VASCULAR COMPLICATIONS OF DIABETES - PART 1 ppt

First published 2002 Second Edition 2005 Library of Congress Cataloging-in-Publication Data Vascular complications of diabetes: current issues in pathogenesis and treatment / edited by R

VASCULAR COMPLICATIONS OF DIABETES

CURRENT ISSUES IN PATHOGENESIS AND TREATMENT

Division of Vascular Medicine University of Nottingham The Medical School

Derby DE22 3DT UK

One Joslin Place Boston MA 02215 USA

VASCULAR COMPLICATIONS OF DIABETES

CURRENT ISSUES IN PATHOGENESIS AND TREATMENT

SECOND EDITION

Division of Vascular Medicine University of Nottingham The Medical School

Derby DE22 3DT UK

One Joslin Place Boston MA 02215 USA

Supported by an Educational Grant by Eli Lilly & Co

Answers That Matter.

© 2005 by Blackwell Publishing Ltd

Blackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USA

Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK

Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia

The right of the Author to be identified as the Author of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988.

All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or other- wise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior per- mission of the publisher.

First published 2002

Second Edition 2005

Library of Congress Cataloging-in-Publication Data

Vascular complications of diabetes: current issues in pathogenesis and

treatment / edited by Richard Donnelly and Ed Horton. 2nd ed.

p ; cm.

Includes bibliographical references and index.

ISBN-13: 978-1-4051-2785-1 (alk paper)

ISBN-10: 1-4051-2785-6 (alk paper)

1 Diabetic angiopathies.

[DNLM: 1 Diabetes Complications 2 Diabetic Retinopathy etiology.

3 Protein Kinase C adverse effects 4 Vascular Diseases etiology.

WK 835 V3305 2005] I Donnelly, Richard, 1960- II Horton, Edward S

A catalogue record for this title is available from the British Library

Set in Branding Serif and Branding Sans

Design and layout by Designers Collective

Printed and bound in the USA by Walsworth Publishing Co., Marceline, Missouri

Commissioning Editor: Alison Brown

Development Editor: Claire Bonnett

Production Controller: Kate Charman

For further information on Blackwell Publishing, visit our website:

http://www.blackwellpublishing.com

The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards

SECTION II DIABETIC NEUROPATHIES

Chapter 8 Classification and clinical features of neuropathy 79

iv

Chapter 13 Treatments options 113

Rayaz A Malik

Chapter 14 Management guidelines for diabetic peripheral

neuropathy and foot ulceration 121

Chapter 23 Role of protein kinase C activation in cardiovascular

and renal complications of diabetes 205

Richard Donnelly

Chapter 24 Experimental pharmacology using isoform-selective

protein kinase C inhibitors 213

Richard Donnelly

Chapter 25 Clinical trials with ruboxistaurin 221

Richard Donnelly

Index 226

Richard DonnellyMD, PhD, FRCP, FRACP

Professor of Vascular Medicine

University of Nottingham

and Honorary Consultant Physician

The Medical School

Derby, UK

Rayaz A MalikMB.ChB, PhD, MRCP

Senior Lecturer and Consultant Physician

Academic Department of Medicine

Manchester Royal Infirmary

Diabetes-related cardiovascular complications often cause premature ity, as well as disabilities such as blindness, foot ulceration and amputation.The health care and social care costs of managing these complications areenormous, but new treatments, devices and clinical management protocolsare steadily improving the longer term outcomes for people with diabetes.This second edition has been revised and updated to reflect state of the artclinical practice In particular, a new section on diabetic neuropathy coversimportant aspects of screening and detection, diagnosis and management.The book is aimed at healthcare professionals involved in the assessment andsurveillance of patients with diabetes complications, and the section on pro-tein kinase C (PKC) explains the basis of a major new pathway responsible forhyperglycaemia-induced vascular injury Recent clinical trials have suggestedthat inhibition of PKC-β is an effective therapeutic intervention for improv-ing the symptoms and outcomes from diabetes-related complications.

mortal-Richard Donnelly

vi

PREFACE

SECTION I

MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES

Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition

Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd

The 21stcentury will see diabetes emerge as the world’s commonest chronic

disease Whilst the bulk of this will be type 2 diabetes (90%) the incidence has

been rising in both types

The direct and indirect costs of diabetes and its complications, plus the

associated reduction in quality and quantity of life, will have considerable

economic consequences This effect will be most noticeable in developing

countries which are going to see a disproportionate increase in the prevalence

of diabetes over the next few decades It has been estimated that the

world-wide prevalence of diabetes will double between 1990 and 2010

Epidemiological studies in the USA have shown that the number of people

with known diabetes has increased from around 1.5 million in 1958 to 10.5

mil-lion in 1998 Most states in the US report a prevalence of over 8% and this fails

to take into account those people with undiagnosed diabetes Most screening

studies indicate that at least 50% of people found to have diabetes were

silent-ly undiagnosed for sometime

THE NATURAL HISTORY OF TYPE 1 DIABETES

Although onset is predominantly in childhood or young adulthood, a

signif-icant proportion will be diagnosed over the age of 30 years The peak ages for

onset, however, are around puberty and between 4–6 years old Life

expectan-cy is reduced, though there is some evidence that this is improving

The British Diabetic Association Cohort study (1972–1993), a prospective

follow-up of insulin-treated patients with diabetes diagnosed under the age of

30, showed increased mortality at all ages Avoidable metabolic complications

such as hypoglycaemia and diabetic ketoacidosis accounted for most of the

excess mortality among those under 30 years but after 20 years of diabetes the

impact of atherosclerotic macrovascular complications steadily increases The

prognosis is particularly disturbing for children diagnosed with type 1

dia-betes under the age of 10 years; previous reports have indicated that 60% were

dead within 40 years of diagnosis With increasing duration of diabetes, the

prevalence of retinopathy, nephropathy and neuropathy is highest in those

with poor glycaemic control and lowest in those with good control The

Diabetes Control and Complications Trial (DCCT 1995) established quite

clearly that good glycaemic control in type 1 diabetes can reduce the incidence

and progression of microvascular complications but the risk of a vascular

event increases with duration of diabetes and the presence of nephropathy

Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition

Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd

SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES

4

The DCCT was under-powered, and the patients too young, to be sure ifimproved glycaemia reduced the risk of macrovascular complications, how-ever, the trend was for good control to be associated with a reduction in vas-cular events

EPIDEMIOLOGY OF TYPE 1 DIABETES

The worldwide variation in incidence is considerable though the pattern ofpresentation is similar The incidence is showing signs of increasing at all agesbut most noticeably in the under 5s In under 16s, Northern Europe (Finland,Scotland, Sweden) has the highest rates with up to 30–35 cases per 100,000 ofthe population aged <16 years per year Japan, China and Korea have ratesthat are as low as 0.5–2 cases per 100,000 per year It is tempting to think thatthis is due mainly to genetic differences but there are different incidences ingenetically similar countries such as Norway and Iceland, suggesting thatenvironmental factors have a very significant influence Whilst the patho-physiology of islet cell destruction has been well defined, the trigger for thisprocess remains uncertain Despite the relatively sudden onset of symptoms,family studies have shown there is a long prodromal period of immune acti-vation Viruses and cow’s milk protein are currently the main contenders thatmay initiate this process in the genetically susceptible

THE NATURAL HISTORY OF TYPE 2 DIABETES

People with type 2 diabetes often have established complications at the time ofdiagnosis In the UK Prospective Diabetes Study (UKPDS), for example, 36% ofnewly diagnosed patients had retinopathy, 12% neuropathy and 2% proteinuria

at recruitment This may well be an underestimate, because in UKPDS patientswith established vascular disease or retinopathy requiring laser therapy wereexcluded Using prospective studies which have studied the rate of progression

of retinopathy, it is estimated that at diagnosis of type 2 diabetes patients willlikely have had their diabetes for between 8 and 12 years and, prior to diabetes,impaired glucose tolerance for very much longer Death from ischaemic heartdisease, stroke or lower extremity ischaemia occurs in over 60% of patients

EPIDEMIOLOGY OF TYPE 2 DIABETES

Although there is good evidence that type 2 diabetes is a heterogeneous dition with a number of genetic sub-groups, the current view supports theidea that for the majority of people this is a metabolic disorder in the geneti-cally susceptible, precipitated by lifestyle changes which have led to a seden-tary lifestyle and obesity Essentially it is a failure of adaptation to a new envi-ronment which has changed in the course of a few generations Elliot Joslin

con-CHAPTER 1 • THE PUBLIC HEALTH IMPACT OF THE DIABETES EPIDEMIC

went to study the Pima Indians at the start of the 20thcentury because of theirlow prevalence of diabetes By the end of the century they ranked alongsidethe Pacific Micronesians from Nauru for having the highest prevalence oftype 2 diabetes in the world

The ‘thrifty gene’ hypothesis postulates that humans evolving in a harshenvironment, where famine and high physical activity was the norm, may havedeveloped fuel efficient systems, which, when faced with limitless supplies offood and a sedentary lifestyle, leads to the metabolic disturbances now charac-terized as the Metabolic Syndrome (central obesity, hypertension, hyperlipi-daemia and glucose intolerance) Underlying this is insulin resistance, whichpartly relates to fat distribution – the greater the proportion of intra-abdomi-nal fat compared to the total, the greater the degree of insulin resistance Thedistribution of fat deposition is genetically determined and there is evidencethat there are ethnic differences in body composition This may explain insulinsensitivity studies which, despite matching for age and BMI, demonstrate sig-nificant differences between ethnic groups BMI tables have been based on theweights and heights of white Europeans and recent studies from India andNew Zealand suggest they are not applicable to all ethnic groups For example,

in Indian populations it is suggested that accumulation of intra-abdominal fatbegins at a BMI of around 23 and this (rather than 25 in white populations)should be the cut-off between ‘normal’ and ‘overweight’ In part, this mayexplain the wide variation in prevalence of type 2 diabetes across the world.Nauruans and Pimas have already been mentioned, but other high risk groupsinclude South Indians, Polynesians, Maori of New Zealand, native AmericanIndians, Mexican Americans and African Americans, all of whom have a high-

er prevalence of diabetes than Whites This is despite the epidemic of obesitywhich affects all ethnic groups in the developed world Recent work hasdemonstrated defective mitochondrial function in the muscles of relatives ofpeople with type 2 diabetes, though whether this is present in all ethnic groupshas yet to be determined There is also an inverse relationship with poverty,but this is insufficient to explain all the population differences in prevalence Unlike infections or cancer which are either present or not, the prevalence

of metabolic disturbances depends very much on the definition, which maychange over time This has certainly been true for the diagnosis of type 2 dia-betes and the associated metabolic syndrome, where the dilemma has been toproduce a workable definition that could be applied to large groups of people,

in order to distinguish those at high risk of complications (Fig 1.1) Recently,

abnormalities of glucose tolerance have been re-defined by the American

Diabetes Association (ADA) and World Health Organisation (WHO) (Table

1.1) and for diabetes the diagnostic cut-off for fasting plasma glucose (FPG) has

been lowered from 7.8 to 7 mmol/l For epidemiological studies and for routine

5

SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES

6

clinical practice the ADA recommended using fasting glucose testing alone, andthe use of the two hour oral glucose tolerance test (OGTT) was not recom-mended Subsequent investigations have shown that fasting and two hour glu-cose criteria do not identify the same group of individuals The DECODEstudy, which combined the results of 13 prevalence studies in nine Europeancountries, found that there was a distinct sex difference in the prevalence of dia-betes, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).Undiagnosed diabetes and IFG were more common in men than in women at30–69 years of age IGT was higher in women than in men and was particular-

ly high in the over 70s In the USA, the NHANES III study (2000), confirmedthat diagnosed diabetes is most prevalent in the middle-aged (6%) and elderly

(11%) compared to only 1.5% of 18–44 year olds (Fig 1.1) The incidence is

increasing in childhood and is related to obesity

Table 1.1 Criteria for the diagnosis of diabetes mellitus (WHO classification 1999).

Note that the American Diabetes Association defines IFG as FPG 5.6–6.9 mmol/l People with IFG and IGT are considered to have “pre-diabetes” An OGTT (75 g) may

be indicated in people with IFG if considered at high risk of diabetes

Criteria for the diagnosis of diabetes mellitus

Plasma venous glucose concentration (mmol/l)

Diabetes Mellitus:

2 hr post glucose load >11.1

Impaired Glucose Tolerance (IGT):

Fasting (if measured) and <7.0 and

2 hr post glucose load >7.8

Impaired Fasting Glycaemia (IFG):

And (if measured)

2 hr post glucose load <7.8

Normal Fasting Plasma Glucose (FPG) < 5.6

For epidemiological or population screening purposes, the fasting or 2hr value after 75g oral glucose may be used alone For clinical purposes, the diagnosis of diabetes should always be confirmed by repeating the test on another day unless there is unequivocal hyperglycaemia with acute metabolic decompensation or obvious symptoms