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Diabetic Medicine 1998;15:539-553
Definition, Diagnosis and Classiciation of Diabetes Mellitus and its Complication Part 1: Diagnosis and Classification of Diabetes Mellitus Provisional Report of a WHO Consultation

K.G.M.M. Alberti, P.Z. Zimmet for the WHO Consultation

"This document is not a formal publication of the World Health Organization (WHO). The views expressed in documents by named authors are solely the responsibility of these authors.

... We would urge you to send comments to the Co-Chairmen of the WHO group before the end of September 1998"


WHO 1998
The classification of diabetes mellitus and the tests used for its diagnosis were broght into order by the National Diabetes Data Group of the USA and the second WHO Expert Committee on Diabetes in 1979 and 1980. Apart from minor modifications by WHO in 1985, little has been changed since that time. There is however considerable new knowledge regarding the aetiology of different forms of diabetes as well as more information on the predictive value of different blood glucose values for the complications of diabetes. A WHO consultation has therefore been taken in parallel with a report by an American Diabetes Association Expert Committee to re-examine diagnostic criteria and classification. The present document includes the conclusions of the former and is intended for wide distribution and discussion before final proposals are submitted to WHO for approval.

The main changes proposed are as follows. The diagnostic fasting plasma (blood) glucose value has been lowered to 7.0 mmol/L or less (6.1 mmol/L). Impaired Glucose Tolerance (IGT) is changed to allow for the new fasting level. A new category of Impaired Fasting Glycaemia (IFG) is proposed to encompass values which are above normal but below the diagnostic cut-off for diabetes (plasma 6.1 or more but less than 7.0 mmol/L; whole blood 5.6 or more but less than 6.1 mmol/L). Gestational Diabetes Mellitus (GDM) now includes gestational impaired glucose tolerance as well as the previous GDM.

The classification defines both process and stage of disease. The process include Type 1, autoimmune and non-autoimmune, with beta-cell destruction; Type 2 with varying degrees of insulin resistance and insulin hyposecretion; Gestational Diabetes Mellitus; and Other Types where the cause is known (e.g. MODY, endocrinopathies). It is anticipated that this group will expand as causes of Type 2 become known. It is hoped that the new classification will allow better classification of individuals and lead to fewer therapeutic misjudgements.

Key words: diabetes mellitus; classification; diagnosis; Type 1 diabetes; Type 2 diabetes; gestational diabetes mellitus

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 glucose loads. In 1985 WHO slightly modified their criteria to coincide more closely with the NIDDG values (3). NDDG later modified their diagnostic requirements for diabetes mellitus in adults, dropping the intermediate sample and becoming identical with WHO. There are now many data available, and 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. In particular it has seemed necessary to modify the diagnostic fasting plasma glucose level and to look at intermediate non-diagnostic, but normal, fasting levels. It also seemed reasonable to place the classification system on a more aetiological basis.

Both the American Diabetes Association (ADA) and a WHO working group met separetly to discuss these issues. Fortunately there was cross-representation on the two groups and, in general, similar conclusions were reached. The ADA published their recommendations in 1997 (4), while the WHO group present their conclusions for consultation and comment. It should be added that the WHO group has also developed proposals for the diagnosis and classification of the complications, and these will be published shortly. At this juncture we are seeking comments and constructive suggestions with the aim of modifying the document. It should be noted that, unlike the ADA, we do not make recommendations about screening as these will vary widely according to local factors. We would urge you to send comments to the Co-Chairmen of the WHO group before the end of September 1998.

Definition and Diagnostic Criteria for Diabetes Mellitus and Other Categories of Glucose Intolerance
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 for 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 non-ketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of treatment, death. Often symtoms are not severe, or may be absent, and consequently hyperglycaemia of sufficient degree to cause pathological and functional changes may be present for a long term before the diagnosis is made. The long-term 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.

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 taget tissues resulting form insensitivity or lack of insulin.

Diagnostic and Diagnostic Criteria
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 symtoms and gross hyperglycaemia differ from those for the asymtomatic person with blood glucose values found to be just above the diagnostic cut-off value. Severe hyperglycaemia detected under conditions of acute infective, traumtic, circulatory or other stress may be transitory and should not in itself be regarded as diagnostic of diabetes. For the asymtomatic person, at least one additional plasma/blood glucose test result with a value in the diagnostic 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 re-testing until the diagnostic situation become clear. In these circumstances, the clinician should take into consideration such additional factors as family history, age, adiposity, and concomitant disorders, before deciding on a diagnostic or therapeutic course of action. It should be reiterated that the diagnosis of diabetes in an asymptomatic subject should never be made on the basis of a single abnormal blood glucose value. An alternative to the single blood glucose estimation or OGTT has long been sought to simplify the diagnosis of diabetes. Glycated haemoglobin, reflecting average glycaemia over a period for weeks, was thought to provide such a test. Although in certain cases it gives equal or almost equal sensitivity and specificity to glucose measurement, it is not available in many parts of the world and is not sufficiently well standardized for its use to be recommended at this time.

Diabetes in Children Diabetes in children usually presents with severe symtoms, 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 injections) is initiated immediately, often as a life-saving 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 a fasting blood glucose and/or an OGTT for diagnosis.

Diagnostic Criteria
The clinical diagnosis of diabetes is often prompted by symptoms such as 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 of the diagnostic values establishes the diagnosis in such cases. The 1985 WHO Study Group Report (1) also defines levels of blood glucose below which a diagnosis of diabetes is unlikely in non-pregnant 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 (i.e. between the levels that establish or exclude diabetes). If an OGTT is performed, it is sufficient to measure the blood glucose values while fasting and at 2 h after a 75 g oral glucose loads (Annexes 1 and 2). For children the oral glucose load is related to body weight: 1.75 g per kg. The diagnostic criteria in children are the same as for adults. Diagnostic interpretations of the fasting and a 2-h post-load concentration are shown in Table 1.

www red: Table 1 =

Change in Diagnostic Value for Fasting Plasma/Blood Glucose Concentrations.
The major change in the diagnostic criteria for diabetes from the previous WHO recommendation (3) is the lowering of the diagnostic value of the fasting plasma glucose concentration to 7.0 mmol/L (126 mg/dL) and above, from the former 7.8 mmol/L (140 mg/dL) and above. For whole blood the proposed new level is 6.1 mmol/L (110 mg/dL) and above, from the former 6.7 mmol/L (120 mg/dL).

The new fasting criterion is chosen to represent a value which in most persons is of approximately equal diagnostic significance to that of the 2-h post-load concentration, which is not changed. The equivalence has been established from several population-based studies (5-7) and it also represents an optimal cut-off point to seperate 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 7.0 mmol/L (126 mg/dL) and over (6), and of macrovascular disease in persons with such fasting concentrations, even in those with 2-h values of less than 7.8 mmol/L (140 mg/dl) (8).

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 2-h values, epidemiological studies of diagnostic screening have in the past been restricted to the 2-h values only (Table 1). If the OGTT is difficult to perform for any reason (e.g. logistical, economic) it is now recommended that the fasting plasma glucose alone can be used for epidemiological purposes. It should be recognized that some of the individuals identified by fasting values may be different from those identified by the 2-h values, and that overall prevalence may be somewhat different (9), although not always (5,10). Ideally both the 2-h and the fasting value should be used.

Earlier Classifications
The first widely accepted classification of diabetes mellitus was published by WHO 1989 (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 new class of Malnutrition-related 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 (ICD-10) 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 aetiolology was unknown. The classification or staging of diabetes mellitus based on clinical descriptive criteria is continued in the proposed classification, but a complementary classification according to the aetiology is now recommended.

Proposed Classification
The proposed classification encompasses both clinical stages and aetiological types of diabetes mellitus and other categories of hyperglycaemia, as suggested by Kuzuya and Matsuda (11).

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.

Application of the New Classification
The new classification contains stages which reflect the various degree 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 stages, 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). A disease process may be present but may not have progressed far enough to cause hyperglycaemia. The aetiological classification reflects the fact that the defect 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 the person has the Type 1 autoimmune process. Unfortunately there are few good highly specific indicators of the Type 2 process at present, although these no doubt will be reversed as aetiology is more clearly defined. The same disease 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. The individuals, therefore, do not require insulin. 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 (e.g. with weight reduction), progress (e.g. with weight gain), or stay the same.

The aetiological classification is given in Table 2.
Type 1 Autoimmune Idiopathic (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
Genetic defects of beta-cell function
Genetic defects in insulin action
Diseases of the exocrine pancreas
Drug- or chemical induced Infections
Uncommon forms of immune-mediated diabetes
Other genetic syndromes sometimes associated with diabetes

Gestational diabetes
Includes the former categories of gestational impaired glucose tolerance and gestational diabetes

  • The terms "insulin-dependent diabetes mellitus" and "non-insulin-dependent diabetes mellitus" and their acronyms IDDM and NIDDM are eliminated. These terms have been confusing and frequently resulted in patients being classified based on treatment rather than on pathogenesis.
  • The terms Type 1 and Type 2 are retained. The aetiological type named Type 1 encompasses the majority of cases which are primarily due to pancreatic islet beta-cell destruction and are prone to keto-acidosis. Type 1 includes those 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 beta-cell destruction or failure to which specific causes can be assigned (e.g. cystic fibrosis, mitochondrial defects). 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 defect(s) in insulin secretion, almost always with a major contribution from insulin resistance.
  • A recent international workshop reviewed the evidence for, and characteristics of, diabetes mellitus seen in undernourished populations (12,13). While 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, the class malnutrition-related diabetes mellitus (MRDM) has been 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 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 term "Impaired Glucose Tolerance" is reclassified as a stage of impaired glucose regulation, since it can be observed in any hyperglycaemic disorder and is itself not diabetes.
  • Gestational diabetes mellitus is retained but now encompasses the groups formerly classified as gestational impaired glucose tolerance (GIGT) and gestational diabetes (GDM).

    Clinical Staging of Diabetes Mellitus and Other Categories of Glucose Tolerance
    Aetiological types and clinical stages are presented in Figure 2.

    Diabetes Mellitus
    Diabetes mellitus, regardless of underlying cause, is subdivided into: insulin requiring for survival (corresponding to the former clinical class of "Insulin Dependent Diabetes Mellitus-IDDM"), e.g. C-peptide deficient; insulin requiring for control, i.e. metabolic control, rather than survival, e.g. some endogenous insulin secretion but insufficient to achieve normoglycaemia without added exogenous insulin; and not insulin requiring, i.e. those who may be controlled satisfactorily by non-pharmacological methods or drugs other than insulin. Together the latter two subdivisions constitute the former class of NIDDM.

    Impared glucose regulation - Impaired Glucose Tolerance and Impaired Fasting Glycaemia (IFG; non-diabetic fasting hyperglycaemia) Impaired Glucose Tolerance (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 Impaired Fasting Glycaemia (IFG) or "non-diabetic fasting hyperglycaemia" is also recognized because such subjects, like those of 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. IFG refers to fasting glucose concentrations which are lower than those required to diagnose diabetes mellitus but higher than the "normal" reference range.

    Impaired glucose regulation (IGT and IFG) refers to a metabolic state intermediate between normal glucose homeostasis and 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 (15. 16). 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) (17). 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 Syndrome that are cardiovascular risk factors. Self-evidently, those individuals with IGT manifest glucose intolerance only when challenged with an oral glucose load.

    An individual with a fasting plasma glucose concentration of 6.1 mmol/L (110 mg/dL) or greater (whole blood 5.6 mmol/L; 100 mg/dL), but less than 7.0 mmol/L (126 mg/dL) (whole blood 6.1 mmol/L; 110 mg/dL) is considered to have Impaired Fasting Glycaemia (IFG). If an OGTT is performed, some individuals with IFG will have IGT. Some may have diabetes but this cannot be determined without an OGTT. If resources allow, it is recommended that those with IFG have an OGTT to exclude diabetes.

    A fasting venous plasma glucose concentration of less than 6.1 mmol/L (110 mg/dL) has been chosen as "normal" (Table 1). Although this choice is arbitrary, such values are observed in people with proven normal glucose tolerance, and values above this are associated with a progressively greater risk of developing micro- and macrovascular complications (7, 8, 16, 18).

    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 earlier 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.

    Aetiological Types
    The aetiological types designate defects, disorders or processes which often result in diabetes mellitus. It should be stressed that an individual with a Type 1 process may be metabolically normal before the disease is clinically manifest, but the process of beta-cell destruction can be detected.

    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.

    Type 1
    Type 1 indicates the processes of beta-cell destruction that may ultimately lead to diabetes mellitus in which "insulin is required for survival" to prevent the development of ketoacidosis, coma and death. Type 1 is usually characterized by the presence of anti-GAD, islet cell or insulin antibodies which identify the autoimmune processes that lead to beta-cell destruction. In some subjects with this clinical form of diabetes, particularly non-Europids, no evidence of an autoimmune disorder is demonstrable and these are classified as "Type 1 idiopathic".

    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.

    Other Specific Types
    Other Specific Types (Table 3) are 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 formely classified as one type of malnutrition-related diabetes mellitus.

    Gestational Hyperglycaemia and Diabetes
    Gestational diabetes is carbohydrate intolerance resulting in hyperglycaemia of variable severity with onset or first recognition during pregnancy. The definition applies irrespective of whether or not insulin is used for treatment or the condition persists after pregnancy. It does not exclude possibility that the glucose intolerance may antedate pregnancy but has been previously unrecognized.

    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.

    Fasting and postprandial glucose concentrations are normally lower in the early part of pregnancy (e.g. first trimester and first half of second trimester) 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 normal 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 pregnancy does not itself establish that gestational diabetes may not develop later.

    Individuals at high risk for gestational diabetes mellitus includes older women, those with previous history of glucose intolerance, those with a history of large for gestational age babies, women from certain high-risk ethnic groups, and any pregnant women who has elevated fasting, or casual, blood glucose levels. It may be appropriate to screen pregnant women belonging to high-risk population 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 48 weeks of gestation.

    Diagnosis of Gestational Diabetes
    To determine if gestational diabetes is present in pregnant women, a standard OGTT should be performed after overnight fasting (8-14 h) by giving 75 g anhydrous glucose in 250-300 ml water (Annex 1). Plasma glucose is measured fasting and after 2 h. Pregnant women who meet WHO criteria for diabetes mellitus or IGT are classified as having Gestational Diabetes Mellitus (GDM). After the pregnancy ends, the women 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 6-week post-pregnancy result, are at increased risk of subsequently developing diabetes. The significance og IFG in pregnancy remains to be established. Any women with IFG, however, should have a 75 g OGTT.

    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, classify the patient.

    Type 1: beta-cell destruction, usually leading to absolute insulin deficiency.
    Auto-immune Diabetes Mellitus This form of diabetes, previously encompassed by the terms of insulin-dependent diabetes, Type 1 diabetes, or juvenile-onset diabetes, results from auto-immune 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 (19). The rapidly progressive form is commonly observed in children, but may also occur in adults (20). The slowly progressive form generally occurs in adults and is sometimes referred as latent autoimmune diabetes in adults (LADA) (20). Some patients, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease (21). 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 beta-cell function, sufficient to prevent ketoacidosis, for many years (22). Individuals with this form of Type 1 diabetes eventually become dependent on insulin for survival and are at risk for ketoacidosis (23). At this stage of the disease, there is little or no insulin secretion as manifested by low or undetectable levels of plasma C-peptide (24).

    Markers of immune destruction, including islet cell autoantibodies, and/or autoantibodies to insulin, and autoantibodies to glutamic acid decarboxylase (GAD65) are present in 85-90% of individuals with Type 1 diabetes mellitus when fasting diabetic hyperglycaemia is initially detected (25). The peak incidence of this form of Type 1 diabetes occurs in childhood and adolescence, but the onset may occur at any age, ranging form childhood to the ninth decade of life (26). There is a genetic predisposition to autoimmune destruction of beta cells, and it is also related to enviromental factors that are still poorly defined. Although patients are rarely 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, Hashimoto´s thyroiditis, and Addison´s disease (27).

    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 (28). 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 (29).

    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-insulin-dependent diabetes, or adult-onset 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 (30, 31). At least initially, and often throughout their lifetime, these individuals do not need insulin treatment to survive. This form of diabetes is frequently underdiagnosed for many years because the hyperglycaemia is often not severe enough to provoke symtoms of diabetes (12, 33). Nevertheless, such patients are at increased risk of developing macrovascular and microvascular complications (32, 33). 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 3-5.

    The majority of patients with this form of diabetes are obese, and obesity itself causes or aggravates insulin resistance (34. 35). 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 (36). Ketoacidosis is infrequent in this type of diabetes; when seen it usually arises in association with the stress of another illness such as infection (37, 38). 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 beta-cell function been normal (39). 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 maybe increased by weight reduction, increased physical activity, and/or pharmacological treatment of hyperglycaemia but is not restored to normal (40, 41). The risk of developing Type 2 diabetes increases with age, obesity, and lack of physical activity (42, 43). It occurs more frequently in women with prior GDM and in individuals with hypertension or dyslipidaemia. Its frequency varies in different ethnic/racial subgroups (42-45). It is often associated with strong familial, likely genetic, predisposition (44-46). 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 been shown to have autoantibodies similar to those found in Type 1 diabetes. This form of diabetes may masquerade as Type 2 diabetes if antibody determinations are not made. Patients who are non-obese or who have relatives with Type 1 diabetes and who are Northern European origin may be suspected of having late onset Type 1 diabetes.

    Other Specific Type
    Genetic Defects of Beta-cell Function
    Several forms of the diabetic state may be associated with monogenic defects in beta-cell 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 (47, 48). Abnormalities at three genetic loci on different chromosomes have now been characterized. The most common is associated with mutations on chromosome 12 in a hepatic nuclear transcription factor referred to as HNF1alpha (49). A second form is associated with mutations in the glucokinase gene on chromosome 7p (50, 51). Glucokinase converts glucose to glucose-6-phosphate, 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 HNF4alpha gene on chromosome 20q (52). HNFalpha is a transcription factor which is involved in the regulation of the expression of HNFalpa. A fourth has recently been ascribed to mutations in another transcription factor gene, IPF-1, which in its homozygous form leads to total pancreatic agenesis (53). Specific genetic defects in other individuals who have similar clinical presentation are currently being defined.

    Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness (54). The most common mutation occurs at position 3243 in the tRNA leucinegene, leading to an A to G substitution. An identical lesion occurs in the MELAS syndrome (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like syndrome); however, diabetes is not part of this syndrome, suggesting for unknown reasons different phenotypic expressions of this genetic lesion (55).

    Genetic abnormalities that result in inability to convert proinsulin to insulin have been identified in a few families. Such traits are usually inherited in an autosomal dominant pattern (56, 57) and the resultant carbohydrate intolerance is mild. Simarly, 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 (58, 59).

    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 symtomatic diabetes (60, 61). Some individuals with these mutations have acanthosis nigricans. Women may have virilization and have enlarged polycystic ovaries. In the past, this syndrome was termed Type A insulin resistance (60). Leprechaunism and Rabson-Mendenhall syndrome are two paediatric syndromes that have mutations in the insulin receptor gene with subsequent alterations in the insulin receptor function and extreme insulin resistance (61). The former has characteristic facial features while the latter is associated with abnormalities of teeth and nails and pineal hyperplasia.

    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 (62, 63). With the exception of cancer, damage to the pancreas must be extensive for diabetes to occur. However, adenocarcinomas that involves only a small portion of the pancreas have been associated with diabetes. This implies a mechanism other than simple reduction in beta-cell mass (64). If extensive enough, cystic fibrosis and haemochromatosis will also damage beta cell and impair insulin secretion (65, 66). Fibrocalculous pancreaticopathy may be accompanied by abdominal pain radiating to the back and pancreatic calcification on X-ray and ductal dilatation (67). Pancreatic fibrosis and calcified stones in the exocrine ducts are found at autopsy.

    Several hormones (e.g. growth hormone, cortisol, glucagon, epinephrine) antagonize insulin action. Diseases associated with excess secretion of these hormones can cause diabetes (e.g. acromegaly, Cushing´s syndrome, glucagonoma and phaechromocytoma) (68). These forms of hyperglycaemia typically resolve when the hormone excess is removed.

    Somatostatinoma, aldosteronoma-induced hypokalaemia, can cause diabetes, at least in part by inhibiting insulin secretion (69, 70). Hyperglycaemia generally resolves following successful removal of the tumour.

    Drug- or Chemical-induced 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 (71, 72). 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 (73-75). Such drug reactions are fortunately rare. There are also many drugs and hormones which can impair insulin action. Examples include nicotinic acide and glucocorticoids (71-72). The list shown in Table 4 is not all-inclusive, but reflects the more commonly recognized drug-, hormone- or toxin-induced forms of diabetes and hyperglycaemia.

    Certain viruses have been associated with beta-cell destruction. Diabetes occurs in some patients with congenital rubella (76) . In addition, Coxsackie B, cytomegalyvirus and other virus (e.g. adenovirus and mumps) have been implicated in inducing the disease (77-79).

    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 Type 1 diabetic proces. Postprandial hyperglycaemia of a severity sufficient to fulfil the criteria for diabetes has been reported in rare individuals who spontaneously develop insulin autoantibodies (80-81). However, these individuals generally present with symtoms 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 (82). Affected people usually have high titres of the GAD autoantibodies and approximately 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 (83).

    Anti-insulin receptor antibodies can cause diabetes by binding to the insulin receptor thereby reducing the binding of insulin to target tissues (84). However, these antibodies also can act as an insulin agonist after binding to the receptor and can thereby cause hypoglycaemia (85). Anti-insulin receptor antibodies are occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases (86). As in other states of extreme insulin resistance, patients with anti-insulin receptor antibodies often have acanthosis nigricans. In the past, this syndrome was termed Type B insulin resistance.

    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 Down´s syndrome, Klinefelter´s syndrome, Turner´s syndrome. Wolfram´s syndrome is an autosomal recessive disorder characterized by insulin-deficient diabetes and the absence of beta cells at autopsy (87). Additional manifestations include diabetes insipidus, hypogonadism, optic atrophy, and neural deafness. These and other similar disorders are listed in Table 5.

    The Metabolic Syndrome
    A major classficiation, 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 (17).

    Often a person with abnormal glucose tolerance (IGT or diabetes) will be found to have at least one or more ofthe other cardiovascular disease (CVD) risk components (17). This clustering has been labelled variously as Syndrome X (17), the Insulin Resistance Syndrome (42) or the Metabolic Syndrome (42).

    Epidemiological studies confirm that this syndrome occurs commonly in a wide variety of ethnic groups including Europids, Afro-Americans, Mexican-Americans, Asian Indians and Chinese, Australian Aborigines, Polynesians and Micronesians (42, 88). In 1988 Reaven focused attention on this cluster, naming it Syndrome X (17). 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 (42, 88, 89), although these 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 become much more powerful (90). This means that the management of people with hyperglycaemia and other features of the Metabolic Syndrome should focus not only on blood glucose control but also strategies for reduction of the other CVD risk factors (91).

    It is well documented that the features of the Metabolic Syndrome can be present for 10 years before detection of the glycaemic disorders (92). 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 of the prevention of both diabetes and cardiovascular disease (93).

    There is no internationally agreed definition for the Metabolic Syndrome. The following, which does not imply causal relationships, is suggested as a working definition; glucose intolerance, IGT or diabetes and/or insulin resistance together with two or more of the other components listed below.

    1. Impaired glucose regulation or diabetes (See Table 1)
    2. Insulin resistance (under hyperinsulinaemic euglycaemic conditions, glucose uptake below lowest quartile for background population under investigation)
    3. Raised arterial pressure 160/90 mm Hg or more
    4. Raised plasma triglycerides (1.7 mmol/L; 150 mg/dL or more) and/or low HDL-cholesterol (less than 0.9 mmol/L, 35 mg/dL men; less than 1.0 mmol/L, 39 mg/dL women)
    5. Central obesity (males: waist to hip ratio more than 0.9; females: more than 0.85) and/or BMI over 30.
    6. Microalbuminuria (urinary albumin excretion rate 20 or more ug/min or albumin:creatinine ratio 20 or less mg/g

    Several other components of the Metabolic Syndrome have been described (e.g. hyperuricaemia, coagulation disorders, raised PAI-1) but they are not necessary for the recognition of the condition.

    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.

    ANNEX 1 The Oral Glucose Tolerance Test
    The oral glucose tolerance test (OGTT) is principally used for diagnosis when glucose levels are equivocal, during pregnancy, or in epidemiological setting to screen for diabetes and impaired glucose tolerance.

    The OGTT should be administered in the morning after at least 3 days of unrestricted diet (greater than 150 g of carbohydrate daily) and usual physical activity. The test should be preceded by an overnight fast of 8-14 h, 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 (e.g. medications, inactivity, infection).

    After collection of the fasting blood sample, the subject should drink 75 g of anhydrous glucose (or partial hydrolysis of starch of the equivalent carbohydrate content) in 250-300 ml of water over the course of 5 min. For children, the test load should be 1.75 g of glucose per kg body weight up to a total of 75 g of glucose. Blood samples must be collected 2 h after the test load.

    Unless the glucose concentration can be determined immediately, the glucose sample should be collected in a tube containing sodium fluoride (6 mg per ml whole blood) and immediately centrifuged to separate plasma; the plasma should be frozen until the glucose concentration can be estimated. For interpretation of results, refer to Table 1.

    ANNEX 2 Methods for Measuring Substances in Blood and Urine
    Measurement of Glucose in Blood Reductiometric methods (the Somogyi-Nelson, the ferricyanide and neocuprine autoanalyser methods) are still in use for blood glucose measurement. The o-toluidine method also remains in use but enzyme-based methods are widely available, for both labaratory and near-patient use. Highly accurate and rapid (1-2 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 fluride show an initial rapid fall in glucose 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 reagent-strip glucose oxidase methods has made bedside estimation of blood glucose very popular. However the cost of the reagent-strips 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 colour-matching techniques. Electrochemical and reflectance meters can give coefficients of variation of well under 5%. Reagent-strip 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 filter-paper) and self-monitoring using glucose reagent-strips with direct colour-matching or meters is now widely practised. Patients should be properly trained in the appropiate techniques to avoid inaccurate or misleading results.

    The insulin-treated patient is commonly requested to build up a glycaemic profile by self-measurement of blood glucose at specific times of the day (and night). A 7-point 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 24-h period, and it may be compiled from samples collected at different times over several days.

    Measurement of Glucose in Urine
    Insulin-treated pateints who do not have access to facilities for self-measuement of blood glucose should test urine samples passed after rising, before main meals, and before going to bed. Non-insulin-dependent 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 may be improved a little by collecting short-term fractions (15-30 min) of the urine output. Benedict´s quantitative solution or self-boiling caustic soda/copper sulphate tablets may be used or more convenient, but costly, semi-quantitative enzyme-based 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 aceto-acetic acid) when tests for glucose are repeatedly positive, or when there is substantial disturbances of health, particularly with infections. Rothera´s sodium nitroprusside test may be used or, alternatively, reagent-strips that are sensitive to ketones. In emergency situations such as diabetic ketoacidosis, a greatly raised concentration of plasma ketones can be detected with a reagent-strip and roughly quantified by serial 1 in 2 dilution of plasma with water

    Diabetic Medicine 1998;15:539-553

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