Diabetes Treatments

D McCarty, International Diabetes Institute, Caulfield, Australia A Ramachandran, Diabetes Research Centre, both WHO (1) and the National Diabetes …

WHO/NCD/NCS/992 Original: English Distr: General

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications
Report of a WHO Consultation

Part 1: Diagnosis and Classification of Diabetes Mellitus

World Health Organization Department of Noncommunicable Disease Surveillance Geneva

World Health Organization 1999 This document is not a formal publication of the World Health Organization WHO, and all rights are reserved by the Organization The document may, however, be freely reviewed, abstracted, reproduced and translated, in part or in whole, but not for sale nor for use in conjunction with commercial purposes The views expressed in documents by named authors are solely the responsibility of those authors

Contents
1 Introduction 2 Definition and diagnostic criteria for diabetes mellitus and other categories of glucose intolerance 21 Definition 22 Diagnosis and diagnostic criteria 221 Diagnosis 222 Diabetes in children 23 Diagnostic criteria 231 Change in diagnostic value for fasting plasma/blood glucose concentrations 232 Epidemiological studies 233 Individual diagnosis 3 Classification 31 Earlier classifications 32 Revised classification 321 Application
of the new classification 33 Terminology Table 2 4 Clinical staging of diabetes mellitus and other categories of glucose tolerance Figure 2 41 Diabetes mellitus 42 Impaired glucose regulation - Impaired Glucose Tolerance and Impaired Fasting Glycaemia 43 Normoglycaemia 5 Aetiological types see also section 7 and Table 2 51 Type 1 52 Type 2 53 Other specific types Table 3 6 Gestational Hyperglycaemia and Diabetes 61 Diagnosis of gestational diabetes 1 2 2 3 3 4 4 5 6 7 8 8 9 9 11 14 14 14 16 17 17 18 18 19 20

7 Description of aetiological types 71 Type 1 beta-cell destruction, usually leading to absolute insulin deficiency 711 Autoimmune Diabetes Mellitus 712 Idiopathic 72 Type 2 predominantly insulin resistance with relative insulin deficiency or predominantly an insulin secretory defect with/without insulin resistance 73 Other Specific Types 731 Genetic defects of beta-cell function 732 Genetic defects in insulin action 733 Diseases of the exocrine pancreas 734 Endocrinopathies 735 Drug- or chemical-induced diabetes 736 Infections 737 Uncommon but specific forms of immune-mediated diabetes mellitus 738 Other genetic syndromes sometimes associated with diabetes 8 The Metabolic
Syndrome 81 Definition 82 Future needs References Annex 1 The Oral Glucose Tolerance Test Annex 2 Methods for measuring substances in blood and urine

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23 25 25 26 27 27 28 28 29 30 31 32 33 34 48 49

Members
KGMM Alberti, University of Newcastle upon Tyne, UK Co Chairman P Aschner, ACD and Javerlana University, Bogota, Colombia JP Assal, University Hospital, Geneva, Switzerland PH Bennett, NIDDK, Phoenix, AZ, USA L Groop, University of Lund, Malmö, Sweden J Jervell, Rikshospitalet, Oslo, Norway Y Kanazawa, Jichi Medical School, Omiya, Japan H Keen, Guys Hospital and Medical School, London, UK R Klein, University of Wisconsin Medical School, Madison, WI, USA JC Mbanya, Centre Hospitalier et Universitaire de Yaoundé, Cameroon D McCarty, International Diabetes Institute, Caulfield, Australia Rapporteur A Motala, University of Natal, Congella, South Africa Pan XR, ChinaJapan Friendship Hospital, Beijing, China PR deceased 8 July 1997 A Ramachandran, Diabetes Research Centre, Madras, India N Samad, Dow Medical College Civil Hospital, Karachi, Pakistan N Unwin, University of Newcastle upon Tyne, UK Rapporteur P Vardi, Schneider Childrens Centre, PetahTikvah, Israel PZ
Zimmet, International Diabetes Institute, Caulfield, Australia Co Chairman

Secretariat
A Alwan, World Health Organization, Geneva, Switzerland H King, World Health Organization, Geneva, Switzerland

Observers
M Berrens, Bayer, Germany R Kahn, American Diabetes Association, USA J Nolan, Institute for Diabetes Discovery, USA S Pramming, Novo Nordisk, Denmark RA Rizza, American Diabetes Association, USA

1

Introduction

In the late 1970s both WHO 1 and the National Diabetes Data Group 2 produced new diagnostic criteria and a new classification system for diabetes mellitus This brought order to a chaotic situation in which nomenclature varied and diagnostic criteria showed enormous variations using different oral glucose loads In 1985 WHO slightly modified their criteria to coincide more closely with the NDDG values 3 There are now many data available, and also much more aetiological information has appeared It seemed timely to re examine the issues and to update and refine both the classification and the criteria, and to include a definition of the Metabolic Syndrome An American Diabetes Association ADA expert group was convened to discuss these issues It published its
recommendations in 1997 4 WHO convened a Consultation on the same subject in London, United Kingdom, in December 1996 In general, the ADA and WHO groups reached similar conclusions The provisional report of the WHO Consultation 5 solicited comments which were considered in preparing the present report Both the provisional and the present report were prepared by Professor KGMM Alberti and Professor PZ Zimmet on behalf of the members of the Consultation The meeting was made possible with financial support from Bayer, UK; Bayer, Germany; Novo Nordisk, Copenhagen, Denmark; and The Institute for Diabetes Discovery, New Haven, USA

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Definition and diagnostic criteria for diabetes mellitus and other categories of glucose intolerance
Definition

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The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both The effects of diabetes mellitus include long term damage, dysfunction and failure of various organs Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria,
blurring of vision, and weight loss In its most severe forms, ketoacidosis or a nonketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death Often symptoms are not severe, or may be absent, and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the diagnosis is made The longterm effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including sexual dysfunction People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular disease

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Several pathogenetic processes are involved in the development of diabetes These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulin action The abnormalities of carbohydrate, fat and protein metabolism are due to deficient action of insulin on target tissues resulting
from insensitivity or lack of insulin

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Diagnosis and diagnostic criteria Diagnosis

If a diagnosis of diabetes is made, the clinician must feel confident that the diagnosis is fully established since the consequences for the individual are considerable and lifelong The requirements for diagnostic confirmation for a person presenting with severe symptoms and gross hyperglycaemia differ from those for the asymptomatic person with blood glucose values found to be just above the diagnostic cutoff value Severe hyperglycaemia detected under conditions of acute infective, traumatic, circulatory or other stress may be transitory and should not in itself be regarded as diagnostic of diabetes The diagnosis of diabetes in an asymptomatic subject should never be made on the basis of a single abnormal blood glucose value For the asymptomatic person, at least one additional plasma/blood glucose test result with a value in the diabetic range is essential, either fasting, from a random casual sample, or from the oral glucose tolerance test OGTT If such samples fail to confirm the diagnosis of diabetes mellitus, it will usually be advisable to maintain surveillance with periodic retesting
until the diagnostic situation becomes clear In these circumstances, the clinician

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should take into consideration such additional factors as ethnicity, family history, age, adiposity, and concomitant disorders, before deciding on a diagnostic or therapeutic course of action An alternative to blood glucose estimation or the OGTT has long been sought to simplify the diagnosis of diabetes Glycated haemoglobin, reflecting average glycaemia over a period of weeks, was thought to provide such a test Although in certain cases it gives equal or almost equal sensitivity and specificity to glucose measurement 6, it is not available in many parts of the world and is not well enough standardized for its use to be recommended at this time 222 Diabetes in children

Diabetes in children usually presents with severe symptoms, very high blood glucose levels, marked glycosuria, and ketonuria In most children the diagnosis is confirmed without delay by blood glucose measurements, and treatment including insulin injection is initiated immediately, often as a lifesaving measure An OGTT is neither necessary nor appropriate for diagnosis in such circumstances A small proportion of children and
adolescents, however, present with less severe symptoms and may require fasting blood glucose measurement and/or an OGTT for diagnosis 23 Diagnostic criteria

The clinical diagnosis of diabetes is often prompted by symptoms such as increased thirst and urine volume, recurrent infections, unexplained weight loss and, in severe cases, drowsiness and coma; high levels of glycosuria are usually present A single blood glucose estimation in excess

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of the diagnostic values indicated in Figure 1 black zone establishes the diagnosis in such cases Figure 1 also defines levels of blood glucose below which a diagnosis of diabetes is unlikely in nonpregnant individuals These criteria are as in the 1985 report 3 For clinical purposes, an OGTT to establish diagnostic status need only be considered if casual blood glucose values lie in the uncertain range ie between the levels that establish or exclude diabetes and fasting blood glucose levels are below those which establish the diagnosis of diabetes If an OGTT is performed, it is sufficient to measure the blood glucose values while fasting and at 2 hours after a 75 g oral glucose load Annexes 1 and 2 For children the oral glucose load is
related to body weight: 175 g per kg The diagnostic criteria in children are the same as for adults Diagnostic interpretations of the fasting and 2h postload concentrations in nonpregnant subjects are shown in Table 1 231 Change in diagnostic value for fasting plasma/blood glucose concentrations

The major change recommended in the diagnostic criteria for diabetes mellitus is the lowering of the diagnostic value of the fasting plasma glucose concentration to 70 mmol l1 126 mg dl1 and above 3, from the former level of 78 mmol l1 140 mg dl1 and above For whole blood the proposed new level is 61 mmol l1 110 mg dl1 and above, from the former 67 mmol l1 120 mg dl1 The new fasting criterion is chosen to represent a value which is at the upper end of the range that corresponds in diagnostic significance in many persons to that of the 2h postload concentration, which is not changed This equivalence has

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been established from several populationbased studies 6 8 and it also represents an optimal cutoff point to separate the components of bimodal frequency distributions of fasting plasma glucose concentrations seen in several populations Furthermore, several studies have shown increased
risk of microvascular disease in persons with fasting plasma glucose concentrations of 70 mmol l1 126 mg dl1 and over 6, and of macrovascular disease in persons with such fasting concentrations, even in those with 2h values of 78 mmol l-1 140 mg dl1 9 Nevertheless, in less obese subjects, in some ethnic groups and in the elderly lower fasting glucose levels may be seen in persons who have 2h postload glucose values that are diagnostic for diabetes 232 Epidemiological studies

For population studies of glucose intolerance and diabetes, individuals have been classified by their blood glucose concentration measured after an overnight fast and/or 2 h after a 75 g oral glucose load Since it may be difficult to be sure of the fasting state, and because of the strong correlation between fasting and 2h values, epidemiological studies or diagnostic screening have in the past been restricted to the 2h values only Table 1 Whilst this remains the single best choice, if it is not possible to perform the OGTT eg for logistical or economic reasons, the fasting plasma glucose alone may be used for epidemiological purposes It has now been clearly shown, however, that some of the individuals
identified by the new fasting values differ from those identified by 2h post glucose challenge values 10,11 The latter include the elderly 12 and those with less obesity, such as many Asian populations On the other hand, middle-aged, more obese 6

patients are more likely to have diagnostic fasting values 10 Overall population prevalence may 13 or may not 7,10,14 be found to differ when estimates using fasting and 2h values are compared 233 Individual diagnosis

The requirements for individual diagnosis differ from those of population studies The diagnosis should not be based on a single glucose determination but requires confirmatory symptoms or blood/plasma determination Diagnosis requires the identification of people at risk for development of complications in whom early preventive strategies are indicated Ideally therefore both the 2h and the fasting value should be used These recommendations contrast with those of the ADA Expert Committee which gives primacy to the fasting plasma glucose 4

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Classification
Earlier classifications

The first widely accepted classification of diabetes mellitus was published by WHO in 1980 1 and, in modified form, in 1985 3 The 1980 and
1985 classifications of diabetes mellitus and allied categories of glucose intolerance included clinical classes and two statistical risk classes The 1980 Expert Committee proposed two major classes of diabetes mellitus and named them, IDDM or Type 1, and NIDDM or Type 2 In the 1985 Study Group Report the terms Type 1 and Type 2 were omitted, but the classes IDDM and NIDDM were retained, and a class of Malnutritionrelated Diabetes Mellitus MRDM was introduced In both the 1980 and 1985 reports other classes of diabetes included Other Types and Impaired Glucose Tolerance IGT as well as Gestational Diabetes Mellitus GDM These were reflected in the subsequent International Nomenclature of Diseases IND in 1991, and the tenth revision of the International Classification of Diseases ICD10 in 1992 The 1985 classification was widely accepted and is used internationally It represented a compromise between clinical and aetiological classification and allowed classification of individual subjects and patients in a clinically useful manner even when the specific cause or aetiology was unknown The recommended classification includes both staging of diabetes mellitus based on clinical descriptive
criteria and a complementary aetiological classification

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Revised classification

The classification encompasses both clinical stages and aetiological types of diabetes mellitus and other categories of hyperglycaemia, as suggested by Kuzuya and Matsuda 15 The clinical staging reflects that diabetes, regardless of its aetiology, progresses through several clinical stages during its natural history Moreover, individual subjects may move from stage to stage in either direction Persons who have, or who are developing, diabetes mellitus can be categorized by stage according to the clinical characteristics, even in the absence of information concerning the underlying aetiology The classification by aetiological type results from improved understanding of the causes of diabetes mellitus 321 Application of the new classification

The new classification contains stages which reflect the various degrees of hyperglycaemia in individual subjects with any of the disease processes which may lead to diabetes mellitus All subjects with diabetes mellitus can be categorized according to clinical stage, and this is achievable in all circumstances The stage of glycaemia may change over time
depending on the extent of the underlying disease processes Figure 2 The disease process may be present but may not have progressed far enough to cause hyperglycaemia The aetiological classification reflects the fact that the defect or

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process which may lead to diabetes may be identifiable at any stage in the development of diabetes even at the stage of normoglycaemia Thus the presence of islet cell antibodies in a normoglycaemic individual makes it likely that that person has the Type 1 autoimmune process Unfortunately, there are few sensitive or highly specific indicators of the Type 2 process at present, although these are likely to be revealed as aetiology is more clearly defined The same disease processes can cause impaired fasting glycaemia and/or impaired glucose tolerance without fulfilling the criteria for the diagnosis of diabetes mellitus In some individuals with diabetes, adequate glycaemic control can be achieved with weight reduction, exercise and/or oral agents These individuals, therefore, do not require insulin and may even revert to IGT or normoglycaemia Other individuals require insulin for adequate glycaemic control but can survive without it These
individuals, by definition, have some residual insulin secretion Individuals with extensive beta cell destruction, and therefore no residual insulin secretion, require insulin for survival The severity of the metabolic abnormality can either regress eg with weight reduction, progress eg with weight gain, or stay the same

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Terminology Table 2

It is recommended that the terms insulindependent diabetes mellitus and noninsulindependent diabetes mellitus and their acronyms IDDM and NIDDM no longer be used These terms have been confusing and frequently resulted in patients being classified on the basis of treatment rather than pathogenesis C The terms Type 1 and Type 2 should be reintroduced The aetiological type named Type 1 encompasses the majority of cases which are primarily due to pancreatic islet betacell destruction and are prone to ketoacidosis Type 1 includes those cases attributable to an autoimmune process, as well as those with beta cell destruction and who are prone to ketoacidosis for which neither an aetiology nor a pathogenesis is known idiopathic It does not include those forms of betacell destruction or failure to which specific causes can be assigned eg cystic
fibrosis, mitochondrial defects, etc Some subjects with this type can be identified at earlier clinical stages than diabetes mellitus The type named Type 2 includes the common major form of diabetes which results from defects in insulin secretion, almost always with a major contribution from insulin resistance It has been argued that a lean phenotype of Type 2 diabetes mellitus in adults found in the Indian subcontinent may be very distinct from the more characteristic form of Type 2 found in

C

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Caucasians Not enough information is available, however, to characterize such subjects separately C A recent international workshop reviewed the evidence for, and characteristics of, diabetes mellitus seen in undernourished populations 16,17 Whilst it appears that malnutrition may influence the expression of several types of diabetes, the evidence that diabetes can be caused by malnutrition or protein deficiency per se is not convincing Therefore, it is recommended that the class Malnutritionrelated diabetes MRDM be deleted The former subtype of MRDM, Protein deficient Pancreatic Diabetes PDPD or PDDM, may be considered as a malnutrition modulated or modified form of diabetes mellitus
for which more studies are needed The other former subtype of MRDM, Fibrocalculous Pancreatic Diabetes FCPD, is now classified as a disease of the exocrine pancreas, fibrocalculous pancreatopathy, which may lead to diabetes mellitus The class Impaired Glucose Tolerance is now classified as a stage of impaired glucose regulation, since it can be observed in any hyperglycaemic disorder, and is itself not diabetes A clinical stage of Impaired Fasting Glycaemia has been introduced to classify individuals who have fasting glucose values above the normal range, but below those diagnostic of diabetes

C

C

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C

Gestational Diabetes is retained but now encompasses the groups formerly classified as Gestational Impaired Glucose Tolerance GIGT and Gestational Diabetes Mellitus GDM

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Clinical staging of diabetes mellitus and other categories of glucose tolerance Figure 2
Diabetes mellitus

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Diabetes mellitus, regardless of underlying cause, is sub divided into: Insulin requiring for survival corresponding to the former clinical class of Insulin Dependent Diabetes Mellitus IDDM, eg Cpeptide deficient; Insulin requiring for control, ie metabolic control, rather than for survival, eg
some endogenous insulin secretion but insufficient to achieve normoglycaemia without added exogenous insulin; and Not insulin requiring, ie those who may be controlled satisfactorily by nonpharmacological methods or drugs other than insulin Together, the latter two subdivisions constitute the former class of NIDDM 42 Impaired glucose regulation Impaired Glucose Tolerance IGT and Impaired Fasting Glycaemia IFG

Impaired glucose regulation IGT and IFG refers to a metabolic state intermediate between normal glucose homeostasis and diabetes It should be stated unequivocally, however, that IFG and IGT are not interchangeable and represent different abnormalities of glucose regulation, one in the fasting state and one postprandial

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IGT, rather than being a class as in the previous classification, is categorized as a stage in the natural history of disordered carbohydrate metabolism A stage of IFG is also recognized because such subjects, like those with IGT, have increased risks of progressing to diabetes and macrovascular disease, although prospective data are sparse and early data suggest a lower risk of progression than IGT 18, although a similar CVD risk factor profile has been
shown in IFG and IGT subjects 19 IFG refers to fasting glucose concentrations which are lower than those required to diagnose diabetes mellitus but higher than the normal reference range The values for IFG are a fasting plasma glucose concentration of 61 mmol l1 110 mg dl1 or greater whole blood 56 mmol l1; 100 mg dl1, but less than 70 mmol l1 126 mg dl1 whole blood 61 mmol l1; 110 mg dl1 If an OGTT is performed, some individuals with IFG will have IGT or diabetes, but this cannot be determined without an OGTT If resources allow, it is recommended that all those with IFG have an OGTT to exclude the diagnosis of diabetes Individuals who meet criteria for IGT or IFG may be euglycaemic in their daily lives as shown by normal or near normal glycated haemoglobin levels IGT and IFG are not clinical entities in their own right, but rather risk categories for future diabetes and/or cardiovascular disease 20,21 They can occur as an intermediate stage in any of the disease processes listed in Table 2 IGT is often associated with the Metabolic Syndrome Insulin Resistance Syndrome 22 Thus, IGT may not be directly involved in the pathogenesis of cardiovascular disease, but rather may serve as
an indicator or marker of enhanced risk by virtue of its correlation with the other elements of the Metabolic 15

Syndrome that are cardiovascular risk factors Selfevidently, those individuals with IGT manifest glucose intolerance only when challenged with an oral glucose load 43 Normoglycaemia

A fasting venous plasma glucose concentration of less than 61 mmol l1 110 mg dlS1 has been chosen as normal Table 1 Although this choice is arbitrary, such values are observed in people with proven normal glucose tolerance, although some may have IGT if an OGTT is performed Values above this are associated with a progressively greater risk of developing micro and macrovascular complications 8,9,21,23 The pathological or aetiological processes which often lead to diabetes mellitus begin, and may be recognizable, in some subjects who have normal glucose tolerance Recognition of the pathological process at an early stage may be useful if progression to more advanced stages can be prevented Conversely, effective treatments, or occasionally the natural history of some forms of diabetes mellitus, may result in reversion of hyperglycaemia to a state of normoglycaemia The proposed classification
includes a stage of normoglycaemia in which persons who have evidence of the pathological processes which may lead to diabetes mellitus, or in whom a reversal of the hyperglycaemia has occurred, are classified

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Aetiological types see also section 7 and Table 2

The aetiological types designate defects, disorders or processes which often result in diabetes mellitus 51 Type 1

Type 1 indicates the processes of betacell destruction that may ultimately lead to diabetes mellitus in which insulin is required for survival to prevent the development of ketoacidosis, coma and death An individual with a Type 1 process may be metabolically normal before the disease is clinically manifest, but the process of betacell destruction can be detected Type 1 is usually characterized by the presence of antiGAD, islet cell or insulin antibodies which identify the autoimmune processes that lead to betacell destruction In some subjects with this clinical form of diabetes, particularly nonCaucasians, no evidence of an autoimmune disorder is demonstrable and these are classified as Type 1 idiopathic Aetiological classification may be possible in some circumstances and not in others Thus, the
aetiological Type 1 process can be identified and sub categorized if appropriate antibody determinations are performed It is recognized that such measurements may be available only in certain centres at the present time If these measurements are performed, then the classification of individual patients should reflect this

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Type 2

Type 2 is the most common form of diabetes and is characterized by disorders of insulin action and insulin secretion, either of which may be the predominant feature Both are usually present at the time that this form of diabetes is clinically manifest By definition, the specific reasons for the development of these abnormalities are not yet known 53 Other specific types Table 3

Other specific types are currently less common causes of diabetes mellitus, but are those in which the underlying defect or disease process can be identified in a relatively specific manner They include, for example, fibrocalculous pancreatopathy, a form of diabetes which was formerly classified as one type of malnutritionrelated diabetes mellitus

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Gestational Hyperglycaemia and Diabetes

Gestational diabetes is carbohydrate intolerance resulting in hyperglycaemia
of variable severity with onset or first recognition during pregnancy It does not exclude the possibility that the glucose intolerance may antedate pregnancy but has been previously unrecognized The definition applies irrespective of whether or not insulin is used for treatment or the condition persists after pregnancy Women who become pregnant and who are known to have diabetes mellitus which antedates pregnancy do not have gestational diabetes but have diabetes mellitus and pregnancy and should be treated accordingly before, during, and after the pregnancy In the early part of pregnancy eg first trimester and first half of second trimester fasting and postprandial glucose concentrations are normally lower than in normal, non pregnant women Elevated fasting or postprandial plasma glucose levels at this time in pregnancy may well reflect the presence of diabetes which has antedated pregnancy, but criteria for designating abnormally high glucose concentrations at this time have not yet been established The occurrence of higher than usual plasma glucose levels at this time in pregnancy mandates careful management and may be an indication for carrying out an OGTT Annex 1 Nevertheless,
normal glucose tolerance in the early part of

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pregnancy does not itself establish that gestational diabetes may not develop later Individuals at high risk for gestational diabetes include older women, those with previous history of glucose intolerance, those with a history of large for gestational age babies, women from certain highrisk ethnic groups, and any pregnant woman who has elevated fasting, or casual, blood glucose levels It may be appropriate to screen pregnant women belonging to highrisk populations during the first trimester of pregnancy in order to detect previously undiagnosed diabetes mellitus Formal systematic testing for gestational diabetes is usually done between 24 and 28 weeks of gestation 61 Diagnosis of gestational diabetes

To determine if gestational diabetes is present in pregnant women, a standard OGTT should be performed after overnight fasting 814 hours by giving 75 g anhydrous glucose in 250300 ml water Annex 1 Plasma glucose is measured fasting and after 2 hours Pregnant women who meet WHO criteria for diabetes mellitus or IGT are classified as having Gestational Diabetes Mellitus GDM After the pregnancy ends, the woman should be reclassified as
having either diabetes mellitus, or IGT, or normal glucose tolerance based on the results of a 75 g OGTT six weeks or more after delivery It should be emphasized that such women, regardless of the 6week postpregnancy result, are at increased risk of subsequently developing diabetes The significance of IFG in pregnancy remains to be established Any woman with IFG, however, should have a 75 g OGTT

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Description of aetiological types

Patients with any form of diabetes may require insulin treatment at some stage of their disease Such use of insulin does not, of itself, define the aetiological class 71 Type 1 betacell destruction, usually leading to absolute insulin deficiency Autoimmune Diabetes Mellitus

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This form of diabetes, previously encompassed by the terms insulindependent diabetes, Type 1 diabetes, or juvenile onset diabetes, results from autoimmune mediated destruction of the beta cells of the pancreas The rate of destruction is quite variable, being rapid in some individuals and slow in others 24 The rapidly progressive form is commonly observed in children, but also may occur in adults 25 The slowly progressive form generally occurs in adults and is sometimes
referred to as latent autoimmune diabetes in adults LADA Some patients, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease 26 Others have modest fasting hyperglycaemia that can rapidly change to severe hyperglycaemia and/or ketoacidosis in the presence of infection or other stress Still others, particularly adults, may retain residual betacell function, sufficient to prevent ketoacidosis, for many years 27 Individuals with this form of Type 1 diabetes often become dependent on insulin for survival eventually and are at risk for ketoacidosis 28 At this stage of the disease, there

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is little or no insulin secretion as manifested by low or undetectable levels of plasma Cpeptide 29 Markers of immune destruction, including islet cell autoantibodies, and/or autoantibodies to insulin, and autoantibodies to glutamic acid decarboxylase GAD are present in 8590 of individuals with Type 1 diabetes mellitus when fasting diabetic hyperglycaemia is initially detected 30 The peak incidence of this form of Type 1 diabetes occurs in childhood and adolescence, but the onset may occur at any age, ranging from childhood to the ninth
decade of life 31 There is a genetic predisposition to autoimmune destruction of beta cells, and it is also related to environmental factors that are still poorly defined Although patients are usually not obese when they present with this type of diabetes, the presence of obesity is not incompatible with the diagnosis These patients may also have other autoimmune disorders such as Graves disease, Hashimotos thyroiditis, and Addisons disease 32 712 Idiopathic

There are some forms of Type 1 diabetes which have no known aetiology Some of these patients have permanent insulinopenia and are prone to ketoacidosis, but have no evidence of autoimmunity 33 This form of diabetes is more common among individuals of African and Asian origin In another form found in Africans an absolute requirement for insulin replacement therapy in affected patients may come and go, and patients periodically develop ketoacidosis 34

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Type 2 predominantly insulin resistance with relative insulin deficiency or predominantly an insulin secretory defect with/without insulin resistance

Diabetes mellitus of this type previously encompassed non insulindependent diabetes, or adultonset diabetes It is a term
used for individuals who have relative rather than absolute insulin deficiency People with this type of diabetes frequently are resistant to the action of insulin 35,36 At least initially, and often throughout their lifetime, these individuals do not need insulin treatment to survive This form of diabetes is frequently undiagnosed for many years because the hyperglycaemia is often not severe enough to provoke noticeable symptoms of diabetes 37,38 Nevertheless, such patients are at increased risk of developing macrovascular and microvascular complications 37,38 There are probably several different mechanisms which result in this form of diabetes, and it is likely that the number of people in this category will decrease in the future as identification of specific pathogenetic processes and genetic defects permits better differentiation and a more definitive classification with movement into Other types Although the specific aetiologies of this form of diabetes are not known, by definition autoimmune destruction of the pancreas does not occur and patients do not have other known specific causes of diabetes listed in Tables 35 The majority of patients with this form of diabetes are
obese, and obesity itself causes or aggravates insulin resistance 39,40 Many of those who are not obese by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region 41

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Ketoacidosis is infrequent in this type of diabetes; when seen it usually arises in association with the stress of another illness such as infection 42,43 Whereas patients with this form of diabetes may have insulin levels that appear normal or elevated, the high blood glucose levels in these diabetic patients would be expected to result in even higher insulin values had their betacell function been normal 44 Thus, insulin secretion is defective and insufficient to compensate for the insulin resistance On the other hand, some individuals have essentially normal insulin action, but markedly impaired insulin secretion Insulin sensitivity may be increased by weight reduction, increased physical activity, and/or pharmacological treatment of hyperglycaemia but is not restored to normal 45,46 The risk of developing Type 2 diabetes increases with age, obesity, and lack of physical activity 47,48 It occurs more frequently in women with prior GDM and in
individuals with hypertension or dyslipidaemia Its frequency varies in different racial/ethnic subgroups 4750 It is often associated with strong familial, likely genetic, predisposition 4951 However, the genetics of this form of diabetes are complex and not clearly defined Some patients who present with a clinical picture consistent with Type 2 diabetes have autoantibodies similar to those found in Type 1 diabetes, and may masquerade as Type 2 diabetes if antibody determinations are not made Patients who are nonobese or who have relatives with Type 1 diabetes and who are of Northern European origin may be suspected of having late onset Type 1 diabetes

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73 731

Other Specific Types Genetic defects of betacell function

Several forms of the diabetic state may be associated with monogenic defects in betacell function, frequently characterized by onset of mild hyperglycaemia at an early age generally before age 25 years They are usually inherited in an autosomal dominant pattern Patients with these forms of diabetes, formerly referred to as maturity onset diabetes of the young MODY, have impaired insulin secretion with minimal or no defect in insulin action 52,53 Abnormalities at
three genetic loci on different chromosomes have now been characterized The most common form is associated with mutations on chromosome 12 in a hepatic nuclear transcription factor referred to as HNF1 54 A second form is associated with mutations in the glucokinase gene on chromosome 7p 55,56 Glucokinase converts glucose to glucose6phosphate, the metabolism of which in turn stimulates insulin secretion by the beta cell Thus, glucokinase serves as the glucose sensor for the beta cell Because of defects in the glucokinase gene, increased levels of glucose are necessary to elicit normal levels of insulin secretion A third form is associated with a mutation in the HNF4 gene on chromosome 20q 57 HNF4 is a transcription factor which is involved in the regulation of the expression of HNF1 A fourth variant has recently been ascribed to mutations in another transcription factor gene, IPF1, which in its homozygous form leads to total pancreatic agenesis 58

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Specific genetic defects in other individuals who have a similar clinical presentation are currently being defined Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness 59 The most
common mutation occurs at position 3243 in the tRNA leucine gene, leading to an A to G substitution An identical lesion occurs in the MELAS syndrome Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Strokelike syndrome; however, diabetes is not part of this syndrome, suggesting for unknown reasons different phenotypic expressions of this genetic lesion 60 Genetic abnormalities that result in the inability to convert proinsulin to insulin have been identified in a few families Such traits are usually inherited in an autosomal dominant pattern 61,62 and the resultant carbohydrate intolerance is mild Similarly, mutant insulin molecules with impaired receptor binding have been identified in a few families These are also associated with autosomal inheritance and either normal or only mildly impaired carbohydrate metabolism 63,64 732 Genetic defects in insulin action

There are some unusual causes of diabetes which result from genetically determined abnormalities of insulin action The metabolic abnormalities associated with mutations of the insulin receptor may range from hyperinsulinaemia and modest hyperglycaemia to symptomatic diabetes 65,66 Some individuals with these
mutations have acanthosis nigricans Women may have virilization and have enlarged,

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cystic ovaries In the past, this syndrome was termed Type A insulin resistance 65 Leprechaunism and Rabson Mendenhall syndrome are two paediatric syndromes that have mutations in the insulin receptor gene with subsequent alterations in insulin receptor function and extreme insulin resistance 66 The former has characteristic facial features while the latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia 733 Diseases of the exocrine pancreas

Any process that diffusely injures the pancreas can cause diabetes Acquired processes include pancreatitis, trauma, infection, pancreatic carcinoma, and pancreatectomy 67,68 With the exception of cancer, damage to the pancreas must be extensive for diabetes to occur However, adenocarcinomas that involve only a small portion of the pancreas have been associated with diabetes This implies a mechanism other than simple reduction in betacell mass 69 If extensive enough, cystic fibrosis and haemochromatosis will also damage beta cells and impair insulin secretion 70,71 Fibrocalculous pancreatopathy may be accompanied by abdominal
pain radiating to the back and pancreatic calcification on Xray and ductal dilatation 72 Pancreatic fibrosis and calcified stones in the exocrine ducts are found at autopsy 734 Endocrinopathies

Several hormones eg growth hormone, cortisol, glucagon, epinephrine antagonize insulin action Diseases associated with excess secretion of these hormones can cause diabetes eg Acromegaly, Cushings Syndrome, Glucagonoma and

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Phaeochromocytoma 73 These forms of hyperglycaemia typically resolve when the hormone excess is removed Somatostatinoma, and aldosteronomainduced hypokalaemia, can cause diabetes, at least in part by inhibiting insulin secretion 74,75 Hyperglycaemia generally resolves following successful removal of the tumour 735 Drug or chemicalinduced diabetes

Many drugs can impair insulin secretion These drugs may not, by themselves, cause diabetes but they may precipitate diabetes in persons with insulin resistance 76,77 In such cases, the classification is ambiguous, as the primacy of beta cell dysfunction or insulin resistance is unknown Certain toxins such as Vacor a rat poison and pentamidine can permanently destroy pancreatic beta cells 7880 Fortunately, such drug
reactions are rare There are also many drugs and hormones which can impair insulin action Examples include nicotinic acid and glucocorticoids 71,72 The list shown in Table 4 is not allinclusive, but reflects the more commonly recognized drug, hormone, or toxin induced forms of diabetes and hyperglycaemia 736 Infections

Certain viruses have been associated with betacell destruction Diabetes occurs in some patients with congenital rubella 81 In addition, Coxsackie B, cytomegalovirus and other viruses eg adenovirus and mumps have been implicated in inducing the disease 8284

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737

Uncommon but specific forms of immune mediated diabetes mellitus

Diabetes may be associated with several immunological diseases with a pathogenesis or aetiology different from that which leads to the Type 1 diabetes process Postprandial hyperglycaemia of a severity sufficient to fulfil the criteria for diabetes has been reported in rare individuals who spontaneously develop insulin autoantibodies 85,86 However, these individuals generally present with symptoms of hypoglycaemia rather than hyperglycaemia The stiff man syndrome is an autoimmune disorder of the central nervous system, characterized by
stiffness of the axial muscles with painful spasms 87 Affected people usually have high titres of the GAD autoantibodies and approximately one-half will develop diabetes Patients receiving interferon alpha have been reported to develop diabetes associated with islet cell autoantibodies and, in certain instances, severe insulin deficiency 88 Antiinsulin receptor antibodies can cause diabetes by binding to the insulin receptor, thereby reducing the binding of insulin to target tissues 89 However, these antibodies also can act as an insulin agonist after binding to the receptor and can thereby cause hypoglycaemia 90 Antiinsulin receptor antibodies are occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases 91 As in other states of extreme insulin resistance, patients with antiinsulin receptor antibodies often have acanthosis nigricans In the past, this syndrome was termed Type B insulin resistance

29

738

Other genetic syndromes sometimes associated with diabetes

Many genetic syndromes are accompanied by an increased incidence of diabetes mellitus These include the chromosomal abnormalities of Downs syndrome, Klinefelters syndrome and Turners
syndrome Wolframs syndrome is an autosomal recessive disorder characterized by insulindeficient diabetes and the absence of beta cells at autopsy 92 Additional manifestations include diabetes insipidus, hypogonadism, optic atrophy, and neural deafness These and other similar disorders are listed in Table 5

30

8

The Metabolic Syndrome

A major classification, diagnostic and therapeutic challenge is the person with hypertension, central upper body obesity, and dyslipidaemia, with or without hyperglycaemia This group of people is at high risk of macrovascular disease 22 Often a person with abnormal glucose tolerance IGT or diabetes will be found to have at least one or more of the other cardiovascular disease CVD risk components 22 This clustering has been labelled variously as Syndrome X 22, the Insulin Resistance Syndrome 47, or the Metabolic Syndrome 47 Epidemiological studies confirm that this syndrome occurs commonly in a wide variety of ethnic groups including Caucasians, AfroAmericans, MexicanAmericans, Asian Indians, Chinese, Australian Aborigines, Polynesians and Micronesians 47,93 In 1988 Reaven focused attention on this cluster, naming it Syndrome X 22 Central obesity
was not included in the original description so the term Metabolic Syndrome is now favoured Evidence is accumulating that insulin resistance may be the common aetiological factor for the individual components of the Metabolic Syndrome 47,93,94, although there appears to be heterogeneity in the strength of the insulin resistance relationship with different components between, and even within, populations Alone, each component of the cluster conveys increased CVD risk, but as a combination they

31

become much more powerful 95 This means that the management of persons with hyperglycaemia and other features of the Metabolic Syndrome should focus not only on blood glucose control but also include strategies for reduction of the other CVD risk factors 96 It is well documented that the features of the Metabolic Syndrome can be present for up to 10 years before detection of the glycaemic disorders 97 This is important in relation to the aetiology of the hyperglycaemia and the associated CVD risk, and the potential to prevent CVD and its morbidity and mortality in persons with glucose intolerance The Metabolic Syndrome with normal glucose tolerance identifies the subject as a member of a
group at very high risk of future diabetes Thus, vigorous early management of the syndrome may have a significant impact on the prevention of both diabetes and cardiovascular disease 98 81 Definition

There is no internationally agreed definition for the Metabolic Syndrome The following, which does not imply causal relationships, is suggested as a working definition to be improved upon in due course: glucose intolerance, IGT or diabetes mellitus and/or insulin resistance together with two or more of the other components listed below: Impaired glucose regulation or diabetes see Table 1

32

Insulin resistance under hyperinsulinaemic, euglycaemic conditions, glucose uptake below lowest quartile for background population under investigation Raised arterial pressure 140/90 mmHg Raised plasma triglycerides 17 mmol l1; 150 mg dl1 and/or low HDLcholesterol 09 mmol l1, 35 mg dl1 men; 10 mmol l1, 39 mg dl1 women Central obesity males: waist to hip ratio 090; females: waist to hip ratio 085 and/or BMI 30 kg m 2 Microalbuminuria urinary albumin excretion rate 20 g min1 or albumin:creatinine ratio 30 mg g1

Several other components of the Metabolic Syndrome have been
described eg hyperuricaemia, coagulation disorders, raised PAI1, etc but they are not necessary for the recognition of the condition 82 Future needs

A clear description of the essential components of the syndrome is needed together with data to support the relative importance of each component Internationally agreed criteria for central obesity, insulin resistance and hyperinsulinaemia would be of major assistance

33

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49 Valle T, Tuomilehto J, Eriksson J Epidemiology of NIDDM in Europids In: Alberti KGMM, Zimmet P, DeFronzo RA, eds International Textbook of Diabetes Mellitus 2nd edn Chichester: John Wiley, 1997: pp 12542 50 de Courten M, Bennett PH, Tuomilehto J,
Zimmet P Epidemiology of NIDDM in NonEuropids In: Alberti KGMM, Zimmet P, DeFronzo RA, eds International Textbook of Diabetes Mellitus 2nd edn Chichester: John Wiley, 1997: pp 14370 51 Knowler WC, Nelson RG, Saad M, Bennett PH, Pettitt DJ Determinants of diabetes mellitus in the Pima Indians Diabetes Care 1993; 16: 21627 52 Byrne MM, Sturis J, Menzel S, Yamagata K, Fajans SS, Dronsfield MJ et al Altered insulin secretory response to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY 3 on chromosome 20 Diabetes 1996; 45: 150310 53 Clement K, Pueyo ME, Vaxillaire M, Rakotoambinina B, Thuillier F, Passa P et al Assessment of insulin sensitivity in glucokinasedeficient subjects Diabetologia 1996; 39: 8290 54 Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M et al Mutations in the hepatocyte nuclear factor1 gene in maturityonset diabetes of the young MODY 3 Nature 1996; 384: 45558 55 Froguel P, Vaxillaire M, Sun F, Velho G, Zouali H, Butel MO et al Close linkage of glucokinase locus on chromosome 7p to earlyonset noninsulindependent diabetes Nature 1992; 356: 16264

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56 Vionnet N, Stoffel M, Takeda J, Yasuda K, Bell GI,
Zouali H et al Nonsense mutation in the glucokinase gene causes earlyonset noninsulindependent diabetes Nature 1992; 356: 72122 57 Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ et al Mutations in the hepatocyte nuclear factor4 gene in maturityonset diabetes of the young MODY 1 Nature 1996; 384: 45860 58 Stoffers DA, Ferrer J, Clarke WL, Habener JF Early onset typeII diabetes mellitus MODY4 linked to IPF1 Nature Genetics 1997; 117: 13839 59 Walker M, Turnbull DM Mitochondrial related diabetes: a clinical perspective Diabet Med 1997; 14: 100709 60 Johns DR Mitochondrial DNA and disease N Engl J Med 1995; 333: 63844 61 Gruppuso PA, Gorden P, Kahn CR, Cornblath M, Zeller WP, Schwartz R Familial hyperproinsulinemia due to a proposed defect in conversion of proinsulin to insulin N Engl J Med 1984; 311: 62934 62 Robbins DC, Shoelson SE, Rubenstein AH, Tager HS Familial hyperproinsulinemia: two cohorts secreting indistinguishable type II intermediates of proinsulin conversion J Clin Invest 1984; 73: 71419 63 Haneda M, Polonsky KS, Bergenstal RM, Jaspan JB, Shoelson SE, Blix PM et al Familial hyperinsulinemia due to a structurally abnormal insulin Definition of an emerging new
clinical syndrome N Engl J Med 1984; 310: 128894

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64 Sanz N, Karam JH, Horita S, Bell GI Prevalence of insulingene mutations in noninsulindependent diabetes mellitus N Engl J Med 1986; 314: 132223 65 Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM et al The syndromes of insulin resistance and acanthosis nigricans N Engl J Med 1976; 294: 73945 66 Taylor SI Lilly Lecture: molecular mechanisms of insulin resistance: lessons from patients with mutations in the insulinreceptor gene Diabetes 1992; 41: 1473 90 67 Gullo L, Pezzilli R, MorselliLabate AM, and the Italian Pancreatic Cancer Study Group Diabetes and the risk of pancreatic cancer N Engl J Med 1994; 331: 8184 68 Larsen S, Hilsted J, Tronier B, Worning H Metabolic control and B cell function in patients with insulin dependent diabetes mellitus secondary to chronic pancreatitis Metabolism 1987; 36: 96467 69 Permert J, Larsson J, Westermark GT, Herrington MK, Christmanson L, Pour PM et al Islet amyloid polypeptide in patients with pancreatic cancer and diabetes N Engl J Med 1994; 330: 31318 70 Moran A, Pyzdrowski KL, Weinreb J, Kahn BB, Smith SA, Adams KS et al Insulin sensitivity in cystic fibrosis Diabetes 1994; 43:
102026 71 Phelps G, Chapman I, Hall P, Braund W, Mackinnon M Prevalence of genetic haemochromatosis among diabetic patients Lancet 1989; ii: 23334

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72 Yajnik CS, Shelgikar KM, Naik SS, Kanitkar SV, Orskov H, Alberti KGMM et al The ketoacidosis resistance in fibrocalculouspancreaticdiabetes Diabetes Res Clin Pract 1992; 15: 14956 73 MacFarlane IA Endocrine diseases and diabetes mellitus In: Pickup JC, Williams G, eds Textbook of Diabetes 2nd edn Oxford: Blackwell, 1997: pp 641 6420 74 Krejs GJ, Orci L, Conlon JM, Ravazzola M, Davis GR, Raskin P et al Somatostatinoma syndrome N Engl J Med 1979; 301: 28592 75 Conn JW Hypertension, the potassium ion and impaired carbohydrate tolerance N Engl J Med 1965; 273: 113543 76 Pandit MK, Burke J, Gustafson AB, Minocha A, Peiris AN Druginduced disorders of glucose tolerance Ann Intern Med 1993; 118: 52940 77 OByrne S, Feely J Effects of drugs on glucose tolerance in noninsulindependent diabetes parts I and II Drugs 1990; 40: 20319 78 Gallanosa AG, Spyker DA, Curnow RT Diabetes mellitus associated with autonomic and peripheral neuropathy after Vacor poisoning: a review Clin Toxicol 1981; 18: 44149 79 Esposti MD, Ngo A, Myers MA Inhibition of
mitochondrial complex I may account for IDDM induced by intoxication with rodenticide Vacor Diabetes 1996; 45: 153134

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80 Assan R, Perronne C, Assan D, Chotard L, Mayaud C, Matheron S et al Pentamidineinduced derangements of glucose homeostasis Diabetes Care 1995; 18: 47 55 81 Forrest JA, Menser MA, Burgess JA High frequency of diabetes mellitus in young patients with congenital rubella Lancet 1971; ii: 33234 82 King ML, Bidwell D, Shaikh A, Voller A, Banatvala JE CoxsackieBvirusspecific IgM responses in children with insulindependent juvenileonset; type 1 diabetes mellitus Lancet 1983; i: 139799 83 Karjalainen J, Knip M, Hyoty H, Linikki P, Ilonen J, Kaar ML et al Relationship between serum insulin antibodies, islet cell antibodies and CoxsackieB4 and mumps virusspecific antibodies at the clinical manifestation of type 1 insulindependent diabetes Diabetologia 1988; 31: 14652 84 Pak CY, Eun H, McArthur RG, Yoon J Association of cytomegalovirus infection with autoimmune type 1 diabetes Lancet 1988; ii: 14 85 Hirata Y, Ishizu H, Ouchi N et al Insulin autoimmunity in a case of spontaneous hypoglycaemia J Jpn Diabet Soc 1970; 13: 31220 86 Bodansky HJ, Grant PJ, Dean BM, McNally J,
Bottazzo GF, Hambling MH et al Isletcell antibodies and insulin autoantibodies in association with common viral infections Lancet 1986; ii: 135153 87 Solimena M, De Camilli P Autoimmunity to glutamic acid decarboxylase GAD in StiffMan syndrome and insulindependent diabetes mellitus Trends Neurosci 1991; 14: 45257

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88 Fabris P, Betterle C, Floreani A, Greggio NA, de Lazzari F, Naccarato R et al Development of type 1 diabetes mellitus during interferon alfa therapy for chronic HCV hepatitis Letter Lancet 1992; 340: 548 89 Flier JS Lilly Lecture: syndromes of insulin resistance: from patient to gene and back again Diabetes 1992; 41: 120719 90 Kahn CR, Baird KL, Flier JS, Jarrett DB Effects of autoantibodies to the insulin receptor on isolated adipocytes J Clin Invest 1977; 60: 1094106 91 Tsokos GC, Gorden P, Antonovych T, Wilson CB, Balow JE Lupus nephritis and other autoimmune features in patients with diabetes mellitus due to autoantibody to insulin receptors Ann Intern Med 1985; 102: 17681 92 Barrett TG, Bundey SE, Macleod AF Neurodegeneration and diabetes: UK nationwide study of Wolfram DIDMOAD syndrome Lancet 1995; 346: 145863 93 Stern MP The insulin resistance syndrome In:
Alberti KGMM, Zimmet P, DeFronzo RA, eds International Textbook of Diabetes Mellitus 2nd edn Chichester: John Wiley, 1997: pp 25583 94 Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP Prospective analysis of the insulin resistance syndrome Syndrome X Diabetes 1992; 41: 71522 95 Kaplan NM The deadly quartet: upper body adiposity, glucose intolerance, hypertriglyceridaemia and hypertension Arch Intern Med 1989; 149: 151420

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96 European Arterial Risk Policy Group on behalf of the International Diabetes Federation European Region A strategy for arterial risk assessment and management in Type 2 noninsulindependent diabetes Diabet Med 1997; 14: 61121 97 Mykkänen L, Kuusisto J, Pyörälä K, Laakso M Cardiovascular disease risk factors as predictors of Type 2 noninsulindependent diabetes mellitus in elderly subjects Diabetologia 1993; 36: 55359 98 Eriksson KF, Lindegärde F Prevention of Type 2 non insulindependent diabetes mellitus by diet and physical exercise Diabetologia 1991; 34: 89198

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Annex 1
The Oral Glucose Tolerance Test
The oral glucose tolerance test OGTT is principally used for diagnosis when blood glucose levels are equivocal, during pregnancy, or in
epidemiological studies The OGTT should be administered in the morning after at least three days of unrestricted diet greater than 150 g of carbohydrate daily and usual physical activity Recent evidence suggests that a reasonable 3050g carbohydrate containing meal should be consumed on the evening before the test The test should be preceded by an overnight fast of 814 hours, during which water may be drunk Smoking is not permitted during the test The presence of factors that influence interpretation of the results of the test must be recorded eg medications, inactivity, infection, etc After collection of the fasting blood sample, the subject should drink 75 g of anhydrous glucose or 825 g of glucose monohydrate or partial hydrolysates of starch of the equivalent carbohydrate content in 250300 ml of water over the course of 5 minutes For children, the test load should be 175 g of glucose per kg body weight up to a total of 75 g of glucose Timing of the test is from the beginning of the drink Blood samples must be collected 2 hours after the test load Unless the glucose concentration can be determined immediately, the blood sample should be collected in a tube containing sodium
fluoride 6 mg per ml whole blood and immediately centrifuged to separate the plasma; the plasma should be frozen until the glucose concentration can be estimated For interpretation of results, refer to Table 1

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Annex 2
Methods for measuring substances in blood and urine
Measurement of glucose in blood Reductiometric methods the SomogyiNelson, the ferricyanide and neocuprine autoanalyser methods are still in use for blood glucose measurement The otoluidine method also remains in use but enzymebased methods are widely available, for both laboratory and nearpatient use Highly accurate and rapid 12 min devices are now available based on immobilized glucose oxidase electrodes Hexokinase and glucose dehydrogenase methods are used for reference Whole blood samples preserved with fluoride show an initial rapid fall in glucose of up to 10 at room temperature, but subsequent decline is slow; centrifugation prevents the initial fall Whole blood glucose values are 15 lower than corresponding plasma values in patients with a normal haematocrit reading, and arterial values are about 7 higher than corresponding venous values The use of reagentstrip glucose oxidase methods has made bedside
estimation of blood glucose very popular However, the cost of the reagentstrips remains high Some methods still require punctilious technique, accurate timing, and storage of strips in airtight containers Reasonably quantitative results can be obtained even with visual colourmatching techniques Electrochemical and reflectance meters can give coefficients of variation of well under 5 Reagentstrip methods have been validated under tropical conditions, but are sensitive to extreme climatic conditions Diabetes may be strongly suspected from the results of reagent strip glucose estimation, but the diagnosis cannot be confidently excluded by the use of this method Confirmation of diagnosis requires estimation by laboratory methods Patients can easily collect small blood samples themselves either in specially prepared plastic or glass capillary tubes or on

49

filterpaper, and selfmonitoring using glucose reagentstrips with direct colourmatching or meters is now widely practised Patients should be properly trained in the appropriate techniques to avoid inaccurate or misleading results The insulintreated patient is commonly requested to build up a glycaemic profile by selfmeasurement of
blood glucose at specific times of the day and night A 7point profile is useful, with samples taken before and 90 min after breakfast, before and 90 min after lunch, before and 90 min after an evening meal, and just before going to bed Occasionally patients may arrange to wake at 0300 h to collect and measure a nocturnal sample The complete profile rarely needs to be collected within a single 24hour period, and it may be compiled from samples collected at different times over several days Measurement of glucose in urine Insulintreated patients who do not have access to facilities for selfmeasurement of blood glucose should test urine samples passed after rising, before main meals, and before going to bed Noninsulindependent patients do not need to monitor their urine so frequently Urine tests are of somewhat limited value, however, because of the great variation in urine glucose concentration for given levels of blood glucose The correlation between blood and urine glucose may be improved a little by collecting shortterm fractions 1530 min of the urine output Benedicts quantitative solution or selfboiling, caustic soda/copper sulphate tablets may be used or the more convenient, but
costly, semiquantitative enzymebased test strips Ketone bodies in urine and blood The appearance of persistent ketonuria associated with hyperglycaemia or high levels of glycosuria in the diabetic patient points to an unacceptably severe level of metabolic disturbance and indicates an urgent need for corrective action The patient should be advised to test for ketone bodies acetone and acetoacetic acid when tests for glucose are

50

repeatedly positive, or when there issubstantial disturbance of health, particularly with infections Rotheras sodium nitroprusside test may be used or, alternatively, reagentstrips that are sensitive to ketones In emergency situations such as diabetic ketoacidosis, a greatly raised concentration of plasma ketones can be detected with a reagentstrip and roughly quantified by serial 1 in 2 dilution of plasma with water

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Table 1 Values for diagnosis of diabetes mellitus and other categories of hyperglycaemia
Venous 61 110 100 180 61 110 67 120 and 100 180 56 100 and 61 110 67 120 Glucose concentration, mmol l1 mg dl1 Whole blood Plasma Capillary Venous 61 110 111 200 61 110 78 140 and 111 200 56 100 and 61 110 78 140 70
126 111 200 70 126 78 140 and 111 200 61 110 and 70 126 78 140

Diabetes Mellitus: Fasting or 2-h post glucose load or both Impaired Glucose Tolerance IGT: Fasting if measured and 2-h post glucose load Impaired Fasting Glycaemia IFG: Fasting and if measured 2-h post glucose load

Corresponding values for capillary plasma are: for Diabetes Mellitus, fasting 70 126, 2-h 122 220; for Impaired Glucose Tolerance,fasting 70 126 and 2-h 89 160 and 122 220; and for Impaired Fasting Glycaemia 61 110 and 70 126 and if measured, 2-h 89 160 For epidemiological or population screening purposes, the fasting or 2-h value after 75 g 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 Glucose concentrations should not be determined on serum unless red cells are immediately removed, otherwise glycolysis will result in an unpredictable under-estimation of the true concentrations It should be stressed that glucose preservatives do not totally prevent glycolysis If whole blood is
used, the sample should be kept at 0-4 C or centrifuged immediately, or assayed immediately

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Table 2

Aetiological Classification of Disorders of Glycaemia

Type 1 beta-cell destruction, usually leading to absolute insulin deficiency Autoimmune Idiopathic Type 2 may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistance Other specific types see Table 3 Genetic defects of beta-cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug- or chemical-induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes Gestational diabetes As additional subtypes are discovered it is anticipated that they will be reclassified within their own specific category Includes the former categories of gestational impaired glucose tolerance and gestational diabetes

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Table 3

Other Specific Types of Diabetes

Genetic defects of beta-cell function Chromosome 20, HNF4 MODY1 Chromosome 7, glucokinase MODY2 Chromosome 12, HNF1 MODY3 Chromosome 13, IPF-1 MODY4 Mitochondrial DNA 3243 mutation Others
Genetic defects in insulin action Type A insulin resistance Leprechaunism Rabson-Mendenhall syndrome Lipoatrophic diabetes Others Diseases of the exocrine pancreas Fibrocalculous pancreatopathy Pancreatitis Trauma / pancreatectomy Neoplasia Cystic fibrosis Haemochromatosis Others Endocrinopathies Cushings syndrome Acromegaly Phaeochromocytoma Glucagonoma Hyperthyroidism Somatostatinoma Others Continued on page 55

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Table 3 continued Drug- or chemical-induced see Table 4 Infections Congenital rubella Cytomegalovirus Others Uncommon forms of immune-mediated diabetes Insulin autoimmune syndrome antibodies to insulin Anti-insulin receptor antibodies Stiff Man syndrome Others Other genetic syndromes see Table 5

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Table 4 Drug- or Chemical-induced Diabetes Nicotinic acid Glucocorticoids Thyroid hormone Alpha-adrenergic agonists Beta-adrenergic agonists Thiazides Dilantin Pentamidine Vacor Interferon-alpha therapy Others

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Table 5 Other Genetic Syndromes Sometimes Associated with Diabetes Downs syndrome Friedreichs ataxia Huntingtons chorea Klinefelters syndrome Lawrence-Moon-Biedel syndrome Myotonic dystrophy Porphyria Prader-Willi syndrome Turners syndrome Wolframs
syndrome Others

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Figure 1: Unstandardized casual, random blood glucose values in the diagnosis of diabetes in mmol l-1 mg dl-1 Taken from the 1985 WHO Study Group Report 3

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Figure 2: Disorders of glycaemia: aetiological types and clinical stages

Stages Normoglycaemia Normal glucose tolerance Types

Hyperglycaemia Impaired glucose Diabetes Mellitus regulation IGT and/or IFG Not Insulin Insulin insulin requiring requiring requiring for for control survival

Type 1 Autoimmune Idiopathic Type 2 Predominantly insulin resistance Predominantly insulin secretory defects Other specific types Gestational diabetes In rare instances patients in these categories eg Vacor Toxicity, Type 1 presenting in pregnancy, etc may require insulin for survival 59

Source:math.tulane.edu