste
Thomas Davies Pryce (England, 1887) Perforating foot ulcers
be distinguished from sugar’. Dobson concluded that the kidneys
Nephropathy excreted sugar and that it was not ‘formed in the secretory organ
Wilhelm Griesinger (Germany, 1859) Renal disease in people but previously existed in the serum of the blood’.
with diabetes The Edinburgh- trained surgeon, John Rollo (d. 1809) was
Paul Kimmelstiel and Clifford Wilson Glomerulosclerosis associated with the first to apply the adjective mellitus (from the Latin word
(USA, 1936) heavy proteinuria meaning honey). He also achieved fame with his animal diet, which
became the standard treatment for most of the nineteenth century.
4
(b)
(a)
Diabetes is a dreadful affliction, not very frequent among

men, being a melting down of the flesh and limbs into
urine. The patients never stop making water and the flow is
incessant, like the opening of aqueducts. Life is short,
unpleasant and painful, thirst unquenchable, drinking
excessive, and disproportionate to the large quantity of
urine, for yet more urine is passed. One cannot stop them
either from drinking or making water. If for a while they
abstain from drinking, their mouths become parched and
their bodies dry; the viscera seem scorched up, the patients
are affected by nausea, restlessness and a burning thirst, and
within a short time, they expire.
Figure 1.2 (a) Clinical description of diabetes by Aretaeus of Cappadocia (second century ce). Source: Adapted from Papaspyros, N.S. (1952) The History of Diabetes
Mellitus. (b) Sushrut (Susrata), an Indian physician who wrote medical texts with Charak (Charuka) between 500 bce and 400 bce.
Figure 1.3 Frontispiece and opening page of the paper by Matthew Dobson (1776) in which he described the sweet taste of both urine and serum from a person with
diabetes [2].
Table 1.2 Milestones in the scientific understanding of diabetes

and its complications.
Matthew Dobson (England, 1776) Diabetic serum contains sugar

Michel Chevreul (France, 1815) The sugar in diabetic urine is glucose
Claude Bernard (France, 1850s) Glucose stored in liver glycogen and
secreted during fasting
Wilhelm Petters (Germany, 1857) Diabetic urine contains acetone
Paul Langerhans (Germany, 1869) Pancreatic islets described
Adolf Kussmaul (Germany, 1874) Describes ketoacidosis
Oskar Minkowski and Josef von Pancreatectomy causes diabetes
Mering (Germany, 1889) in the dog
Gustave Edouard Laguesse Glucose-lowering pancreatic
(France, 1893) secretion produced by islets
M.A. Lane (USA, 1907) Distinguished A and B islet cells
Jean de Meyer (Belgium, 1909) Hypothetical islet secretion
named insuline
Frederick Banting, Charles Best, J.J.R. Isolation of insulin
Macleod, James Collip
(Canada, 1922)
Richard Murlin (USA, 1923) Discovered and named glucagon
Bernado Houssay (Argentina, 1924) Hypophysectomy enhances insulin
sensitivity
Frederick Sanger (England, 1955) Determined primary sequence
of insulin
W.W. Bromer (USA, 1956) Determined primary sequence
of glucagon
Rosalyn Yalow and Solomon Berson Invented radioimmunoassay
(USA, 1959) for insulin
Donald Steiner (USA, 1967) Discovered proinsulin
Dorothy Hodgkin (England, 1969) Determined three-dimensional
structure of insulin
Pierre Freychet (USA, 1971) Characterized insulin receptors
Pedro Cuatrecasas (USA, 1972) Isolated insulin receptor protein
Axel Ullrich (USA, 1977) Reported sequence of rat insulin
Ralph DeFronzo and Reuben Andres Invented insulin clamp technique
(USA, 1979)
Graham Bell (USA, 1980) Reported sequence of human Figure 1.4 Extract from John Rollo’s account of two cases of diabetes (1797). Rollo
insulin gene was well aware of the problem of not following a treatment regimen. Note that ‘the
Joel Habener (USA), Jens Juel Holst Determined primary sequence of patient was strongly remonstrated with, and told of the consequences of repeated
(Denmark) (1986) glucagon-like peptide 1 (GLP-1) deviations’. Source: Courtesy of the Wellcome Library, London.
skilled chemists, but needed so much blood that it was rarely used
Rollo thought that sugar was formed in the stomach from vegeta- in either clinical care or research. It only became practicable with
bles and concluded that the obvious solution was a diet of animal the introduction in 1913 of a micromethod by the Norwegian-born
food. Thus, the regimen described in his 1797 book, An Account of physician Ivar Christian Bang (1869–1918), and it was the ability to
Two Cases of the Diabetes Mellitus [3], allowed his patient Captain measure glucose repeatedly that led to development of the glucose
Meredith to have for dinner ‘Game or old meats which have been tolerance test between 1913 and 1915.
long kept; and as far as the stomach may bear, fat and rancid old Glucose metabolism was clarified by the work of Claude Bernard
meats, as pork’. Rollo was probably the first to note the difficulty (1813–1878) [5], the Frenchman whose numerous discoveries have
that some people with diabetes find in following a treatment regi- given him a special place in the history of physiology (Figure 1.5).
men, a difficulty he blamed for the death of his second patient When Bernard began work in 1843, the prevailing theory was that
(Figure 1.4). sugar could only be synthesized by plants, and that animal
metabolism broke down substances originally made in plants. It
was also thought that the blood only contained sugar after meals, or
Nineteenth century in pathological states such as diabetes. Between 1846 and 1848,
Bernard reported that glucose was present in the blood of normal
In 1815, the French chemist Michel Chevreul (1786–1889) proved animals, even when starved. He also found higher concentrations
that the sugar in diabetic urine was glucose [4]. In the middle of the of glucose in the hepatic than in the portal vein, and ‘enormous
century, tasting the urine to make the diagnosis was superseded quantities’ of a starch-like substance in the liver that could be read-
by chemical tests for reducing agents such as glucose, as introduced ily converted into sugar. He called this glycogen (i.e. sugar-forming)
by Trommer in 1841, Moore in 1844, and – the best known – Fehling and regarded it as analogous to starch in plants. His hypothesis – the
in 1848. Measurement of blood glucose could only be done by glycogenic theory – was that sugar absorbed from the intestine was
6
The History of Diabetes Mellitus Chapter 1
Figure 1.5 Claude Bernard (1813–1878). Source: Courtesy of the Wellcome

Figure 1.6 Oskar Minkowski (1858–1931).
Library, London.
converted in the liver into glycogen and then constantly released Table 1.3 Milestones in the understanding of the causes
into the blood during fasting. of diabetes.
Another discovery by Bernard made a great impression in an era
when the nervous control of bodily functions was a scientifically Thomas Willis (England, Overindulgence in food and drink
seventeenth century)
fashionable concept. He found that a lesion in the floor of the fourth
Thomas Cawley (England, 1788) Pancreatic stones cause diabetes
ventricle produced temporary hyperglycaemia (piqûre diabe- Oskar Minkowski and Josef von Pancreatectomy causes diabetes
tes) [6]. This finding spawned a long period in which nervous Mering (Germany, 1889) in the dog
influences were thought to be important causes of diabetes; indeed, Etienne Lancereaux (France, 1880) Lean and obese subtypes of diabetes
one piece of ‘evidence’ – cited by J.J.R. Macleod as late as 1914 – was distinguished
that diabetes was more common among engine drivers than other Eugene Opie (USA, 1900) Hyaline degeneration (amyloidosis)
railway workers because of the mental strain involved [7]. of islets (type 2 diabetes)
In the first part of the nineteenth century the cause of diabetes Eugene Opie (USA, 1910) Lymphocytic infiltration of islets
was a mystery, because autopsy usually did not show any specific (insulitis; type 1 diabetes)
lesions. A breakthrough came in 1889 when Oskar Minkowski Wilhelm Falta (Vienna) and Harold Distinguished insulin-resistant and
Himsworth (England, insulin-sensitive forms of diabetes
(Figure 1.6) and Josef von Mering (1849–1908) reported that pan-
early 1930s)
createctomy in the dog caused severe diabetes [8]. This was seren- Willy Gepts (Belgium, 1965) Suggested that insulitis caused β-cell
dipitous, because they were investigating fat metabolism; it is said destruction (type 1 diabetes)
that the laboratory technician mentioned to Minkowski that the Deborah Doniach and GianFranco Suggested that insulin-dependent
dog, previously house- trained, was now incontinent of urine. Bottazzo (England, 1979) diabetes is an
Minkowski realized the significance of the polyuria, and tested the autoimmune disease
dog’s urine (Table 1.3). Andrew Cudworth and John Insulin-dependent diabetes
Possible explanations for the role of the pancreas were that it Woodrow (England, 1975) associated with specific human
removed a diabetogenic toxin, or produced an internal secretion leucocyte antigens
that regulated carbohydrate metabolism. The concept of internal
7
of diabetic retinopathy, in his beautiful Atlas of Diseases of the

Ocular Fundus, published in 1869 [14]. In fact, the features illus-
trated (Figure 1.8), from a 22-year-old man, look more like hyper-
tensive retinopathy. In 1879, Stephen Mackenzie (1844–1909) and
Sir Edward Nettleship (1845–1913) found microaneurysms in flat
preparations of the retina and, in 1888, Nettleship described new
vessels and the beaded appearance of retinal veins [15]. The full pic-
ture of diabetic retinopathy was described in 1890 by Julius
Hirschberg (1843–1925), who was the first to claim that it was spe-
cific to diabetes [16].
Neuropathic symptoms in people with diabetes had been
mentioned by Rollo at the end of the eighteenth century, and in
1864 Charles Marchal de Calvi (1815–1873) concluded that
nerve damage was a specific complication of diabetes. In 1885, the
Guy’s Hospital physician Frederick Pavy (1829–1911) gave a
description of neuropathic symptoms that could grace any modern
textbook [17]:
The usual account given by these patients of their condition is that they
cannot feel properly in their legs, that their feet are numb, that their legs
seem too heavy – as one patient expressed it, ‘as if he had 20 lb weights
on his legs and a feeling as if his boots were great deal too large for his
feet.’ Darting or ‘lightning’ pains are often complained of. Or there may
be hyperaesthesia, so that a mere pinching of the skin gives rise to great
Figure 1.7 Paul Langerhans (1847–1888). Source: Courtesy of the Wellcome pain; or it may be the patient is unable to bear the contact of the seam
Library, London. of the dress against the skin on account of the suffering it causes. Not
infrequently there is deep-seated pain located, as the patient describes
secretions had been publicized in June 1889 by the well-known it, in the marrow of the bones which are tender on being grasped, and
physiologist Charles-Édouard Brown-Séquard (1817–1894), who I have noticed that these pains are generally worse at night.
claimed to have rejuvenated himself by injections of testicular
extract [9]. It was given further credence in 1891, when Murray Pavy also recorded unusual presentations, including a 67-year-old
reported that myxoedema could be cured by sheep thyroid extract who complained of ‘lightning pains on the right side of the waist’
by injection or orally. and cases in which the third nerve was affected with ‘dropped lid
In 1893, Gustave Laguesse suggested that the putative internal and external squint’ [18].
secretion of the pancreas was produced by the islands of cells Kidney disease was known to be relatively common in diabetes.
scattered through the gland’s parenchyma [10], which had been In 1859, Wilhelm Griesinger (1817–1868) reported 64 autopsies in
discovered in 1869 by the 22-year-old Paul Langerhans (1847– adults, half of whom had renal changes that he attributed to hyper-
1888) (Figure 1.7). Langerhans had described these clusters of cells, tension and atherosclerosis [19]; however, the histological features
having teased them out from the general pancreatic tissue, but had of diabetic kidney disease and the importance of renal complica-
not speculated about their possible function [11]; it was Laguesse tions were not reported until the 1930s.
who named them the islets of Langerhans. At this time the glucose- In the latter part of the nineteenth century it was becoming
lowering internal secretion of the islets was still hypothetical, but in apparent that there were at least two clinically distinct forms of
1909 the Belgian Jean de Meyer named it insuline (from the Latin diabetes. In 1880, the French physician Etienne Lancereaux (1829–
for island) [12]. 1910) identified individuals who were lean and those with obesity
It would be wrong to give the impression that Minkowski’s as having diabète maigre and diabète gras, respectively [20], and
experiments immediately established the pancreatic origin of dia- this observation laid the foundations for subsequent aetiological
betes. In fact, during the next two decades it was widely agreed that classifications of the disease.
diabetes was a heterogeneous disorder with various subtypes, and
that its pathogenesis involved at least three organs: brain, pancreas,
and liver [13]. The discovery by Blum in 1901 that injection of an
adrenal extract caused glycosuria implicated other glands, and led Twentieth century
to the polyglandular theory of Carl von Noorden (Vienna), who
proposed that the thyroid, pancreas, adrenals, and parathyroids Murray’s cure of myxoedema in 1891 led to a belief that pancreatic
controlled carbohydrate metabolism. extract would soon result in a cure for diabetes, but, in the face of
repeated failures over the next 30 years, even believers in an anti-
Clinical diabetes in the nineteenth century diabetes internal secretion were depressed about the likelihood of
Doctors in the nineteenth century were therapeutically impotent; isolating it, and diverted their attention to diet as a treatment for
their main role was as taxonomists who described symptom com- the disease.
plexes and the natural history of disease. As a result, most of the Best known was the starvation regimen of Frederick Madison
major complications of diabetes were well described before 1900. Allen (1876–1964), which Joslin (Figure 1.9) described in 1915 as
Eduard von Jaeger (1818–1884) is credited with the first description the greatest advance since Rollo’s time [22]. This approach was an
8
Figure 1.8 Pictures from Jaeger’s Atlas of the

Optic Fundus, 1869 [14]. Top left: Bright’s disease.
Top right: Jaeger’s retinitis haemorrhagica is now
recognized as central retinal vein occlusion. Bottom left:
A 22-year-old man with suspected diabetes. Bottom
right: Central retinal artery occlusion. Source: Courtesy
of W.B. Saunders.
extreme application of one that had been proposed as early as 1875 was not recognized, either because hypoglycaemia was misinter-
by Apollinaire Bouchardat (1806–1886), who advocated intensive preted as a toxic reaction or because blood glucose was not
exercise and ‘manger le moins possible’. Starvation treatment did measured. Those who came closest were the Berlin physician

work in a limited sense, in that some people could survive for many Georg Zuelzer (1840–1949) in 1907 [23], Ernest Scott (1877–1966)
months or even years, instead of a few weeks or months with in Chicago in 1911 [24], and Nicolas Paulesco (1869–1931) in
untreated type 1 diabetes. The quality of life, however, was very Romania in 1920–1921 [25] (Figure 1.10).
poor, and some died of malnutrition rather than diabetes. In 1921, The story of how insulin was discovered in Toronto in 1921 is
Carl von Noorden (1858–1944), proponent of the oatmeal cure, well known, at least superficially (Figure 1.11). A young orthopae-
turned away in disapproval when he saw Joslin’s prize patient, dic surgeon, Frederick Banting, inspired after reading an article by
17-year-old Ruth A, who at just over 1.52 m in height weighed only the pathologist Moses Barron (1884–1975), wondered whether the
24.5 kg (a body mass index of 10.6 kg/m2). anti-diabetes pancreatic principle was digested by trypsin during
extraction, and decided to prevent this loss by ligating the pancre-
Discovery of insulin atic duct, thus causing the exocrine tissue to degenerate. He
Many attempts were made between 1889 and 1921 to isolate the approached the professor of physiology in Toronto, J.J.R. Macleod,
elusive internal secretion of the pancreas. These largely failed an authority on carbohydrate metabolism, who poured scorn on
because the extracts were inactive or had unacceptable side effects; the idea and suggested that the only likely outcome would be
some preparations may have had limited biological activity, but this ‘a negative result of great physiological importance’.
9
(a) (b)
Figure 1.9 (a) Elliott P. Joslin (1869–1962), arguably the most famous diabetes specialist of the twentieth century, and (b) the frontispiece to his 1916 textbook [21].
Source: Courtesy of the Wellcome Library, London.
Eventually, Macleod relented and installed Banting in a rundown marked clinical improvement and complete elimination of glycosu-
laboratory, later leaving for Scotland and a fishing holiday. A ria and ketonuria. Initial clinical results in seven cases were p
ublished
student, Charles Best, was chosen by the toss of a coin to help in the March 1922 issue of the Canadian Medical Association
Banting. Within six months of this unpromising start, Banting and Journal [27], which had the following dramatic conclusions:
Best (referred to in Toronto academic circles as B2) had discovered • Blood sugar can be markedly reduced, even to normal values.
the most important new therapy since the anti-syphilitic agent • Glycosuria can be abolished.
salvarsan. These events are described in detail in the excellent book • The acetone bodies can be made to disappear from the urine.
by Michael Bliss [26]. • The respiratory quotient shows evidence of increased utilization
Their approach began with the injection of extracts of atrophied of carbohydrates.
pancreas (prepared according to Macleod’s suggestions) into dogs • A definite improvement is observed in the general condition of
rendered diabetic by pancreatectomy. Subsequently, they discovered these patients and, in addition, the patients themselves report a
that active extracts could be obtained from beef pancreas, which subjective sense of well-being and increased vigour for a period fol-
Best obtained from the abattoir. The extraction procedure (using lowing the administration of these preparations.
ice-cold acid-ethanol) was greatly refined by James B. (Bert) Collip, The term insulin was coined by Macleod, who was unaware of de
a biochemist who was visiting Toronto on sabbatical leave. Meyer’s earlier suggestion of insuline. News of its miraculous effects
The first clinical trial of insulin (using an extract made by Best) spread astonishingly rapidly [28]. In 1922, there were only 19 refer-
took place on 11 January 1922, on 14-year-old Leonard Thompson, ences in the world literature to insulin or equivalent terms such as
who had been on the Allen starvation regimen since 1919 and pancreatic extract; by the end of 1923, there were 320 new reports, and
weighed only 30 kg (Figure 1.12). After the first injection, his blood a further 317 were published during the first six months of 1924.
glucose level fell slightly, but his symptoms were unchanged and he By October 1923, insulin was available widely throughout North
developed a sterile abscess. On 23 January, he was given another America and Europe. International recognition followed rapidly
extract prepared by Collip, and this normalized his blood glucose by for its discoverers, and the 1923 Nobel Prize for Physiology or
the next morning; further injections over the next 10 days led to Medicine was awarded jointly to Banting and Macleod. Banting
10
(a) (b)
(c)
Figure 1.10 (a) Georg Zuelzer (1840–1949) and (b) the title page from his paper (1907) reporting that a pancreatic extract reduced glycosuria in pancreatectomized
dogs [23]. (c) Nicolas Paulesco (1869–1931).
was angered by the decision, and announced publicly that he would Insulin had to be injected in measured amounts that varied from
share his prize with Best, whereupon Macleod decided to do the day to day, and carried the ever-present danger of hypoglycaemia.
same with Collip. One often reads that insulin ‘revolutionized’ the treatment of dia-
betes; it did so in the sense that it saved the lives of many who
The post-insulin era would otherwise have died, but its unforeseen effect was to trans-
It was confidently anticipated that insulin would do for diabetes form an acute, rapidly fatal illness into a chronic disease with seri-
in the young what thyroid extract had done for myxoedema, but it ous long-term complications. For example, only 2% of deaths
soon became obvious that insulin was a very different type of treat- among Joslin’s young patients with diabetes before 1937 were
ment. Thyroid was given once a day by mouth and at a fixed dosage. caused by kidney disease, while over 50% dying between 1944 and
11
(a) (b)
(c) (d)
Figure 1.11 The discoverers of insulin. (a) Frederick G.

Banting (1891–1941); (b) James B. Collip (1892–1965);
(c) J.J.R. Macleod (1876–1935); and (d) Charles H. Best
(1899–1978). Source: Courtesy of the Fisher Rare Book
Library, University of Toronto.
1950 had advanced renal failure. Strategies to avoid and prevent the
chronic complications of diabetes remain important scientific and
clinical priorities today.
The rest of this chapter highlights some developments that can
be regarded as landmarks in the understanding and management of
the disease; to some extent this is a personal choice, and it is obvi-
ous from the other chapters in this book that the history of diabetes
is being rewritten all the time.
Causes and natural history of diabetes
The recognition that diabetes was not a single disease was impor-
tant in initiating research that has helped to unravel the causes of
hyperglycaemia.
The broad aetiological subdivision into type 1 (juvenile-onset, or
insulin-dependent) diabetes and type 2 diabetes (maturity-onset,
or non-insulin-dependent) stemmed ultimately from Lancereaux’s
diabète maigre and diabète gras distinction, as well as observations
soon after the discovery of insulin that some individuals did not
react normally to insulin. In the 1930s, Wilhelm Falta (1875–1950)
in Vienna [29] and Harold Himsworth (1905–1993) in London [30]
Figure 1.12 Leonard Thompson, the first person to receive insulin, in January 1922. proposed that some individuals with diabetes were more sensitive
Source: Courtesy of the Fisher Rare Book Library, University of Toronto. to the glucose-lowering effects of insulin, whereas others were
12
insulin insensitive, or insulin resistant. The former were usually

thin and required insulin to prevent ketoacidosis, while the latter
were older, had obesity, and were ketosis resistant.
The insulin clamp technique developed in the 1970s by Ralph
DeFronzo and colleagues [31] in the USA was the first to measure
rigorously the hypoglycaemic action of insulin, and has led to count-
less studies of insulin resistance and its relationship to type 2 diabe-
tes and vascular disease. Various groups, including DeFronzo’s, have
helped to clarify the role of β-cell failure in type 2 diabetes, and how
it relates to insulin resistance. Maturity-onset diabetes of the young
(MODY) was recognized in 1974 by Robert Tattersall (1943–2020)
as a distinct, dominantly inherited subset of type 2 diabetes [32];
since 1993 many different molecular defects have been identified in
this condition.
The causes of the profound β-cell loss that led to the severe insu-
lin deficiency of type 1 diabetes remained a mystery for a long time.
Insulitis, predominantly lymphocytic infiltration of the islets, was
noted as early as 1901 by Eugene L. Opie (1873–1971) and col-
leagues [33], but because it was apparently very rare, found in only 6
of 189 cases studied by Anton Weichselbaum (1845–1920) in 1910,
its importance was not appreciated. The possible role of insulitis in
β-cell destruction was not suggested until 1965, by the Belgian Willy
Gepts (1922–1991) [34]. The theory that type 1 diabetes results
from autoimmune destruction of the β cells was first made in 1979
by Deborah Doniach (1912–2004) and GianFranco Bottazzo (1946–
2017) [35]. Unlike other autoimmune endocrine diseases where the
autoantibody persists, islet cell antibodies turned out to be transient
and disappeared within a year of the onset of diabetes. An unex-
pected finding from the Barts–Windsor prospective study of the
epidemiology of diabetes in childhood started by Andrew Cudworth
(1939–1982) was that islet cell antibodies could be detected in sib-
lings of young people with diabetes up to 10 years before they devel-
oped apparently acute- onset diabetes. This long lead- in period Figure 1.13 Nodular glomerulosclerosis. Figure from the paper by Kimmelstiel and
raised the possibility of an intervention to prevent continuing β-cell Wilson, 1936 [41]. Source: Courtesy of the British Medical Association Library.
destruction. Cyclosporine in people with newly diagnosed type 1
diabetes prolonged the honeymoon period, but without permanent other signs of vascular disease must mean that diabetes alone does
benefit once the drug was stopped [36]. Nicotinamide and small something to injure the finer arterioles or venules of the retina,
doses of insulin (together with many other interventions) prevented probably the latter’.
diabetes in the non-obese diabetic (NOD) mouse, but were without In 1936, Paul Kimmelstiel (1900–1970) and Clifford Wilson
effect in relatives of people with type 1 diabetes with high titres of (1906–1997) described the striking histological finding of intercap-
islet cell antibodies [37, 38]. illary glomerulosclerosis, large hyaline nodules in the glomeruli in
From 1967, when Paul Lacy (1924–2005) showed that it was pos- the kidneys of eight people at autopsy (Figure 1.13) [41]. Seven of
sible to cure diabetes in inbred rats with an islet cell transplant, it the eight individuals had a known history of diabetes, and
always seemed that the problem of islet cell transplantation in Kimmelstiel and Wilson noted the common features of hyperten-
humans was about to be solved. Hope was rekindled in 2000 by a sion, heavy albuminuria with ‘oedema of the nephrotic type’, and
team in Edmonton, Canada. After five years 80% of those who had renal failure. In fact, this paper led to considerable confusion dur-
received a transplant were producing some endogenous insulin, but ing the next 15 years: according to one writer, the Kimmelstiel–
only 10% could manage without any injected insulin [39]. Wilson syndrome came to mean all things to all people [42].
Nonetheless, it was significant because it drew attention to a spe-
cific diabetic renal disease.
Acceptance of the concept that diabetic angiopathy was specific
Chronic diabetic complications to the disease owed much to the work of Knud Lundbæk from
Aarhus, Denmark (Figure 1.14), who published his findings in a
It had been assumed that arteriosclerosis caused chronic diabetic book in 1953–1954 and a paper in the Lancet in 1954 [43, 44]. His
complications, but this notion was challenged by two papers pub- key arguments were that long-standing diabetic vascular disease
lished in the mid-1930s, which pointed to specific associations of differed fundamentally from atherosclerosis, in that both sexes
diabetes with retinal and renal disease (Table 1.2). In 1934, Henry were equally affected, and that microaneurysms, ocular phlebopa-
Wagener (1890–1961) and Russell Wilder (1885–1959) from the thy, and Kimmelstiel–Wilson nodules were unique to diabetes and
Mayo Clinic reported people who had retinal haemorrhages but no usually occurred together.
other clinical evidence of vascular disease [40], and concluded that The molecular and cellular mechanisms underlying diabetic tis-
‘The very existence of retinitis in cases in which patients have no sue damage remain controversial after decades of intensive research.
13
One of the early landmarks in this field was the work of J.H.
Kinoshita (b. 1922) during the early 1970s, which pointed to the
involvement of the polyol pathway in the formation of diabetic
cataracts [45].
Physiology
In 1907, M.A. Lane, a student of Robert Bensley (1867–1956),

professor of anatomy in Chicago, used conventional histological
techniques to distinguish two different cell types in the islet of
Langerhans, which he termed A and B [46]. The hormones secreted
by these respective cell types were not identified until much later
(Table 1.2). Frank Young (1908–1988) and colleagues reported in
1938 that injections of anterior pituitary extract could induce per-
manent diabetes in the dog, and that this was accompanied by
selective degranulation and loss of the β cells [47]; it was surmised
that these cells produced insulin, and this was finally confirmed
using immuno-histochemistry by Paul Lacy in 1959 [48]. Glucagon
was similarly localized to the α cells in 1962 by John Baum and
colleagues [49].
The amino acid sequence of insulin was reported in 1955 by
Frederick Sanger in Cambridge, UK [50], and the three-dimensional
structure of the molecule in 1969 by Dorothy Hodgkin in
Oxford [51]; both discoveries were recognized by the award of
Nobel Prizes (Figure 1.15). The complete insulin molecule was
synthesized from amino acids by Wang Ying-lai (1908–2001) and
colleagues in Shanghai in 1965 [52]. The insulin precursor, proin-
sulin, was described in 1967 by Donald Steiner (1930–2014) in
Chicago [53]. The first bioassay for insulin, based on the hormone’s
ability to lower blood glucose in the alloxan-diabetic rat, was
reported in 1950 by the Australian Joseph Bornstein (1918–1994),
Figure 1.14 Knud Lundbæk (1912–1995). Source: Courtesy of Dr Carl working in London with Robin D. Lawrence [54]. This method was
Erik Mogensen. superseded in 1956 by Rosalyn Yalow and Solomon Berson in the
(a) (b)
Figure 1.15 (a) Frederick Sanger (1918–2013) and (b) Dorothy Hodgkin, née Crowfoot (1910–1994). Source: Courtesy of Godfrey Argent Studio, London.
14
Table 1.4 Selected milestones in the management of diabetes.
Lifestyle modification
Li Hsuan (China, seventh century) Avoid wine, sex, and salty cereals
Thomas Willis (England, Food restriction
seventeenth century)
John Rollo (England, 1797) Animal diet
Apollinaire Bouchardat Food restriction and
(France, 1875) increased exercise
Carl von Noorden (Germany, 1903) Oatmeal cure
Frederick Allen (USA, 1913) Starvation diet for early-
onset diabetes
Karl Petrén (Sweden, 1915) High-fat, low-carbohydrate diet
Roy Taylor (England, 2015) [63] Very low-calorie diet – remission
of diabetes
Figure 1.16 Solomon Berson and Rosalyn Yalow. Insulin treatment

Georg Zuelzer (Germany, 1907) and Isolated pancreatic extracts with
Nicolas Paulesco (Romania, 1921) hypoglycaemic activity
Frederick Banting, Charles Best, J.J.R. Isolation and first clinical use
USA, who discovered that insulin was antigenic; they exploited Macleod, and James Collip of insulin
the binding of the hormone to anti-insulin antibodies to develop (Canada, 1922–1923)
the first radioimmunoassay [55]. This assay method revolutionized Hans Christian Hagedorn Protamine insulin, the first
(Denmark, 1936) long-acting insulin
endocrinology – and, indeed, many areas of physiology and
David Goeddel (USA, 1979) Synthetic human-sequence insulin
medicine – and was also rewarded with a Nobel Prize (Figure 1.16).
produced by recombinant DNA
The sequence of rat insulin genes was described in 1977 by Axel technology
Ullrich (b. 1945) and colleagues [56], and the human sequence by John Pickup (London, 1978) Described continuous subcutaneous
Graham Bell (b. 1948) and his group in 1980 [57]. The existence of insulin infusion
insulin receptors was inferred from the insulin-binding character- John Ireland (Scotland, 1981) Invented pen-injection device
istics of liver-cell membranes by Pierre Freychet (b. 1935) and col-
Oral anti-diabetes agents
leagues in 1971 [58], and the receptor protein was isolated by Pedro
Avicenna (Arabia, tenth century) Recommended lupin, fenugreek,
Cuatrecasas (b. 1936) in the following year [59]. The gene encoding
and zedoary seeds
the insulin receptor was cloned and sequenced in 1985 by two Willhelm Ebstein (Germany, 1876) Recommended sodium salicylate
groups [60, 61]. In recent years, numerous advances have helped to E. Frank (Germany, 1926) Biguanide derivative (Synthalin)
clarify how insulin exerts its biological actions. Among these was introduced, but withdrawn
the discovery in 1985 of the first of the glucose transporter (GLUT) because of toxicity
proteins by Mueckler and colleagues in the USA [62]. Celestino Ruiz (Argentina, 1930) Noted hypoglycaemic action of
some sulfonamides
Auguste Loubatières (France, 1942) Discovered hypoglycaemic action of
prototype sulfonylurea
Management of diabetes H. Franke and J. Fuchs Carbutamide introduced
(Germany, 1955)
An objective observer surveying clinical diabetes during the half- G. Ungar (USA, 1957) Phenformin introduced
century after the discovery of insulin and the ‘resurrection’ (a word Parke-Davis (1997) Troglitazone, first thiazolidinesione
used by Joslin) of young people with diabetes would have been dis- introduced
mayed by what they saw (Table 1.4). In particular, young people Eli Lilly (2005) Exenatide, first GLP-1 receptor
were dying of complications that had previously been assumed to agonist introduced
MSD (2007) Sitagliptin, first DPP-4 inhibitor
be the preserve of older people. Two particularly depressing papers
introduced
were published in 1947 and 1950. First, Henry Dolger (1909–1997)
Janssen (2013) Canagliflozin, first SGLT2 inhibitors
in New York described 20 people who fulfilled the then-accepted
criteria for excellent diabetic control, but who all developed severe Diabetic monitoring and
retinopathy after 6–22 years [72]; among these was the first person treatment targets
ever to receive insulin at Mount Sinai Hospital, New York, who also University Group Diabetes Program First randomized trial in diabetes
had heavy albuminuria and hypertension by the age of 32. Second, (USA, 1969)
Peter Sönksen and Robert Introduction of self-blood glucose
Ruth Reuting reported a cohort of 50 young individuals with diabe-
Tattersall (1978) monitoring
tes originally identified in 1929 [73]. By 1949, one-third had died
R. Flückiger and K.H. Winterhalter Showed that HbA1c was glycated
(mostly from cardiovascular and renal disease) at an average age of (Germany, 1975) haemoglobin
25 years, after only 18 years of diabetes, and the survivors showed World Health Organization (1991) St. Vincent Declaration identified
‘ominous signs of hypertension, azotemia, and proteinuria in sig- targets for diabetes care
nificant numbers’. This had occurred despite the introduction of James Scott; Exactech First direct electronic glucose
more versatile insulin preparations; the situation was so hopeless (England, 1991) testing [64]
that it inaugurated 20 years of treatment with ‘heroic’ measures
(continued )
such as adrenalectomy and hypophysectomy.
15
Table 1.4 (Continued)
Diabetes Control and Complications Proved that improved glycaemic

Trial (USA, 1993) management prevents and slows
progression of microvascular
complication in type 1 diabetes
UK Prospective Diabetes Study Proved that improved glycaemic and
(UK, 1998) blood pressure management
improve microvascular and
macrovascular outcomes in type
2 diabetes
Steno-2 study (Denmark, 1999) Multiple risk factor interventions
improve outcomes [65]
UK Prospective study 10-year Early treatment legacy effects [66]
follow-up (UK, 2008)
Complications
Wilhelm Manz (Germany, 1876) Described Retinitis proliferans
Gerd Meyer-Schwickerath First use of Xenon photocoagulation
(Germany, 1964)
University of Minnesota Team First combined kidney–pancreas Figure 1.17 Hans Christian Hagedorn (1888–1971) from the Hagedorn Medal.
(USA, 1966) transplants Source: Courtesy of C. Binder, Steno Diabetes Center Copenhagen, Denmark.
John A. Hartford Foundation Argon laser therapy [67]
(USA, 1968)
Carl Erik Mogensen and Hans-Henrik Strict blood pressure controls slows injections of soluble insulin. Indeed, delayed-action preparations
Parving (Denmark, 1980s) progression of diabetic were initially condemned by some diabetes specialists, such as
neuropathy Russell Wilder of the Mayo Clinic, because the person with diabetes
EMPA-REG trial (2015) SGLT-2 inhibitors ameliorate heart could slip without apparent warning into hypoglycaemia.
failure and cardiovascular
The number and variety of insulin preparations proliferated, but
disease [68]
LEADER trial GLP-1 receptor agonists ameliorate
the main advances were in methods to produce highly purified
cardiovascular disease [69] preparations from porcine or bovine pancreas, which remained the
CREDENCE trial SGLT-2 inhibitors ameliorate chronic source for therapeutic insulin until the early 1980s. Insulin was
kidney disease [70] the first therapeutic protein to be produced by recombinant
DNA technology, initially by David Goeddel (b. 1951), who
Surgical approaches expressed synthetic genes encoding the A and B chains separately
SOS study (Sweden, 2013) Demonstrated resolution of diabetes
in Escherichia coli and then combined these chemically to produce
with gastric by-pass surgery [71]
human-sequence insulin [75]. From there, genetic engineering has
DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide-1; SGLT, sodium- been used to produce designer insulins such as the fast-acting insu-
dependent glucose cotransporters. lin analogues lispro and aspart and the peakless basal insulins such
as glargine, detemir, and degludec. These insulins are more expen-
sive than NPH but the evidence suggests that there is less clinical
These and other studies raised questions about whether lower- hypoglycaemia with their use [76].
ing blood glucose levels to normal could prevent diabetes-related Most people with diabetes still inject insulin subcutaneously.
complications or reverse them once they had appeared. The Major milestones in its administration were the replacement of
hypothesis remained untestable for four more decades, until the glass and steel syringes by disposable plastic syringes with fine-
means to achieve optimal glycaemic levels and measure them had gauge needles, and then by pen-injection devices invented by John
been devised. Ireland (1933–1988) in Glasgow in 1981 [77]. Portable insulin
infusion pumps were developed by John Pickup (b. 1947) and
colleagues in London during the late 1970s [78], and have become
progressively smaller and more sophisticated. Both people with
Insulin diabetes and manufacturers hope that there will eventually be an
insulin that can be given without injection. The first inhaled insulin
For the first decade after its discovery, insulin was available only in was marketed in 2006, although withdrawn a year later because of
its soluble (regular) formulation, whose short- action profile lack of demand and concerns about safety [79], but other products
required multiple daily injections. The first delayed-action pre have reached the market more recently.
paration, protamine insulinate, was introduced in 1936 by Hans
Christian Hagedorn at Steno Diabetes Center in Denmark
(Figure 1.17) [74]. This was followed by protamine zinc insulin Other anti-diabetes agents
later the same year, then globin insulin in 1939, NPH (neutral The first orally active glucose-lowering drug, synthalin, a guanidine
protamine Hagedorn, or isophane) in 1946, and the lente series in derivative, was developed by Frank and colleagues in Breslau in
1952. Long-acting insulins were welcomed by diabetes specialists 1926 [80], but had to be withdrawn because of toxicity (a recurrent
and people with diabetes, but their use as a single daily injection problem for oral anti-diabetes drugs). The sulfonylureas originated
probably produced worse glycaemic levels than three or four from the work of Auguste Loubatières (1912–1977) in France
16
Figure 1.18 Dan Drucker, Joel Habener, and Jens Juel

Holst – recipients of the Warren Alpert Prize (2020) and
Canada Gairdiner Award (2021).
uring the early 1940s on the glucose-lowering action of a sulfona-

d of maturity-onset diabetes was a waste of time, a myth that was only
mide derivative, 2254RP. Loubatières made the crucial observations laid finally to rest by the UK Prospective Diabetes Study
that proved that these drugs act as insulin secretagogues and that they (UKPDS) [87]. Beyond the UKPDS, there have been many cardio-
were effective in intact, but not in pancreatectomized, animals [81]. vascular outcome trials addressing separate issues relating to indi-
In 1955 carbutamide was the first sulfonylurea to enter clinical prac- vidual pharmacological agents.
tice and tolbutamide followed in 1957. Phenformin, the first
biguanide, was introduced in 1959 following research into the Glucose management and treatment targets
metabolic effects of guanidine derivatives that had built on Frank’s During the 1920s, opinion leaders advocated normalizing blood
initial studies [82]. Metformin appeared on the European market glucose in young people with diabetes, the rationale being to rest
in 1960, but was not marketed in the USA until 1994. Troglitazone, the pancreas, in the hope that it might regenerate. The only way of
the first of a class of anti- diabetes drugs – the glitazones or monitoring the diabetes was by testing the urine for glucose, and
thiazolidinediones – was marketed in 1997 but withdrawn because attempts to keep the urine free from sugar inevitably resulted in
of liver damage. It was followed by rosiglitazone and pioglitazone. severe hypoglycaemia and often psychological damage. This led to
Another class of drugs, acting on the incretin system, was intro- the so-called free diet movement – linked particularly with Adolf
duced in 2005. In 1986, Joel Habener (b. 1937) and Jens Juel Holst Lichtenstein (Stockholm) and Edward Tolstoi (New York) – which
(b. 1945) simultaneously identified the amino acid sequence of encouraged people with diabetes to eat whatever they liked and not
biologically active, truncated glucagon-like peptide 1 (GLP-1), while to worry about glycosuria, however heavy. Tolstoi’s view [88] was
Dan Drucker (b. 1956) described the first direct actions of GLP-1 on that a life saved by insulin should be worth living, and that people
the β cell, specifically the glucose-dependent stimulation of insulin with diabetes should be able to forget that they had diabetes after
secretion and biosynthesis (Figure 1.18) [83]. Holst discovered the each morning’s injection; it seems likely that many physicians fol-
glucagon-suppressing and appetite-regulating effect of GLP-1 in lowed this policy for the next 40 years.
humans. Importantly, the islet actions of GLP-1 are glucose depend- Adult physicians were similarly ambivalent about the impor-
ent, making GLP-1 a safer treatment than sulfonylureas or insulin. tance of optimal glycaemic management. Only one-third of diabe-
Today, long-acting GLP-1 receptor agonists are very effective tes physicians questioned in England in 1953 thought that
treatments for hyperglycaemia in type 2 diabetes and highly normoglycaemia would prevent diabetes- related complications,
efficacious for inducing weight loss. Inhibitors of the enzyme and only one-half advised urine testing at home [89].
dipeptidylpeptidase- 4 (DPP- 4), which breaks down GLP- 1 Practical monitoring of diabetes management became feasible in
(gliptins), are also widely used. Oral versions of GLP-1 receptor the late 1970s with the introduction into clinical practice of test
agonists are now on the market. strips for measuring blood glucose in a fingerprick sample and the
In the 2010s another class of agents, the sodium-glucose cotrans- demonstration that most people with diabetes could use them at
porter 2 (SGLT-2) inhibitors – the gliflozins – became widely avail- home [90, 91]. The discovery of haemoglobin A1c by Samuel Rahbar
able with action blocking the renal sodium-glucose cotransporters (1929–2012) paved the way for glycated haemoglobin (HbA1c)
and thereby causing glycosuria; their effects were to lower plasma assays that gave an objective measure of overall glucose levels [92].
glucose, reduce blood pressure, and cause weight loss. A landmark These methods in turn made possible the North American Diabetes
trial using empagliflozin in high-risk people with existing cardio- Control and Complications Trial (DCCT), which in 1993 finally
vascular disease showed a marked reduction in mortality [68]. established that optimal glycaemic management prevents and
Tolbutamide, phenformin, and insulin were compared in the delays the progression of microvascular complications in type 1
treatment of maturity-onset diabetes in the first randomized diabetes [93]. For type 2 diabetes, the importance of optimal glycae-
controlled trial, the University Group Diabetes Program (UGDP) mic management was definitively proved by another landmark
[84–86]. This much-criticized study concluded that the death rate study, the UKPDS, masterminded in Oxford by Robert Turner
was higher for both oral agents than for placebo, and that insulin (Figure 1.19). The UKPDS, which reported in 1998, not only
(whether given in a fixed or variable dose) was no better than pla- showed a beneficial effect of improved glycaemic levels on micro-
cebo [85]. The UGDP study, however, did not have correct rand- vascular complications [87], but also established the importance of
omization for pre-existing conditions such as myocardial infarction treating hypertension [94]. By the late 1990s it was clear that lower-
and its conclusions were uninterpretable and unsafe. Nevertheless, ing glucose levels, high blood pressure, or cholesterol separately
these findings were considered by some as suggesting that treatment would reduce the frequency of heart disease and death, and it was
17
lockade of the renin-angiotensin system may be particularly

b
beneficial; Carl Erik Mogensen (b. 1938) and Hans- Henrik
Parving (b. 1943) published studies in the early 1980s demon-
strating that lowering blood pressure slowed the progression of
nephropathy [98]. The detection of very low albumin concentra-
tions in urine (microalbuminuria), now used throughout the
world to screen for and monitor the course of diabetic nephropa-
thy, is derived from a radioimmunoassay developed in 1969 by
Harry Keen (1925–2013) and Costas Chlouverakis, at Guy’s
Hospital in London [99].
Diabetic ketoacidosis
The introduction of insulin was only one aspect of the management

of this acute and previously fatal complication of diabetes. Of the
first 33 cases treated by Joslin and his colleagues between 1 January
1923 and 1 April 1925, 31 survived – an excellent outcome, even by
modern standards, which Joslin [100] attributed to ‘Promptly
applied medical care, rest in bed, special nursing attendance,
warmth, evacuation of the bowels by enema, the introduction of
liquids into the body, lavage of the stomach, cardiac stimulants, and
above all the exclusion of alkalis’.
Sadly, other centres did not pay so much attention to detail. In
1933, the death rate from ketoacidosis in Boston was only 5%, but
elsewhere in North America and Europe it averaged 30% and
could be as high as 75%. An important advance in management
was the acceptance of relatively low-dose insulin replacement, fol-
lowing the example of Ruth Menzel and colleagues in Karlsburg,
Germany [101]. This broke with the tradition of high-dose regi-
mens such as that proposed by Howard Root in the USA, which
had recommended an average of 1200 units of insulin during the
first 24 hours of treatment [102]. Another step forward was the
Figure 1.19 Robert Turner (1939–1999), instigator of the UK Prospective Diabetes recognition by Jacob Holler in 1946 of the danger of hypokalae-
Study, the first study to show that optimal management of blood glucose and blood mia [103]. Holler’s observation helped to establish the need for
pressure was beneficial in type 2 diabetes. Source: Courtesy of the British Diabetic monitoring plasma potassium levels, which became feasible with
Association. the introduction of the flame photometer and replacing potassium
accordingly.
natural to wonder whether tackling them simultaneously (multiple Diabetes in pregnancy

risk factor intervention) would be even better. The Steno-2 study,
which began at the Steno Diabetes Center in Copenhagen in 1992, As late as 1950, the outcome of pregnancy in women with diabetes
enrolled people with type 2 diabetes with microalbuminuria, and was still very poor in most units, with perinatal fetal losses of
after 13 years of follow-up showed that multiple risk factor inter- 45–65%, some 10 times higher than in the general population.
vention reduced the risk of death by 20% and the risk of developing Exceptions to this depressing rule were the units run by Priscilla
nephropathy, retinopathy, and neuropathy by 50% [95]. White at the Joslin Clinic in Boston, who had published excellent
results as early as 1935 [104], and by Jørgen Pedersen in Copenhagen
Diabetes-related complications (Figure 1.20). Pedersen identified the common features underpin-
Apart from the general benefits of improving blood glucose, some ning success as optimal glucose management and care provided by
specific treatments have emerged for certain chronic complica- an experienced and dedicated team comprising a physician, obste-
tions. Well-conducted clinical trials during the late 1970s showed trician, and paediatrician [105]. Pedersen’s target of a fetal mortal-
the effectiveness of laser photocoagulation in preventing visual loss ity rate of 6% was not achieved in most European or US units until
from both maculopathy and proliferative retinopathy [96]. This the 1980s.
technique was derived from the xenon arc lamp originally described
in the late 1950s by Gerd Meyer-Schwickerath (1921–1992) of Delivery of care for people with diabetes
Essen, Germany [97]. From the earliest days of insulin injection and urine testing, it
The importance of blood pressure management in preventing was apparent that people with diabetes needed knowledge and
the progression of nephropathy is now fully recognized, and practical skills to manage their disease effectively. Lip service
18
(a) (b)
Figure 1.20 (a) Jørgen Pedersen (1914–1978) and (b) Ivo Drury (1905–1988), pioneers, with Priscilla White (1900–1989), in the management of pregnancy in women with
type 1 diabetes. Source: Courtesy of Dr Carl Erik Mogensen and the Royal College of Physicians of Ireland.
was often paid to the importance of diabetes education, but most inspiring visit to Joslin’s clinic in Boston (Figure 1.21). The
individuals with diabetes were badly informed. In 1952, Samuel Association’s aim was to provide free insulin and education for peo-
Beaser (1910–2005) questioned 128 people with diabetes attend- ple with diabetes and their families. In the UK, the Diabetic
ing the Boston Diabetes Fair, and found that ‘all were distinctly Association (later the British Diabetic Association, and now
deficient in knowledge of their disease’ [106]; he felt that Diabetes UK) was established in 1934 by Robin Lawrence of King’s
responsibility lay with both doctors and administrators. Further College Hospital, London, helped by the novelist H.G. Wells
studies during the 1960s by Donnell Etzwiler (1927–2003) in (Figure 1.21). Similar organizations were later founded in France
Minneapolis showed that many doctors and nurses were also (1938), the USA (1940), and Belgium (1942), and now exist in most
ignorant about managing diabetes. Since the 1980s, diabetes spe- countries.
cialist nurses and nurse educators have been appointed in On a wider scale, the American Diabetes Association (ADA) was
increasingly large numbers, thus fulfilling a suggestion originally founded in 1939, the International Diabetes Federation was estab-
made by Joslin in 1916. lished in 1950, and the European Association for the Study of
National and international diabetes associations have also played Diabetes (EASD) in 1964. These organizations are devoted to the
an important part by supporting scientific and clinical research, practice of diabetes care as well as the basic and clinical science of
providing practical and moral help for people with diabetes, and the disease, and have been valuable in coordinating treatment tar-
lobbying governments on their behalf. The first of these organiza- gets and strategies at international level; an important example was
tions was the Portuguese Association for the Protection of Poor the St. Vincent Declaration, issued jointly in 1990 by the EASD and
Diabetics, founded in 1926 by Ernesto Roma of Lisbon after an the World Health Organization [107].
19
(a) (b)
Figure 1.21 (a) Ernesto Roma (1887–1978) and (b) Robin D. Lawrence (1892–1968). Source: Photograph of Dr Roma by courtesy of Manuel Machado Sá Marques and the
Associação Protectura das Diabéticos de Portugal.
Albert [Translation of Ophthalmoskopischer 32 Tattersall, R.B. (1974). Q. J. Med. 43: 339–357.

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78 Pickup, J.C., Keen, H., Parsons, J.A. et al. (1978). 105 Pedersen, J. and Brandstrup, E. (1956). Lancet ers of insulin are preserved at the Thomas Fisher
Br. Med. J. i: 204–207. i: 607–610. Rare Book Library, University of Toronto, Canada.
21
2 Classification and Diagnosis of Diabetes
Ambady Ramachandran, Chamukuttan Snehalatha, Arun Raghavan,
and Arun Nanditha
Dr. A. Ramachandran’s Diabetes Hospitals and India Diabetes Research Foundation, Chennai, India
Key points
• Diabetes is a complex metabolic disease characterized by high levels • Recent suggestions to classify diabetes according to β-cell defects may
of blood glucose and/or glycated haemoglobin (HbA1c) resulting from facilitate personalized, optimal therapy, but the diagnostic tests are
defects in insulin secretion, insulin action, or both. too costly or unavailable in most laboratories.
• There are three main types of diabetes and other less common specific • Varied diagnostic criteria for gestational diabetes are still being used.
types of diabetes with varied and overlapping aetiology. • Impaired glucose tolerance (IGT) is a predictor of future type 2 diabetes
• Although blood glucose remains the mainstay for the diagnosis of diabetes, and is also a cardiovascular risk factor.
HbA1c is approved as an alternative diagnostic test for hyperglycaemia and
in many countries is being increasingly used in place of glucose.
Diabetes is one of the most common metabolic diseases with a

complex, multifactorial aetiology and has varied clinical and
Definition
biochemical manifestations. Multiple and varied therapeutic

approaches are required for the glycaemic management of the Diabetes is a group of metabolic diseases characterized by hyper-
different types of diabetes. The main pathological abnormalities of glycaemia resulting from defects in insulin secretion, insulin action,
diabetes are an inadequate secretion and/or impaired action of or both. Diabetes is distinguished by disturbances in carbohydrate,
insulin on target t issues. The severity of the resultant hyperglycae- fat, and protein metabolism. The clinical symptoms include polyu-
mia and the symptoms and signs vary widely. The development of ria, polydipsia, polyphagia, weight loss, tiredness, and blurring of
diabetes-related microvascular complications depends largely on vision. With severe metabolic dysregulation, ketoacidosis or hyper-
the degree and duration of hyperglycaemia. osmolar non-ketotic coma may occur. However, symptoms may be
Diabetes mellitus has been known since ancient times. The term mild or absent among people with type 2 diabetes for many years,
diabetes was probably first used by Apollonius of Memphis around especially when hyperglycaemia is minimal. Although the disease
250 bce. The Latin word mellitus was added later, as the urine of may remain undetected, tissue damage may develop and therefore
people with diabetes was sweet and was used to distinguish diabe- diabetes- related complications may be present at the time of
tes mellitus from diabetes insipidus caused by defects in diagnosis [4, 5]. Chronic hyperglycaemia may impair growth in
vasopressin [1]. children and increase the susceptibility to certain infections.
Diabetes was described as early as 1500 bce by Hindu scholars In addition to the classic symptoms, people with diabetes may
and Egyptian and Greek physicians as a mysterious disease causing present with vague symptoms such as unexplained weight loss,
emaciation and excess urination. If the urine tasted sweet, diabetes fatigue, restlessness, and body pain.
was diagnosed [2]. It was only in the 1800s that chemical tests were Diabetes is associated with the development of long-term compli-
developed to detect the presence of sugar in the urine. The early cations that can be divided into two main types. Microvascular
descriptions were probably related to severe forms of the disease, complications include retinopathy (with potential loss of vision),
either type 1 diabetes or overt type 2 diabetes. nephropathy (leading to renal impairment), peripheral neuropathy
In the late nineteenth century two categories were recognized: (with risk of foot ulcers, amputations, or Charcot joints), and
one category was described as occurring in young people with a a
utonomic neuropathy (causing gastrointestinal, genitourinary,
short time course before ketoacidosis occurred, and the second one and cardiovascular symptoms, and sexual dysfunction) [4, 5].
was described as common in older people and those with obesity. Macrovascular complications include cardiovascular diseases with
In 1936, Himsworth showed that diabetes could be divided into increased incidence of atherosclerotic cardiovascular, peripheral
insulin-resistant and insulin-sensitive types, with the former being arterial, and cerebrovascular diseases as well as heart failure.
more common among older people [3]. Hypertension and dyslipidaemia often coexist in people with diabetes.
Textbook of Diabetes, Sixth Edition. Edited by Richard I.G. Holt and Allan Flyvbjerg.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
22
Classification and Diagnosis of Diabetes Chapter 2
Diagnosis and classification of diabetes Table 2.1 Criteria for the diagnosis of diabetes.
Although variations in the presentation and course of diabetes have FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for
at least 8 h.
been known for many centuries, a clear distinction between two
types of diabetes emerged only in the twentieth century. The first OR
real attempt to classify diabetes was by the World Health 2 h PG ≥200 mg/dl (11.1 mmol/l) during OGTT. The test should be performed, as
Organization (WHO) Expert Committee on Diabetes Mellitus, described by the WHO, using a glucose load containing the equivalent of 75 g
which classified diabetes based on the age of onset of the disease anhydrous glucose dissolved in water.
into juvenile- onset diabetes and maturity- onset diabetes [6]. OR
Although other phenotypes such as the brittle, gestational, pancre- HbA1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory
atic, endocrine, insulin- resistant, and iatrogenic varieties were using a method that is NGSP-certified and standardized to the DCCT assay.
described at that time, there was no clear understanding of the
OR
aetiology.
Blood glucose measurements became common, but no stand- In a person with classic symptoms of hyperglycaemia or hyperglycaemic crisis, a
random plasma glucose ≥200 mg/dl (11.1 mmol/l).
ard criteria for diagnosis were used. The diagnosis was usually
made if there were clinical symptoms with high blood glucose
In the absence of unequivocal hyperglycaemia, the diagnosis requires two
levels and glycosuria. In juvenile-onset diabetes, ketonuria was abnormal test results from the same sample or in two separate test samples.
noted to be common. Later on, with the availability of insulin DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose;
measurement using radioimmunoassay, insulin deficiency or NGSP, National Glycohemoglobin Standardization Program; OGTT, oral glucose
lack of insulin secretion in juvenile-onset diabetes and apparently tolerance test; PG, plasma glucose; WHO, World Health Organization.
normal or raised levels in maturity- onset diabetes could be Source: Reproduced from the American Diabetes Association Standards of Care
demonstrated. 2021 [12].
The WHO has published several guidelines for the diagnosis of
diabetes since 1965 [5–7]. Its second report, published in 1980 [7],
marked the beginning of the modern classification, which was a Diagnostic thresholds
revision of the criteria published by the National Diabetes Data The thresholds for the diagnosis of diabetes are currently based on
Group (NDDG) [8]. For the first time, four major groups were the glycaemic levels above which diabetes-related microvascular
defined: insulin-dependent diabetes mellitus (IDDM, type 1); non- complications mostly occur. However, these thresholds have
insulin-dependent diabetes mellitus (NIDDM, type 2); the ‘other changed over time. The oral glucose tolerance test (OGTT) was
types’; and gestational diabetes mellitus. Two risk classes, previous first introduced by Hofmeister in 1889, but this was not standard-
abnormality of glucose intolerance and potential abnormality of ized and various amounts of glucose with different two-hour
glucose tolerance, were also suggested in place of the terms pre- thresholds were used throughout the 1960s and 1970s. The second
diabetes or potential diabetes. WHO report published in 1980 [7] marked a breakthrough in har-
Both diagnosis and classification were reviewed in 1985 [9] and monizing the diagnosis of diabetes. The report established that
1999 [5]. At the same time the American Diabetes Association diabetes could be diagnosed with a casual plasma glucose of
(ADA) published a report of an expert committee on the diagno- >11.0 mmol/l (200 mg/dl) or with a 75 g OGTT using fasting and
sis and classification of diabetes [10]. Both WHO and ADA clas- two-hour thresholds of ≥8.0 mmol/l (145 mg/dl) and >11.0 mmol/l
sifications attempted to encompass both aetiology and clinical (200 mg/dl), respectively. The two-hour threshold was based on
stages of the disease based on the suggestions of Kuzuya and the observed risk of developing retinopathy in several popula-
Matsuda [11]. tions, but there were less robust data for the fasting glucose thresh-
It was known that diabetes could progress through several old, which was later revised to the current value of 7.0 mmol/l
clinical stages from normoglycaemia to ketoacidosis. With the (126 mg/dl).
discovery of human leucocyte antigen (HLA) and islet cell anti- In the development of diabetes, there is a stage when the blood
bodies, it became clear that juvenile-onset diabetes or insulin- glucose values are above normal, but below the thresholds
dependent diabetes had an autoimmune aetiology. Although used for defining diabetes, which is termed pre-diabetes or inter-
maturity-onset diabetes was thought to be a milder form of the mediate hyperglycaemia. Pre-diabetes encompasses abnormalities
disease, it was recognized that people with type 2 diabetes could in fasting glucose (impaired fasting glycaemia) and two- hour
progress through varying levels of hyperglycaemia to a stage post-glucose challenge glucose (impaired glucose tolerance, IGT).
where insulin was required. By contrast, it was also possible to Both impaired fasting glycaemia and IGT increase the risk of
revert from a stage of requiring insulin to a point where normo- developing diabetes, with approximately one-third of people with
glycaemia could be maintained through non-pharmacological IGT developing type 2 diabetes; the annual incidence rate ranges
intervention with modification of health behaviours, which is between 2% and 10% depending on the population and the pres-
now termed remission of diabetes. ence of risk factors [13]. Use of the term ‘pre-diabetes’ has been
criticized on the basis that not all people with this condition
progress to type 2 diabetes, and the term ‘intermediate hypergly-
Methods and criteria for diagnosing diabetes caemia’ is preferred by many. The diagnostic thresholds for
pre-diabetes have also changed over time. The category of IGT was
The criteria for the diagnosis of diabetes recommended by the ADA introduced by the WHO in 1965 and after a few iterations it
in 2021 [12] and approved by the WHO [13] and the International was defined as a fasting glucose value of <7 mmol/l (126 mg/dl)
Diabetes Federation (IDF) are shown in Table 2.1. and post- glucose value between ≥7.8 mmol/l (140 mg/dl) and
23
<11.1 mmol/l (200 mg/dl) [14]. The 1997 ADA and 1999 WHO
Table 2.2 Advantages and limitations of using HbA1c.
criteria defined impaired fasting glucose (IFG) as a fasting glucose
value between ≥6.1 mmol/l (110 mg/dl) and <7.0 mmol/l (126 mg/
Advantages Limitations
dl). In 2003, the ADA revised the lower cut-off value to ≥100 mg/dl
(5.5 mmol/l). The reduction of normal fasting value to ≤100 mg/dl • Random sampling • Depends on changes in lifespan of
was partly to ensure that the prevalence of IFG was similar to that • Fasting not required erythrocytes
of IGT. Furthermore, many studies have shown that 5.6 mmol/mol • High sample stability • Genetic and ethnic variations
(100 mg/dl) provides the best cut- point for predicting future • Negligible biological variability • Affected by haemoglobinopathies
diabetes and the level at which insulin secretion becomes abnor- • Highly reproducible • Affected by severe anaemia, hence
mal. However, lowering this threshold significantly increases the • Indicator of long-term may not be valid in people with
prevalence of pre-diabetes, which has important personal and glycaemic status chronic renal and liver diseases
public health implications [15, 16]. As such, the WHO and other • Single whole blood sample • May be unreliable in individuals with
• Minimal assay variability and human immunodeficiency virus (HIV)
organizations did not adopt this change [15].
accuracy are assured when • May not be valid in children, in older
In 2011, glycated haemoglobin (HbA1c) was also introduced as a standard methods are used people, and in pregnancy
further diagnostic criterion for diabetes, with a threshold of 6.5% • Standardized across instruments • Assays are not standardized in many
(48 mmol/mol) [4, 17]. The HbA1c test should be performed • Guides physicians on the middle-and low-income countries
using the method certified by the National Glycohemoglobin appropriate treatment • High cost
Standardization Program or International Federation of Clinical • Predictive of development of • Lack of awareness among citizens
Chemistry. A value of <6.5% (<48 mmol/mol) does not exclude dia- vascular complications and physicians in
betes diagnosed using glucose tests. The ADA report recognizes that • Point-of-care tests are available in developing countries
individuals with an HbA1c between 5.7% and 6.5% are at risk of dia- high-income countries
betes and includes HbA1c as a means of diagnosing pre-diabetes [17].
It should be noted that the risk of diabetes is continuous, can extend
below the lower limit of the range, and is disproportionately greater
at the higher end of the range [4]. However, high biological variability, poor reproducibility, and
influence by acute factors such as stress, food, exercise, and some
Number of abnormal tests required medications are the main disadvantages of using blood glucose.
In an individual with classic symptoms of hyperglycaemia, only one Moreover, precautions must be taken to reduce the lowering of
measurement of glucose or HbA1c above the diagnostic threshold is sample glucose by glycolysis by adding anti-glycolytic agents, such
required to make the diagnosis. In the absence of a clear history of as sodium fluoride. Despite this, the rate of decline in glucose con-
diabetes symptoms, however, the diagnosis of diabetes requires two centration continues for up to four hours in small quantities. In
abnormal test results from the same sample or in two separate test addition, there are differences in glucose concentrations in whole
samples. Where there is uncertainty, the WHO and ADA recom- blood, plasma and serum and between capillary and venous blood.
mend that a standard 75 g OGTT is used if possible in conjunction The availability of point- of-
care testing with glucometers has
with HbA1c measurement. However, clinical practice is changing helped to reduce the disadvantages of blood glucose measurement
and in many high-income countries, where procedures for the to some extent. Moreover, rapid bedside measurements have also
accurate measurement of HbA1c are readily available, the OGTT is become possible with these meters.
being used less and less frequently. In these settings, a single blood HbA1c, initially identified as an index of chronic hyperglycaemia,
sample with measure of either fasting or random glucose and has now evolved into a valuable tool to monitor glycaemic manage-
HbA1c is more commonly used for the diagnosis. ment, for screening and diagnosis of diabetes and pre-diabetes, and
as a predictor of micro-and macrovascular complications [20, 21].
Further considerations of method of diagnosis Presently the results are traceable to the Diabetes Control and
When used on a population basis, fasting glucose, two-hour glu- Complications Trial (DCCT) assay values (measured as %) [22] and
cose, and HbA1c identify slightly different groups of people as hav- can also be compared to the highly accurate International Federation
ing diabetes. Thus, an individual may test positive for diabetes with of Clinical Chemistry (IFCC) standardized values (mmol/mol) [20].
one test but not another. As the OGTT combines both fasting and Measuring HbA1c has multiple advantages over blood glucose, but
two-hour glucose, using fasting glucose alone will identify fewer also has a few limitations, particularly in middle-and low-income
people with diabetes than an OGTT. Studies in Asian popula- developing countries (Table 2.2). Healthcare professionals using the
tions [18] and the Diabetes Epidemiology: Collaborative analysis of test should be aware of these limitations and employ their discretion
Diagnostic criteria in Europe (DECODE) study [19] showed that if in interpreting the results [20, 23].
only fasting blood glucose was used, nearly one-third of cases with
diabetes might be missed at diagnosis. There are similar concerns
about HbA1c, but with time the groups coalesce to the point where Classification of diabetes types
all three tests become positive.
The aetiological classification of diabetes was described by the
Analytical considerations WHO [5] and also approved by the ADA [12]. The classification of
Blood glucose measurement has been the mainstay of diagnosis type 2 diabetes is largely characterized by exclusion. The most
and monitoring glycaemic levels in diabetes for many decades. The recent WHO classification published in 2019 is shown in
OGTT is a comparatively inexpensive, sensitive index of hypergly- Table 2.3 [13].
caemia including impaired glucose homeostasis. Standard As new causes are discovered they are included as ‘other specific
enzymatic methods of glucose estimation are in widespread use. types’, such as maturity-onset diabetes of the young (MODY).
24
Table 2.3 Classification of diabetes.
Type of diabetes Brief description
Type 1 diabetes β-cell destruction (mostly immune mediated) and absolute insulin deficiency; onset most common in
childhood and early adulthood
Type 2 diabetes Most common type, various degrees of β-cell dysfunction and insulin resistance; commonly associated
with overweight and obesity
Hybrid forms of diabetes
Slowly evolving, immune-mediated diabetes of adults Similar to slowly evolving type 1 diabetes in adults, but more often has features of the metabolic syndrome,
has a single glutamic acid decarboxylase (GAD) autoantibody, and retains greater β-cell function
Ketosis-prone type 2 diabetes Presents with ketosis and insulin deficiency but later does not require insulin; common episodes of ketosis,
not immune mediated
Other specific types
Monogenic diabetes
Monogenic defects of β-cell function Caused by specific gene mutations; has several clinical manifestations requiring different treatment, some
occurring in the neonatal period, others by early adulthood
Monogenic defects in insulin action Caused by specific gene mutations; has features of severe insulin resistance without obesity; diabetes
develops when β cells do not compensate for insulin resistance
Diseases of the exocrine pancreas Various conditions that affect the pancreas can result in hyperglycaemia (trauma, tumour, inflammation, etc.)
Endocrine disorders Occur in diseases with excess secretion of hormones that are insulin antagonists
Drug or chemical induced Some medicines and chemicals impair insulin secretion or action, some can destroy β cells
Infection-related diabetes Some viruses have been associated with direct β-cell destruction
Uncommon specific forms of immune-mediated diabetes Associated with rare immune-mediated diseases
Other genetic syndromes sometimes associated Many genetic disorders and chromosomal abnormalities increase the risk of diabetes
with diabetes
Unclassified diabetes Used to describe diabetes that does not clearly fit into other categories. This category should be used
temporarily when there is not a clear diagnostic category, especially close to the time of diagnosis
Hyperglycaemia first detected during pregnancy
Diabetes in pregnancy Type 1 diabetes or type 2 diabetes first diagnosed during pregnancy
Gestational diabetes Hyperglycaemia below diagnostic thresholds for diabetes in pregnancy
Source: Adapted from the World Health Organization Report, 2019 [13].
The WHO has revisited the classification several times with no Hashimoto’s thyroiditis, Addison’s disease, vitiligo, coeliac-sprue,
major modifications. IGT was removed from the formal classifica- autoimmune hepatitis, myasthenia gravis, and pernicious anaemia.
tion of type 2 diabetes, but was retained as a risk state. A new cate- About 2–12% of people diagnosed with type 1 diabetes show
gory of risk status, IFG, was introduced. phenotypic characteristics of type 2 diabetes at diagnosis and ini-
tially have glucose levels within target on oral anti-diabetes agents,
before rapidly progressing to requiring insulin. They also show the
Type 1 diabetes presence of autoimmune markers of β-cell destruction, such as
GAD autoantibodies. This subgroup was termed latent autoim-
In most cases, type 1 diabetes occurs as a result of cellular-mediated mune diabetes of adults (LADA), but in the recent WHO classifica-
autoimmune destruction of pancreatic β cells, causing an absolute tion the term LADA was removed because there was considerable
deficiency of endogenous insulin. People with type 1 diabetes are controversy as to whether this was a separate condition to type 1
dependent on exogenous insulin for survival and are ketosis diabetes. It now comes under hybrid forms of diabetes with slowly
prone. Markers of the immune destruction of the β cell include evolving immune-mediated diabetes of adults [13].
islet cell autoantibodies, autoantibodies to insulin, glutamic acid A few people with type 1 diabetes may have no evidence of auto-
decarboxylase (GAD), and autoantibodies to the tyrosine phos- immunity, but are prone to episodic ketoacidosis and may exhibit
phatases IA-2 and IA-2β. One or more of these autoantibodies are varying degrees of insulin deficiency and insulin dependency dur-
present in 85–90% of individuals when fasting hyperglycaemia is ing those periods. This form, termed idiopathic diabetes, is com-
initially detected. The disease also has strong HLA associations, monly seen in people of African and Asian ethnicity and is strongly
with linkage to the DQA and DQB genes, and is influenced by the familial [4].
DRB genes.
The rate of destruction of β cells is usually rapid in infants, young
children, and adolescents and they often have ketoacidosis at the Type 2 diabetes
time of first presentation. Some people with type 1 diabetes, mostly
adults, have a slower deterioration of β-cell function and show detec Type 2 diabetes constitutes more than 95% of the total population
table levels of plasma C-peptide for many years. Type 1 diabetes is with diabetes. Its prevalence is increasing globally, but the most
associated with other autoimmune disorders such as Graves’ disease, striking changes are now seen in low-and middle- income
25
countries. Type 2 diabetes may remain asymptomatic for many Other specific types
years and is undetected in nearly 50% of people affected by the These forms of diabetes are relatively less common. The underlying
disease [4, 5]. It is commonly diagnosed incidentally when a medi- defects of the disease processes can be identified in these forms,
cal check-up is done for other reasons. Type 2 diabetes is charac- such as those listed in Table 2.3. Some of these defects are remedi-
terized by a relative insulin deficiency; although there is insulin able and the diabetes can be cured [4, 5].
secretion, this is insufficient to overcome insulin resistance.
Though many people with type 2 diabetes manage their diabetes
with lifestyle changes alone, with time oral anti-diabetes agents are Gestational diabetes
needed to maintain normoglycaemia, with many people eventually
requiring insulin. Chronic exhaustion of β-cell function is a major
For many years, gestational diabetes was defined a state of carbohy-
cause of this.
drate intolerance resulting in hyperglycaemia of variable severity,
Although research studies have focused on the molecular mech-
with onset or first recognition during pregnancy. It does not exclude
anisms underlying type 2 diabetes, only modest success has been
the possibility that the glucose intolerance may antedate pregnancy
achieved in unravelling the genetic abnormalities. In the past two
but has previously gone unrecognized. The definition applies irre-
decades, type 2 diabetes in children and adolescents has become
spective of whether or not insulin is used for treatment or whether
common in Asian populations and could be partly attributed to the
the condition persists after pregnancy [12, 13]. According to this
rising rates of obesity and changing lifestyle patterns [24]. A minor-
definition, gestational diabetes may develop at any stage of preg-
ity of people with type 2 diabetes are prone to episodes of ketosis.
nancy, but many now consider diabetes detected during the first
They have insulin deficiency but no immune markers. This hybrid
trimester of pregnancy to be previously undiagnosed pre-existing
form is termed ketosis-prone type 2 diabetes [13].
diabetes. The term gestational diabetes is then reserved for diagno-
There has been a proposal to modify the classification of type 2
ses made in the second or third trimester of pregnancy. Women
diabetes to identify people at increased risk of complications and
who have diabetes and subsequently become pregnant are termed
support precision treatment by tailoring the type of therapy with
as having diabetes mellitus and pregnancy and should be treated
greatest benefit for the individual with diabetes. Recently, a sub-
accordingly during and after the pregnancy. This is discussed in
stratification in 8980 individuals with newly diagnosed diabetes
greater detail in Chapter 71. The International Association of
was undertaken in Sweden using clusters based on six variables:
Diabetes and Pregnancy Study Groups’ (IADPSG) criteria for diag-
GAD antibodies, age at diagnosis, body mass index (BMI), HbA1c,
nosis of gestational diabetes are shown in Table 2.4 [27]. These cri-
and estimates of β-cell function and insulin resistance. The analy-
teria have been adopted by main national guidelines, including
sis was based on prospective data from medical prescriptions and
development of complications from electronic records of the
examined individuals [25]. Five clusters of phenotypes with dis-
tinct characteristics were identified. Individuals in cluster 1
Table 2.4 Screening for and diagnosis of gestational diabetes.
(severe autoimmune diabetes) had early-onset disease, low BMI,
relatively higher HbA1c, insulin deficiency, and presence of GAD One-step strategy
antibodies. Cluster 2 (severe insulin-deficient diabetes) was GAD Perform a 75 g OGTT, with plasma glucose measurement when the individual is
antibody negative, with low age at onset, low BMI, low insulin fasting and at 1 h and 2 h, at 24–28 weeks of gestation in women not
secretion, and relatively higher HbA1c. Cluster 3 (severe insulin- previously diagnosed with diabetes. The OGTT should be performed in the
resistant diabetes) had high insulin resistance and high BMI, while morning after an overnight fast of at least 8 h. The diagnosis of gestational
cluster 4 (mild obesity-related diabetes) had obesity but not insu- diabetes is made when any of the following plasma glucose values are met
lin resistance. Cluster 5 (mild age-related diabetes) was older but or exceeded:
was similar to cluster 4 with modest metabolic derangements. • Fasting: 92 mg/dl (5.1 mmol/l)
• 1 h: 180 mg/dl (10.0 mmol/l)
Among these the highest percentage (39.1%) was cluster 5 and the
• 2 h: 153 mg/dl (8.5 mmol/l)
lowest cluster 1 (6.4%).
The clusters had varied dispositions to specific complications of Two-step strategy
diabetes such as kidney disease, coronary events, and stroke. Step 1: Perform a 50 g GLT (non-fasting), with plasma glucose measurement at
Clusters 1 and 2 had a higher HbA1c at diagnosis than the other 1 h, at 24–28 weeks of gestation in women not previously diagnosed with
clusters and a higher frequency of ketoacidosis. Cluster 2 had the diabetes. If the plasma glucose level measured 1 h after the load is ≥130,
highest risk of retinopathy, and cluster 3 had the highest prevalence 135, or 140 mg/dl (7.2, 7.5, or 7.8 mmol/l, respectively), proceed to a
100 g OGTT.
of non-alcoholic fatty liver disease and chronic kidney disease.
Step 2: The 100 g OGTT should be performed when the individual is fasting. The
Cluster 4 had an increased risk of diabetes kidney disease and diagnosis of gestational diabetes is made when at least twoa of the following
cluster 5 appeared to have a lower risk of renal disease. four plasma glucose levels (measured fasting and at 1, 2, and 3 h during
The authors suggested that further improvement in the stratifi- OGTT) are met or exceeded:
cation may be possible through the inclusion of additional variables • Fasting: 95 mg/dl (5.3 mmol/l)
such as biomarkers, genotypes, or genetic risk scores. Therefore, • 1 h: 180 mg/dl (10.0 mmol/l)
the study suggested the superiority of identifying the new clusters • 2 h: 155 mg/dl (8.6 mmol/l)
during classification, which will possibly provide better guidance • 3 h: 140 mg/dl (7.8 mmol/l)
for appropriate treatment regimens. However, the tests required for
identifying the clusters are costly and are available only in a limited GLT, glucose load test; OGTT, oral glucose tolerance test.
a American College of Obstetricians and Gynaecologists notes that one elevated
number of advanced research institutions and hospitals. More
value can be used for diagnosis [26].
detailed clinical trials are required to confirm the utility of this Source: Adapted from American Diabetes Association, 2021 [12].
classification.
26
those of the ADA, but not by all countries [12]. Establishing a stage should be treated with lifestyle interventions and in some
uniform approach to diagnosis will have extensive benefits for circumstances metformin.
women, caregivers, and policy makers.
Women with any of the following risk factors should be
screened with an appropriate blood test as shown in Table 2.4, Conclusion
during the first prenatal visit; if the result is found to be normal,
they should be tested again between 24 and 28 weeks of preg- The advances made in the past two decades in diagnostic and
nancy [12, 13]. The risk factors for gestational diabetes include research methodologies for identifying pathophysiological compo-
older age, obesity (BMI >30 kg/m2), history of elevated blood glu- nents of various types of diabetes have provided significant clarity
cose levels or gestational diabetes during previous pregnancy, in the classification and diagnosis of diabetes [26]. This has helped
women who have large-for-gestational age babies, a strong family to establish some uniformity in data collection and has also allowed
history of diabetes, and women from high-risk ethnic groups such comparison of the international profile of the disease. Consensus in
as Asians [28]. establishing diagnostic criteria for gestational diabetes is lacking.
Hyperglycaemia may resolve after the delivery, but 5–10% of Emphasis should be given to identifying the pre-diabetes states that
women may continue to have diabetes, most often type 2 diabe- are the strongest predictors of incident type 2 diabetes.
tes. These women require treatment with lifestyle changes and The classification of diabetes should facilitate optimal personal-
appropriate anti-diabetes agents. Women with gestational dia- ized diabetes care. There are many diabetes subtypes, especially
betes should be screened for diabetes immediately postpartum among type 2 diabetes, type 1 diabetes, and the autoimmune type of
and again at 6–12 weeks postpartum using non-pregnant OGTT diabetes. The current state of knowledge suggests that the classifica-
criteria [29]. HbA1c cannot be used in the immediate postpar- tion should be based on β-cell pathology contributing to β-cell dys-
tum period, but is an effective alternative way of screening for function [30]. At present, the facilities for specialized analysis
persistent glucose abnormalities from 12 weeks postpartum required for such a classification, such as genotyping and advanced
where the facilities for accurate measurement are available. immune pathology, are available only in a few advanced specialized
Women with gestational diabetes are at risk of future diabetes research laboratories and are too costly [31, 32]. Nevertheless, the
outside pregnancy and should be offered screening on an annual classification of diabetes continues to evolve as underlying genetic
basis. Women who show impaired glucose regulation at this and other factors become identified with increasing precision.
10 (1997). Report of the Expert Committee on 24 International Diabetes Federation (2019).

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of a WHO Consultation. Part 1: Diagnosis and 16 Borch- Johnsen, K., Colagiuri, S., Balkau, B. Association of Diabetes and Pregnancy Study
Classification of Diabetes Mellitus. WHO/NCD/ et al. (2004). Diabetologia 47: 1396–1402. Groups Consensus Panel (2010). Diab. Care 33
NCS/99.2. Geneva: WHO. 17 Expert Committee Report on the Diagnosis of (3): 676–682.
6 WHO Expert Committee on Diabetes Mellitus Diabetes (2009). Diab. Care 32: 1327–1334. 28 Ramachandran, A., Snehalatha, C., Shetty, A.S.,
& World Health Organization (1965). Diabetes 18 Wong, T.Y., Liew, G., Tapp, R.J. et al. (2008). and Nanditha, A. (2012). World J. Diab. 15 (3):
mellitus: report of a WHO Expert Committee Lancet 371: 736–743. 110–117.
[meeting held in Geneva from 24 to 30 November 19 Balkau, B. (2000). Diab. Metab. 26: 282–286. 29 Committee on Practice Bulletins- Obstetrics
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27
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which he had made in his terror. Accordingly they said, imprudently
for their purpose, but prudently for the purpose of the Lord, ‘We will
not chastise this one with severe blows, because he is young; we will
only punish him by cutting with a knife the hard part of his feet.’ They
took the covering off his feet. Albinus instantly protected himself with
the sign of the Cross. Then he chanted with all intentness the twelfth
psalm, ‘In the Lord put I my trust’; and then the rustic, half dead, the
boy going before him with agile step, fled into the basilica to the
protection of the saints.”
A cynical reader might suggest that the disciplinary officers of the
School of York resorted in those early times to unusual methods of
making an impression on a careless boy.
The Life proceeds to inform us that Alcuin was trained under the
prelate Hechbert, whom we know as Ecgbert, Bishop and later
Archbishop of York, 732 to 766. That learned man was a disciple of
Bede. He had under his tuition a flock of the sons of nobles, some of
whom studied grammar, others the liberal arts, others the divine
scriptures.[12] They studied the doctrine set forth by “the holy apostle
of the English, Gregory; by Augustine, his disciple; by holy
Benedict[13]; also by Cuthbert and Theodore, who followed in all
things [a word is omitted here, presumably the footsteps[14]] of their
first father and apostle[15]; and by the man most loved of the Lord,
Bede the presbyter, Hechbert’s own preceptor.”
Then follows a very lifelike description of an ordinary day’s work,
when no inevitable expedition came in the way, nor any high
solemnity or great festival of the saints. “From dawn of day to the
sixth hour, and very often to the ninth hour, Ecgbert lay on his couch
and opened to his disciples such of the secrets of scripture as suited
each. Then he rose, and betook himself to most secret prayer,
offering first to the Lord fat burnt-offerings with the incense of rams,
and afterward, following the example of the blessed Job, lest by
chance his sons should slip into the pit of benediction,[16] offering the
Body of Christ and the Blood for all. By this time the vesper hour was
coming near, and, except in Lent, all through the year, winter and
summer, he took with his disciples a meal, slight but fittingly
prepared, not sparing the tongue of the reader, that both kinds of
food might bring refreshment. Then you might see the youths
piercing one another with shafts prepared, discussing in private what
afterwards they are to shoot forth in proper order in public. Does it
not seem to you that of this too it might be said,[17] “As an eagle
provoketh her young ones to fly, fluttereth over them, spreadeth
abroad her wings, taketh them, beareth them on her wings”?
“Twice in the day did this father of the poor, this great lover and
helper of Christ, pour out most secret prayer, watered from the most
pure fountain of tears, both knees bent on the ground, hands long
raised to heaven in the form of the Cross; once, namely, before
taking food, and again before celebrating Compline with all his flock.
Which ended, no one of his disciples ever dared commit his limbs to
his bed without the master’s blessing laid upon his head.
“He loved all his disciples, but of all he loved Alcuin the most, for
Alcuin more closely than any of them followed his example in act and
deed. There were two special virtues in Alcuin—one, that he never
did anything which he was not quite clear that his master’s approval
covered; the other, that whatever devices and temptations the
enemy brought to his mind, he told them all straight out to his master
without any sense of shame. Thus it came to pass that any stimulus
of lust which he ever felt was most gloriously conquered by this
wonderful method, dashing the children of Babylon against the
stones, bruising the head of the serpent with the heel. He was
careful that against him the words of Christ should not be spoken
—‘Every one that doeth evil hateth the light, neither cometh to the
light, lest his deeds should be reproved’; but rather that his lot should
be with them of whom it is added—‘But he that doeth truth cometh to
the light, that his deeds may be made manifest that they are wrought
in God.’ O true monk without the monk’s vow! how very seldom is thy
example followed by one whose vow binds him to it[18].”
In the chapter from which these details are taken the author three
times uses the name “Albinus” for his hero, in place of “Alchuinus”
with which he began the chapter. Throughout the Life he much more
often calls him Albin than Alcuin. We must probably understand that
he was known from his boyhood by both names; and it is evident
that Albin would be more easy to pronounce than Alcuin, and would
not unnaturally be more generally used. On the other hand, it is quite
possible that he himself elected to call himself Albin.
If Alcuin took the name Albinus from any English source, the
source is not far to seek. The English nation owes to the original
Albinus the first suggestion to Bede that he should write the Church
History of the English race. Bede tells us this in the Preface to his
great work; and we have it still more directly expressed in a letter
from him to Albinus in which he speaks of the History as ad quam
me scribendam iamdudum instigaveras, and of Albinus as semper
amantissimus in Christo pater optimus. He was Abbat of St. Peter
and St. Paul, Canterbury, a pupil of Theodore and Hadrian, the latter
of whom he succeeded. He greatly helped Bede by sending him full
details of the conversion of Kent, “as he had learned the same from
written records and from the oral tradition of his predecessors.” Bede
sent to him the completed copy of the History, that he might have it
transcribed, and informs us that Albinus had no small knowledge of
Greek, and knew Latin as well as his native tongue, English. Alcuin
may well have taken his name of Albinus from one with whom he
had so much in common, who died only two or three years before
Alcuin’s birth.
If, on the other hand, Alcuin took the name from some foreign
source, again we have not far to seek. In Karl’s first year as King of
the Franks he gave a confirmatory charter to “the Monastery of St.
Albinus, which is built near to the walls of Angers”. The Tour St.
Aubin and the Rue St. Aubin are still to be found at Angers, at the
extreme south-east corner of the ancient city. Little is known of this
martyr Albinus, and in consequence the Acts of our St. Alban have
been transferred to him. At Angers, as at Alcuin’s own Tours, there
are remains of a great church of St. Martin; and, as was in early
times the case at Tours, the Cathedral is dedicated to St. Maurice. It
is possible that Alcuin took his name of Albinus from this local
source, but it does not seem at all probable.
Alcuin’s supremacy in wisdom and other virtues caused jealousy
among his fellow disciples. This went so far that they could not look
at him with unclouded eye or address him with pleasant words. He
consulted his master, who by this time was Elcbert (Archbishop of
York, 767-78), known to Alcuin as Aelbert, and to us as Albert. The
master advised him to try the effect of heaping coals of fire on their
heads. He followed this advice, taking care that they should never
hear from him a contrary word, and very often yielding to them when
their arguments were unsound. This course of conduct he pursued
until a complete change took place, and they all rejoiced to
acknowledge in him the second master of their studies, next under
Albert.
The Life relates at this point an interesting episode, in the
description of which we may seem to hear Alcuin himself speaking to
us:—
“Alcuin was reading the Gospel of St. John before the master, in
company of his fellow disciples. He came to a part of the Gospel
which only the pure in heart can comprehend—that part, namely,
from where John says that he lay on the Lord’s breast, down to the
point at which he relates that Jesus went with His disciples across
the brook Cedron.[19] Inebriated with the mystical reading of the
Gospel, suddenly, as he sat before the master’s couch, his spirit was
carried away in ecstasy, and by those same who once in a ray of
sunlight showed before the eyes of the most holy father Benedict the
whole world, collected as it were in an enclosure, the whole world
was now set before the eyes of Alcuin. And as he looked intently at
what he saw, he saw the whole of the enclosure surrounded by a
circle of blood. While he was held by this marvellous vision, his
fellow disciples gazed at him in wonder, for the blood seemed to
have left his face. They tried to rouse him, as one asleep; the noise
they made attracted the attention of Albert, who looked at him for
some time in silence, and then said, ‘Go on reading, my sons, do not
disturb him; if he rests awhile he will be able to follow me more
effectively when I expound the passage.’ When the reading was
completed, and Albin came to himself again, the father told them all
to go except Alcuin. When they were gone, he said, ‘What hast thou
seen? I beg thee, do not hide it.’ Alcuin wished to keep secret what
he had seen, fearing to fall into the pitfall of elation; so he said, ‘Why,
my lord father?’ The blessed man said again, ‘Do not, my son, do not
hide it from me. It is not from vain curiosity that I require this of you,
but for your own good.’ Alcuin saw that he could not keep it secret,
and he told, humbly, how he had seen the whole world. Then the
father said to him, ‘See, my son, see that thou tellest not this vision
to any but that one whom after my decease thou shalt hold to be the
most faithful to thy person. And charge him to keep it secret up to the
time of thy death.’ Acting on this counsel, he told it only to Sigulf[20]
during his lifetime. If any one desires to know how the whole world
could be seen in one enclosure, he may turn to the book of
Dialogues of the holy Gregory[21]; and in the meantime he may know
that it was not the heaven and the earth that were contracted into a
small space, but the mind of the seer that was dilated, so that when
rapt in the Lord he could without difficulty see everything that was
under God. Perhaps some one inquiring further may ask why under
this figure of an enclosure, or why surrounded by blood? He may
know that the Blood of Christ surrounds the fold of the holy Church,
so that from the rising of the sun to the setting thereof those who are
redeemed by His Passion can say the words which, without doubt,
dominated the mind of Albin when he read before the master: ‘O give
thanks unto the Lord, for He is gracious, and His mercy endureth for
ever.’[22] The whole world, then, is seen in one enclosure surrounded
by the Blood of Christ; for all that the holy fathers have done and
have written figuratively since the beginning of the world is unlocked
by the Passion of Christ alone, who is the lion of the tribe of Juda,
the root of David. But if by the encircled enclosure any should wish
to be understood the life of his own carnal crimes surrounded by
blood, thus shown to him that it may be trodden under foot by him,
let that interpretation be left to his own judgement.”
Alcuin had been tonsured in early years. He was ordained deacon
at York on the day of the Purification of the holy Mary, in or about the
year 768. Elcbert, who had been for some time in bad health, felt
that his death was drawing nigh, and he gave to Alcuin a sketch of
the course of life which he wished him to pursue. The writer gives us
a report of his actual words, stating that “they are now known”; this
means, presumably, that here also Alcuin had communicated them
to Sigulf, to be made public only after his death. They run thus:—“My
will is that you go to Rome, and on the way back visit France.[23] For
I know that you will do much good there. Christ will be the leader of
your journey, guiding you and controlling you on your arrival, that you
may demolish that most nefarious heresy which will attempt to set
forth Christ as adoptive man, and that you may be the firmest
defender and the clearest preacher of the faith in the Holy Trinity.[24]
You will persevere in the land of your peregrination, illumining the
souls of many.”
The holy father, Bishop Elcbert, after blessing him with the
benedictions of his predecessor above named, migrated to God on
the eighth day of November, 780. “The pious Albinus mourned with
tears, as for his mother, and would not take comfort. Endowed in
hereditary right with the holy benedictions of the fathers,[25] he took
pains to multiply exceedingly the talent of his lord.[26] He taught
many in Britain, and not few later in France. It was now that he
associated with him a man dear to God, remarkable for the nobility of
mind and of body, Sigulf, the presbyter, Warden of the Church of the
City of York, to remain with him perpetually.[27] Sigulf had gone as a
boy to France with his uncle Autbert the presbyter, and by him had
been taken to Rome to learn the ecclesiastical order; he had then
been sent to the city of Metz to learn chanting. There he worked hard
for some time, in great poverty, but with much profit. After the holy
man, his uncle, migrated to the Lord, he came back to his own land.”
We can almost see and hear Sigulf getting these little facts about
himself and his uncle incorporated in the Life of Alcuin.
“When the Almighty God willed to glorify France with spiritual
riches, as already with earthly riches, granting to the land a King
after His own heart, a man of faith, fortitude, love of wisdom, and
ineffable beauty of body, namely Karl, most illustrious in these
respects, He put it into the mind of Albinus that he should fulfil the
counsel and command of his father Albert, by going to Rome and
then visiting France.
“By the command of Eanbald I, the Archbishop of York, the
successor of Elcbert, he went to Rome to obtain the pallium for the
archbishop from the Apostolic—that is, Hadrian I. On his way back
with the pallium he met King Karl in the city of Parma.[28] The king
addressed him with great persuasiveness and many prayers,
begging that after completing his embassage he would come and
join him in France. The king had become acquainted with him some
years before, for Alcuin had been sent on a legation to him by the
archbishop of the time.”
We may interrupt our author’s narrative at this point to state that
the fact and the date of this former visit to Karl are recorded in the
Life of Hadrian I, as also the further fact, not here hinted at, that Karl
on that occasion sent Alcuin on to Rome. “In the year 773 Karl sent
to Hadrian an embassy, consisting of the most holy bishop George,
[29] the religious abbat Uulfhard,[30] and the king’s favourite
counsellor Albinus.”
We may now return to the author of the Life. He tells us, to quote
his own words, that when Karl begged Alcuin to come to him, Alcuin
desired to do what would be useful, and therefore asked permission
of his own king, Alfwald, and of his archbishop, Eanbald I, to leave
his mastership of the School of York. He obtained permission, but on
condition that he should in time come back to them. Under Christ’s
guidance he came to Karl. Karl embraced him as his father,[31] by
whom he had been introduced to the liberal arts, in the study of
which he could be somewhat cooled, but in his fervour he could
never be too completely saturated with them. After Alcuin had spent
some little time with him, he gave him two monasteries, that of
Bethlehem, otherwise called Ferrières,[32] and that of St. Lupus[33] of
Troyes.
CHAPTER II
Alcuin finally leaves England.—The Adoptionist heresy.—Alcuin’s retirement to
Tours.—His knowledge of secrets.—Karl and the three kings his sons.—Fire at St.
Martin’s, Tours.—References to the life of St. Martin.—Alcuin’s writings.—His
interview with the devil.—His last days.
At length Alcuin felt that he ought not, without the authority of his
own king and bishop, to desert the place in which he had been
educated, tonsured, and ordained deacon. He asked leave of the
great king to return to his fatherland. Karl received his request in a
flattering manner. We may suppose that Alcuin retained an accurate
recollection of the pleasant words and of his own answer, and
reported them eventually to Sigulf, probably with a feeling that he
had made a Yorkshire rejoinder to the king’s rather pointed balance-
sheet. On a formal occasion such as this, they probably addressed
each other as scholars, in the Latin tongue, so that in reading the
Life we seem to hear them speaking the actual words reported. The
manner of address we may take to be correctly represented.
“Karl. Illustrious master,—of earthly riches we have enough,
wherewith it is our joy to honour thee. With thy riches, long desired
by us and scarce anywhere found, we pray thee illumine us in the
wealth of thy piety.
“Alcuin. My lord king,—I am not inclined to oppose thy will, when it
shall have been confirmed by the authority of the canons. Endowed
in my paternal country with no small heritage, I am delighted to fling
it away and stand here a pauper, so that I may be of use to thee. Thy
part is only this,—to obtain for me the permission of my own king
and bishop.”
Karl was at last persuaded to let him go; but he was not satisfied
until it was settled that when Alcuin came back again he would stay
with him always.
Some years after he came back to Karl a second time, he was
placed at the head of the Monastery of St. Martin of Tours. In a godly
manner he ruled this with his other monasteries. He corrected the
lives of those under him as far as he could. Some were untamed
when they came under his rule, but he so bestirred himself that they
became reasonable, of honest morals, and seekers after truth. That
is the author’s statement. We shall hear more on the subject in the
course of our study.
“Meantime the heresy hateful to God, which flourished in the parts
of Spain, asserting that the Son of God is adoptive according to the
flesh, is brought to the ears of Karl. The great king, in all things
catholic, looked into this, and strove with all his might that the seed
of the devil should be destroyed, and the tares completely eradicated
from the wheat of God. Summoning to him Albinus his instructor
from Tours, and the wretched Felix the constructor of this heresy
from the parts of Spain, he collected a great synod of bishops in the
imperial palace of Aix. Seated himself in the midst, he ordered Felix,
who was most unwilling, to dispute in argument with the most
learned Albinus on the nature of the Son of God according to the
flesh. What silence reigned among the bishops! How clear and
unanswerable, with the authority of Karl, was the master’s
confession and defence of the faith! Felix tried to hide himself in all
sorts of obscurities; Albinus pierced him with more and more darts,
at such length that he ‘went through almost all the cities of Israel[34]
till the Son of Man should come’. Little else was done from the
second to the seventh day of the week. At length his stupidity was
laid bare to all. The heresy was confuted by the whole of the bishops
with apostolic authority. To himself alone his folly was foully hidden,
up to the point when he read with lamentable voice the words of Cyril
the martyr, turned against him by Albinus: That nature which was
corrupted by the devil is exalted above the angels by the triumph of
Christ, and is set down at the right hand of the Father. When he read
this sentence, he at last testified by voice and by excessive weeping
that he had found himself out, that he had acted impiously. Any one
who thirsts to know this more perfectly should read the master’s
letters to Felix and Elipantus, and theirs to him. He will then at once
learn what he desires to know.
“By permission of Christ,” the biographer continues, “I have up to
this point written a little about the early part of the Life of Albinus,
facts that I have supposed to be not known to all. I have not thought
of inserting in this little work facts about him which all know. From
this point I shall attempt to trace to his last days my shaken reed of a
pen, though it be with contemptible roughness.
“When he felt himself affected by old age, and increasingly by one
infirmity,[35] he informed King Karl that he wished to retire from the
world, as he had long had it in mind to do. He asked leave to live the
monastic life, in accordance with the Rule of St. Benedict, at St.
Boniface of Fulda,[36] and to distribute among his disciples the
monasteries which had been granted to him, if that might be done.
But the king, terrible and pious, with all regard for Alcuin’s request,
denied the one part, while he received the other gladly. He begged
that he would reside at Tours, in perfect quiet and in the greatest
honour, and would not refuse to continue the spiritual care of Karl
himself and of all the holy Church committed to him; the secular
burdens which he had borne, the king, at his request, most willingly
portioned out among his disciples. Albinus acted as the most wise
king had asked, seeking what would be useful, not to himself but to
many; and at Tours he awaited his last day. His manner of life was
not inferior to the monastic life which he had desired. He abounded
in fastings, in prayers, in mortification of the flesh, in almsgivings, in
much celebration of psalms and masses,[37] and in the other virtues
with which it is possible for human nature to be adorned. When he
had fasted till evening, there very frequently was sent from heaven to
his mouth such sweetness as no human speech could utter;
whatever he then willed, he could dictate most rapidly without any
effort, so that he could say,—I have loved, Lord, Thy commandments
above gold and precious stone; how sweet are thy words unto my
mouth, yea, sweeter than honey and the honeycomb. In his youth he
had not loved the study of the Psalms so much as another kind of
reading; in his old age he could never have too much of them. As
has been described in the case of his master,[38] he poured forth
most secret prayer during the day, with long extension of his hands
in the form of a cross, and with much groaning, for he very rarely
found tears. This practice he passed on to his disciples, of whom the
most noble was Sigulf, ‘the little old fellow,’ and the magnanimous
Withso[39]; after them, Fredegisus[40] and his companions. In his
latest days there clung to him assiduously Raganard and Waldramn,
who still survive; Adalbert of blessed memory, who was with him as
much as he could, being at that time the son of Sigulf, afterwards a
venerated father as Abbat of Ferrières; and many others, the names
of all of whom I trust that Christ knows. These with all circumspection
earnestly studied to do nothing in his presence with which he could
find fault, and very often in his absence too. For they knew that he
was in close communion with God, and was enlightened by His
Spirit; and though with his bodily eyes he could no longer see clearly,
from old age and infirmity, they feared that nothing which they did
escaped his knowledge.
“Filled as he was with the Spirit, he foretold to some their future,
as he did to Raganard about Osulf.[41] This Raganard had in his
sleep a horrible vision, which it is better not to describe. He told it the
next day to the father, in fear lest it referred to himself. The father
knew that it referred not to Raganard but to Osulf. With great grief he
spoke thus: ‘O Osulf, thou wretched one, how oft have I warned
thee, how oft corrected! Much labour did I devote to thine uncle, that
he should reform and begin to walk in the way of the commandments
of God; and I told him that if he did not he would be smitten with the
plague of leprosy; which thing happened to him. And to thee, my
son, I predict of Osulf, of whom is this vision, that neither in this land,
nor in the land of his birth, shall he die.’ The prediction was true; he
died in Lombardy.
“This same Raganard, unknown to everybody, tried himself by
vigils of too long duration and by an excess of abstinence; by this
intemperance he fell into a most dangerous fever. Father Albinus
came to visit him, and sent out of the house all except Sigulf. Then
he rebuked Raganard thus: ‘Why hast thou tried to act so
intemperately, without advice of any? I knew that thou didst wish to
act thus, and therefore it was that I ordered thee to sleep in the
dwelling in which I sleep. But thou didst immediately, when all were
asleep, secretly light a candle, conceal it in a lantern, and going to
that place didst watch through the whole night.’ And then all that he
did there secretly, known to God alone, he told him of, and added:
—‘When thou didst go with me to the refectory, and I bade thee drink
wine, in the most crafty way thou didst say—I have drunk sufficiently,
my lord father, with my uncle. But when thou didst come to thy uncle,
and he too bade thee drink wine, thou didst say thou hadst drunk
with me. Thy will was to delude us, and thou art deceived. When
thou hast risen up from the fever, take thou care never to attempt
anything of this kind again.’
“When Raganard heard this, he turned red, and was in great fear,
knowing that he was caught. In wonder that his secret deeds could
not escape the knowledge of Albinus, he asked how was this made
known. To this day he bears witness that no man knew it before it
was revealed; God alone. He repented, and for the rest of Alcuin’s
life he never attempted anything of the kind without his advice and
command.
“It very often happened that when messengers were coming to
Alcuin from the king and other friends, while they were yet a long
way off, he would tell of their coming and of the cause of their
coming, what they brought with them, what they wished to take back.
Certain disciples, when they heard him speak thus, set it down to the
folly of an old man, till it was proved to be true. Benedict[42], the man
of the Lord, who beyond all monks was bound in intimacy with
Alcuin, used often to come to him from the parts of Gothia, to obtain
advice for himself and his monks. On one occasion Benedict wished
to come secretly, unknown to any one at Tours, so that Alcuin should
not know till he stood in the doorway. When he was by no means
near Tours, Albinus summoned an attendant, and said to him,
‘Hasten to meet Benedict in such and such a place, and tell him to
come to me quickly.’ The messenger did as he was told, and on the
third day arrived at the place, found Benedict there, and delivered his
message. Astonished that his plan was discovered, Benedict went
with all haste to Tours. When they had joyously kissed one another,
Benedict, the reverend father, began suppliantly, ‘Lord father, who
foretold to thee my arrival?’ He answered, ‘No man told me by word
of mouth.’ Benedict asked again, ‘Who then, my lord? Perhaps thou
hast heard in a letter from some one?’ He replied, ‘Of a truth, not in a
letter.’ Again Benedict asked, ‘If neither from the words of any man,
nor from any man’s letter, thou knewest this beforehand, pray, my
father, in what way didst thou know it?—tell me.’ Albinus said, ‘Do
not interrogate me further on this.’ There the matter ended. When
the venerable man Benedict was minded to return, he asked Albinus
to tell him in what special words he prayed, when he prayed for
himself. Albinus said, ‘This is what I ask of Christ:—Lord, grant me to
understand my sins, and to make true confession, and to do fitting
penance; and grant unto me remission of my sins.’ The godly man
Benedict said, ‘Let us add, my father, to this thy prayer, one word,
namely this, after remission, save me.’ Albinus rejoiced, and said,
‘Let it be so, most reverent son, let it be so.’ Benedict then asked
another question, would he tell him what were the words that silently
moved his lips when he saw the Cross and bent before it? Albinus
answered, ‘Thy Cross we adore, O Lord; Thy glorious Passion we
recall. Have mercy on us, Thou Who didst die for us.’ Albinus then
saw him on his way for a short distance, and sent him back rejoicing
to his own place and people.”
The biographer next sets before us a remarkable picture of the
four most important personages of the time.
“The great king and powerful emperor Karl, wishing to offer prayer
and to have some mutually desired conversation with Alcuin, paid a
visit to the tomb of the holy Martin at Tours, with his sons Charles,
Pepin, and Louis. The emperor took Alcuin by the hand, and said to
him privately, ‘My lord master, which of these sons of mine does it
seem to thee that I shall have as my successor in this honour to
which God has raised me, all unworthy?’ Alcuin turned his face
towards Louis, the youngest of the three, and the most remarkable
for his humility, on account of which he was regarded by many as of
little account, and said, ‘In the humble Louis thou shalt have an
illustrious successor.’ The emperor alone heard what he said. But
when, later on, sitting on the spot where he wished to be buried,
Alcuin saw these same three kings[43] enter the Church of St.
Stephen for prayer, with head erect, and Louis with head bent, he
said to those who stood by—‘Do you see that Louis is more humble
than his brothers? You will most certainly see him the most exalted
successor of his father.’ When with his own hand he administered to
them the Communion of the Body of Christ and the Blood, the same
Louis, most noted above all for humility, bent before the holy father
and kissed his hand.[44] The man of the Lord said to Sigulf who
stood by, ‘Whosoever exalteth himself shall be abased, and he that
humbleth himself shall be exalted. Certainly the Frankish land shall
rejoice to have this man emperor after his father.’ That this has taken
place, the biographer adds, we both see and rejoice.[45] They who
seemed to be cedars are cast down, and the fruitful olive tree in the
house of God is exalted.[46]
“The father Alcuin had with great care instructed Karl in liberal arts
and in divine scripture, so that he became the most learned of all
kings of the Franks who have been since the coming of Christ. He
taught him, also, which of the Psalms he should sing throughout his
whole life for various occasions; for times of penitence, with litany
and entreaties and prayers; for times of special prayer; of praising
God; of any tribulation; and for his being moved to exercise himself
in divine praise. Any one who wishes to know all this may read it in
the little book which he wrote to Karl on the principles of prayer.”[47]
At this point in his narrative the biographer relates the scrape into
which “the little old fellow” got in connexion with his secret study of
Vergil, already described on page 2. As a further instance of Alcuin’s
remarkable knowledge of what was going on, he adds the interesting
little story about a present of wine to Cormery which will be found on
p. 223. Then comes the following amusing account, with its
revelation of a dislike of Karl’s favourites the foreigners, a dislike
which Eginhard thus frankly reports in his vivid picture of the great
King,[48] “He loved foreigners, and took great pains to attract them to
him and to maintain them, so much so that the multitude of them not
unreasonably seemed a heavy burden, not to the palace only but to
the kingdom. His greatness of mind, however, was such, that he was
not troubled by a burden of this kind; indeed even great
inconveniences he regarded as compensated by the praise won by
liberality and by the reward of good report.”
This is the story. The presbyter Aigulf[49], an Anglo-Saxon[50]
himself too, came to Tours to visit the father. When he was standing
at the door of Alcuin’s dwelling, there happened to be four of the
brethren of Tours talking together. When they saw him, they said one
to another, not imagining that he knew anything of their language,
“Here’s a Briton, or a Scot[51], come to see that other Briton inside. O
God, deliver this monastery from these Britons! Like bees coming
back to the mother-bee, these all come to this man of ours!” What
would we not give to have this in the words in which they spoke it,
instead of in the author’s Latin. The presbyter went into Alcuin’s
dwelling, and, after other matters, told him what he had heard. “Do
you know which they are?” Alcuin asked. “Indeed I do not. I could not
for shame look at them when they said that.” Alcuin said, “I am sure I
know who they are.” He called in some of the brethren by name, and
said, “These are they.” Greatly grieved by their folly, Alcuin yet
spared them, saying, “May Christ, the Son of God, spare them.”
Then he gave them each a cup of wine to drink, and without severity
sent them away. Aigulf afterwards made diligent inquiry, and found
that they were the right men. We of to-day may remark that Alcuin
evidently knew the characters of his pupils; but his ideas of discipline
differed from ours. We should not have let them know that we had
heard personal remarks of that kind; and we should not have given
them glasses of wine. We may remember the words of Archbishop
Temple to Bishop Creighton, when the Bishop had received the late
Mr. John Kensit for an interview at Fulham, and had given him tea. “It
was all right to receive the man; but you shouldn’t ha’ given him tea.”
As we have seen, the biographer on the whole confines himself to
those parts of Alcuin’s Life which were not of common knowledge.
But there was one story of sufficient importance in his judgement to
be related at length, although it was well known. We may well take
the same view, and be grateful to our author for having departed
from his self-imposed limitations.
“I ought not”, he writes, “to pass over in silence one fact which
many know. The Keeper of the Sepulchre of St. Martin, who provided
the wax and all the vestments which pertained to the basilica itself,
entering with a lighted candle the sacristy where they were kept,
fixed the candle on a spike, and when he left he forgot to take it with
him. He locked the door and went away. The burning candle fell
upon some wax and sent a great flame which set fire to the
vestments hanging on the pegs; and the vestments sent the flame
up to the roof.[52] When the warden saw this, he fled with the key to
another monastery.[53] People rushed from all sides; they beat at the
door, but all their efforts failed to burst it open. The clerks threw out
of the windows any valuables they had in their abode. The Church of
St. Martin was denuded of some vestments, and no one expected
anything but the burning of the whole monastery. The roof was all
stripped of lead. Albinus came; he was now blind. He asked what
was being done. One of his disciples, his ‘little old fellow’, said,
‘Come away, father, or you will be killed by the lead they are
throwing down or burned to death.’ When Albinus was willing to go,
Vetulus said to him, ‘My lord father, go to the sepulchre of the lord
Martin, and intercede for us.’ Albinus did as was suggested, and
when he got to the place, he stretched himself on the ground in the
form of a cross, and uttered groans heavenward. As soon as Albinus
cast himself on the ground, in some wonderful and incredible way
the whole fire was put out, as completely as if extinguished by a
great river. When the clerks saw this, they rushed in joyous
stupefaction to the spot where Albinus lay prostrate before the
sepulchre of St. Martin, in the form of a cross, praying to God for
them. They raised him from the ground, blessing God who through
the prayers of Albinus had saved the whole monastery of Saint
Martin from being consumed by fire. These be thy worthy examples,
holy Martin, who once when thou wouldest escape the fire couldest
not; turned to God in prayer thou hast extinguished this fire that
threatened us. Lofty of a truth is the faith that by its ardour can
extinguish globes of fire. Nor is it a matter of wonder that the
elements leave their proper force at the prayers and commands of
Albinus, since he rests in the heart of Him who loves them that love
Him, and permits them not to be singed by the flame when they walk
in fire. Thee in these we adore, Thee we glorify, Thee we laud, who,
as Thou hast deigned to make promises to Thy servants who keep
Thy commandments, hast shown them forth most clearly by Thy
works in Thine own Albinus. Thou hast said, O Christ Jesus,
whatsoever ye shall ask of Me in My name, that will I do, that the
Father may be glorified in the Son.”
It will have been noticed that this passage from the Life attributes
to St. Martin a failure to prevent the progress of a fire. The reference
appears at first sight to be to the eleventh chapter of the Life of St.
Martin by Sulpicius Severus[54], written some four hundred years
before the fire here described, and published in the lifetime of St.
Martin, whom Severus had visited at Tours for the special purpose of
learning the facts of his life.
“In a certain town, Martin set fire to a very ancient and famous
pagan shrine. A house was attached to the walls of the temple, and
the wind blew the globes of fire on to this house. When Martin saw
this, he climbed rapidly to the roof of the house, and faced the
flames. Then you would see the flame turn back in a marvellous
manner against the force of the wind, the two elements fighting the
one against the other. Thus by the virtue of Martin the fire operated
only where it was bidden.”
This is the only account in the Life of St. Martin to which the
remark in the text could apply. But, as a matter of fact, the occasion
referred to was quite different from this. The little story is an
interesting example of the keenness of criticism in those very early
times, and of the need of immediate corrections.
The contemporary readers of the Life were well aware of the fact
that Martin himself was once half-burned. Knowing this, they
fastened on the passage quoted, and spoke in a depreciatory way of
Martin. They asked how could he be so great as to prevent houses
being burned, if he was not great enough to prevent himself from
being set on fire and nearly burned to death. These depreciatory
remarks came to the ears of Sulpicius, and the very next day[55], he
sat down and wrote a letter to the presbyter Eusebius, to tell the
actual facts of the other story with which unfavourable comparison
has been made. The facts were as follows:—
The saint was visiting his diocese in midwinter. A bed had been
prepared for him in a vestry, which was warmed by a fire below the
floor. The pavement was rough and dilapidated. They had made for
the saint a specially soft and comfortable bed of straw, but his
practice was to sleep on the bare ground. Not being able to endure
the blandient comfort of the straw, he threw it away and slept on the
ground. By midnight the fire below had got at the straw through the
crevices in the pavement, and Martin awoke to find the vestry full of
fire. Then came, as he told Sulpicius, the temptation of the devil.
Martin tried to escape, instead of turning to prayer. He rushed to the
door and struggled with the bolt, in vain. The flames caught his dress
and set it on fire. He fell down, and then remembered to pray. The
flames felt the change and spared him. The monks, who had heard
the fire crackling and roaring, burst open the door and looked for his
dead body; they found him safe and sound. He confessed to
Sulpicius, not without groaning, that the devil had for the time
overcome him. In these modern times, to lie down on the floor is a
common precaution against being smothered by the smoke in a
burning room.
This Life of St. Martin is very interesting reading. It is too tempting
to give the substance of the chapter previous to the one given
above. The saint was at his usual work of destroying a very ancient
temple. When he had accomplished this, he set to work to fell a pine-
tree which stood near. The chief priest and the pagan crowd drew
the line at that, and would not allow it. Martin told them there was
nothing worthy of worship in a piece of wood; it was dedicated to a
demon and it must come down. Thereupon a crafty pagan, seeing
his way to getting rid of this objectionable destroyer of temples, and
regarding the sacred tree as well lost for such a gain, proposed a
bargain. “If you have sufficient confidence in your God whom you
say you serve, we will ourselves cut down the tree, and it shall fall
upon you; if your Lord is with you, as you say, you will escape with
your life.” The bargain was struck on both sides. The tree leaned in a
certain direction, so that there was no doubt where it would fall.
Martin was tied by the rustics in the right place, and they began to
cut with their axes. The tree began to nod, leaned more and more to
the precise spot they had selected. At last they had cut deep
enough; the crash of the rending trunk was heard; the monks turned
pale; the saint raised his hand and made the sign of the cross; at the
moment a whirlwind came and blew the tree far to one side.
We must now return to the life of St. Martin’s faithful follower,
Alcuin.
“This also must be mentioned to the praise of the Lord, that very
frequently many infirm people, when they came to Albinus and
received his benediction with faith, recovered bodily health. On a
certain occasion, as is reported by some of the chief authorities, a
poor man came, having his eyesight obstructed by a grievous
dimness. He reached the door of the outer dwelling of Albinus, and
begged that water be given him with which his eyes might be bathed;
for he said it had been revealed to him that if he could wash his eyes
with some of it he would recover his sight.[56] Unknown to Albinus,
some of the water in which he had washed his own face and eyes
was secretly given to the poor man who begged for water. The poor
man bathed his eyes with the water, in full faith; the dimness
disappeared, and he recovered his clearness of sight. We, too, are
enlightened by thy sweat, father, and the sins of our souls are
washed by thy pious doctrine. Thou, too, didst scarce see anything
with thy bodily sight, but wast always engaged in lightening the eyes
of others; and those whom thou couldest not enlighten in bodily
presence thou didst in absence instruct by letters, writing many
things profitable to the whole church.
“For at the request of Karl he wrote a most useful book on the Holy
Trinity; also on rhetoric, dialectic, and music. He wrote to Gundrad
on the nature of the soul. At the most honourable request of the
ladies Gisla and Rotruda, he composed a remarkable book on the
Gospel of St. John, partly his own and partly taken from the holy
Augustine. He wrote also on four Epistles of Paul, to the Ephesians,
to Titus, to Philemon, and to the Hebrews;[57] to Fredegisus on the
Psalms;[58] to Count Wido[59] homilies on the principal vices and
virtues; to his own Sigulf very useful notes on Genesis; on the
Proverbs of Solomon, on Ecclesiastes, on the Song of Songs clearly,
briefly, indescribably. Under the names Frank and Saxon[60] he wrote
a most able book on grammar in the form of question and answer.
He collected two volumes of homilies from many works of the
Fathers. He wrote on orthography. On the 118th Psalm (our 119th)
he wrote with a pen of gold. There are many other writings in which
any one who reads and studies them attentively will find no small
edification, as in the letters which he wrote to many persons. In
these and like works he spent the remainder of his days, living on
earth the life of heaven. Preparing himself in his latest days for the
coming of the Son of Man, that he might go in with Him to the
wedding, he washed every night his couch with tears,[61] always
fortifying himself with the intercessions of the saints, whose
solemnities he regularly celebrated, lest he should be pierced by any
darts of the ancient enemy, who never could steal into his dwelling
so secretly as not to be at once detected by him and driven out by
the sign of the Cross.
“On a certain night, when he desired to pour forth prayer in secret
after his wont, with chanting of Psalms, he was oppressed by very
heavy sleep. But he rose from his couch, and put on his cape; and
when again he was oppressed with sleep, he took off all his clothes
except his shirt and drawers. The sleepiness continuing, he took a
censer, and going to the place where fire was kept burning, he filled
it with live coal and put incense on it, and a sweet odour filled the
chamber. In that hour the devil presented himself to him in bodily
form, as it were a large man, very black and misshapen and
bearded, hurling at him darts of blasphemy. ‘Why dost thou act the
hypocrite, Alcuin?’[62] he asked. ‘Why dost thou attempt to appear
just before men, when thou art a deceiver and a great dissimulator?
Dost thou suppose that for these feignings of thine Christ can hold
thee to be acceptable?’ But the soldier of Christ, invincible, standing
with David in the tower[63] builded for an armoury, wherein there
hang a thousand bucklers, all shields of mighty men, said with a
heavenly voice, ‘The Lord is my light and my salvation; whom then
shall I fear? He is the strength of my life; of whom then shall I be

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Textbook of Diabetes 6E April 1 202 - 1119697425 - Wiley Blackwell Richard I G Holt Full Chapter

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Textbook of Diabetes, 6e (April 1,

RICHARD I.G. HOLT MA, MB BChir, PhD, FRCP, FHEA

ALLAN FLYVBJERG MD, DMSc

Limit of Liability/Disclaimer of Warranty

Library of Congress Cataloging-in-Publication Data

Names: Holt, Richard I. G., editor. |Flyvbjerg, Allan, editor.

Cover Design: Wiley

Set in 9.25/11pt MinionPro by Straive, Pondicherry, India

List of Contributors, viii Part 3 Pathogenesis of Diabetes

6 Overview of Glucose Metabolism, 77

Part 5 Managing the Person with Diabetes 44 Diabetic Nephropathy, 640

34 Whole Pancreas and Islet Cell Transplantation, 473

Part 10 Psychosocial Aspects of Diabetes 72 Diabetes in Old Age, 1072

Part 11 Diabetes in Special Groups Part 13 Future Directions

Ahmed H. Abdelhafiz Angelo Avogaro David Beran

Kimberly M. Alonge Katharine D. Barnard-­Kelly

Frank L. Bowling Mikkel Christensen Stefano Del Prato

Hannah Forde Andrew T. Hattersley University Autònoma de Barcelona

Olga Kordonouri Andrea O.Y. Luk David R. Matthews

Rayaz A. Malik Viswanathan Mohan

Jakob A. Østergaard Dimitri J. Pournaras Michael Roden

Kitt Falk Petersen

Charles D. Ponte Nicole E. Richardson A.M. James Shapiro

Jonathan E. Shaw Jane Speight Second Medical Department, Aristotle University of

Robert B. Tattersall Roman Vangoitsenhoven

Tina Vilsbøll Morris F. White Kirsty Winkley

AACE American Association of Clinical Endocrinologists CML carboxymethyllysine

GDF growth differentiation factor LV left ventricular

PI3K phosphatidylinositol 3-­kinase SGA second-­generation antipsychotics

Diseases with the cardinal features of diabetes mellitus were

Table 1.1 Milestones in the clinical descriptions of diabetes and its

Hyperlipidaemia Seventeenth and eighteenth centuries

Retinopathy In Europe, diabetes was neglected until Thomas Willis (1621–1675)

Diabetes is a dreadful affliction, not very frequent among

Table 1.2 Milestones in the scientific understanding of diabetes

Matthew Dobson (England, 1776) Diabetic serum contains sugar

Figure 1.5 Claude Bernard (1813–1878). Source: Courtesy of the Wellcome

of diabetic retinopathy, in his beautiful Atlas of Diseases of the

Figure 1.8 Pictures from Jaeger’s Atlas of the

Figure 1.11 The discoverers of insulin. (a) Frederick G.

Causes and natural history of diabetes

i­nsulin insensitive, or insulin resistant. The former were usually

In 1907, M.A. Lane, a student of Robert Bensley (1867–1956),

Table 1.4 Selected milestones in the management of diabetes.

Figure 1.16 Solomon Berson and Rosalyn Yalow. Insulin treatment

Table 1.4 (Continued)

Diabetes Control and Complications Proved that improved glycaemic

Figure 1.18 Dan Drucker, Joel Habener, and Jens Juel

­ uring the early 1940s on the glucose-­lowering action of a sulfona-

­ lockade of the renin-­angiotensin system may be particularly

The introduction of insulin was only one aspect of the management

natural to wonder whether tackling them simultaneously (multiple Diabetes in pregnancy

Albert [Translation of Ophthalmoskopischer 32 Tattersall, R.B. (1974). Q. J. Med. 43: 339–357.

Diabetes is one of the most common metabolic diseases with a

Table 2.3 Classification of diabetes.

Type of diabetes Brief description

10 (1997). Report of the Expert Committee on 24 International Diabetes Federation (2019).

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Kimberly M. Alonge Katharine D. Barnard-Kelly

PI3K phosphatidylinositol 3-kinase SGA second-generation antipsychotics

insulin insensitive, or insulin resistant. The former were usually

uring the early 1940s on the glucose-lowering action of a sulfona-

lockade of the renin-angiotensin system may be particularly