These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly.ORIGINAL ARTICLE Crucial Points at Diagnosis Type 2 diabetes or slow type 1 diabetes Paul Zimmet, MD, PHD Two major types of diabetes have been recognized since the late 1930s.
However, in recent times there have been major changes in classification and understanding
of these types, including improved knowledge of maturity-onset diabetes in the young, with
the identification of mutations relating to impaired insulin secretion and the recognition
of slow-onset type 1 diabetes in adults now designated as latent autoimmune diabetes in
adults (LADA). A major problem area in diabetes classification concerns cases of slowly
progressive forms of type 1 and type 2 diabetes, particularly in adults aged 25–50
years. This is a more contemporary problem because cases of type 2 diabetes are presenting
at an increasingly younger age. In the landmark U.K. Prospective Diabetes Study of type 2
diabetes, islet cell antibodies (ICAs) and antibodies to glutamic acid decarboxylase
(anti-GAD) were measured at diagnosis in 3,672 patients. The overall proportion with ICAs
was 6%, and anti-GADs was 10%. These subjects clearly had type 1 diabetes or LADA by both
phenotypic and genotypic features. The presence of autoantibodies correlated particularly
with a younger age and phenotypic features consistent with type 1 diabetes (e.g., early
age at diagnosis, lower BMI, and reduced Diabetes Care 22 (Suppl. 2):B59–B64, 1999 Diabetes has been known to medicine for over 2,000 years (1). The more ancient descriptions probably related to the currently recognized type 1 diabetes (2). In the previous century, a less symptomatic variant was identified characterized by heavy glycosuria, occurrence in later life, and an association with obesity rather than wasting (2), representing the currently recognized type 2 diabetes. A functional basis for these two paradigmatic types of diabetes was established by the bioassay studies of Bornstein and Lawrence (3). A rational classification of diabetes was attempted in 1979 by the U.S. National Diabetes Data Group (NDDG) (4) and in 1980 by a World Health Organization (WHO) Expert Committee (5). These provided a much-needed departure point for a standardized approach to classification of disorders of glucose tolerance. These reports have provoked both intense debate and research directed toward the development of a classification that would fulfill not only the need of clinicians for optimal management of diabetes, but also the needs of laboratory and clinical researchers and epidemiologists interested in the causes of diabetes. One particular problem area concerned those "unclassifiable" cases of diabetes that included slowly progressive forms of type 1 and type 2 diabetes, particularly in adults in the 25- to 50-year age range. Moreover, cases of type 2 diabetes appeared to be presenting at an increasingly younger age at onset. Formerly, younger-onset type 2 diabetes was seen only in genetically enriched groups, notably Pima Indians and Nauruans (6), but younger-onset type 2 diabetes has become evident in Europid groups, and this is confounding for the initial diagnosis and therapy of diabetes in young adults, particularly in those who are nonobese (6). In adult-onset diabetes, including cases regarded
as type 2 diabetes, there can be a wide range of insulin levels representing
hyperinsulinemia to hypoinsulinemia, as well as variations in insulin sensitivity and
resistance (1,6,7).
The association of hyperinsulinemia with other metabolic and cardiovascular disease risk
factors to form the metabolic syndrome provides yet another dimension to the problem (6). We can also note those forms of type 2 diabetes that comprised
the former maturity-onset diabetes of the young attributable to mutations of the
glucokinase genes (8) and hepatocyte nuclear factor-1 The essence of the classification problem is, of course, the incomplete understanding of the pathogenesis of the two major types of diabetes, given that knowledge of causation is the optimal basis for classification of disease. Previously, the two major types were designated as "juvenile" or "adult" onset or as "insulin-dependent" or "non-insulin-dependent"; but because neither provided for mutual exclusivity nor was etiology-based, the noncommittal type 1/type 2 classification was adopted (4). The high association of autoimmune serological reactions and particular HLA alleles in type 1 diabetes strongly implicated autoimmunity in pathogenesis, so that "autoimmune" and "type 1" diabetes became virtually synonymous (4,5,14). However, what is vexing for classifiers is that autoimmunity does not contribute to type 1 diabetes as substantially in non-Europid as in Europid populations, at least in our experience (6,15), and the onset of autoimmune diabetes is characteristically abrupt with insulin deficiency in childhood but can be slower and without insulin dependency for some years in adults. The level of genetic "loading" for islet cell autoimmunity may account for these differences (15). The ensuing text reviews the experiences of our laboratories in defining the features of slow-onset or latent autoimmune diabetes in adults (LADA) and how this entity can be accommodated in current systems of classification. TYPE 2 DIABETES OR SLOW-ONSET TYPE 1 DIABETES?— An adult presenting with diabetes is usually assumed to have type 2 diabetes, but type 1 diabetes is more frequent in adults than formerly believed (6). In fact, in some 60% of cases, type 1 diabetes develops after the age of 20 years. Mølbak et al. (16) in Denmark observed that type 1 diabetes often developed in the elderly. The fact that the cumulative incidence of type 1 diabetes from the age of 30 years onward is stable indicates that the lifetime risk of developing type 1 diabetes is higher than has previously been recognized. A population-based study of insulin-treated
adults in New Zealand by Scott and Brown (17) showed that 14.4%
of all known adults with diabetes were insulin-treated, and most of these subjects (83%)
commenced insulin as a permanent treatment within 1 year of diagnosis and hence were most
likely to have type 1 diabetes. These findings were confirmed in Sweden by Hagopian et al.
(13), who reported that of newly diagnosed patients with
adult-onset diabetes who were seropositive for antibodies to GAD (anti-GAD) at the time of
diagnosis, 60% required insulin within 18 months. However, in adults, type 1 diabetes may
not present as the classic acute disease seen in children and adolescents (6). Adult-onset type 1 diabetes cases can masquerade, and initially
be misclassified, as type 2 diabetes because autoimmune destruction of The usual patient with latent autoimmune diabetes in adults is 25 years or older and nonobese, presents with what clinically appears to be type 2 diabetes (12), and often is maintained in good metabolic control on diet or oral hypoglycemic therapy for up to several years before insulin dependency (Table 1). This suggests that the underlying autoimmune process proceeds slowly over many years in such patients before this form of disease becomes overt, and there is slow progression thereafter to insulin dependency (12). In fact, we have shown in a study on Finnish women that up to 10 years may elapse before insulin dependency ensues (19). Studies in our laboratories show the presence of all of the usual serological markers of autoimmunity (12) and certain DR and DQ alleles associated with type 1 diabetes susceptibility (20,21). In several recent reports, a high frequency of anti-GAD positivity has been noted in cases of LADA from a wide range of ethnic groups and populations (15,22–24).
Given that type 1 diabetes in adults is presumably preceded by a slowly evolving autoimmune insulitis, detection of various of the serum autoantibodies that mark this process may provide clues to the natural history of the disease, although the actual predictive capacity of the presence of one or more autoantibodies still awaits detailed analysis because of the unknown duration of the latency period in adults. The possibility also exists that a protracted phase of nondestructive insulitis may exist in humans as it does in the NOD mouse (25). RECOGNITION OF LADA— Suggestions that slow-onset diabetes in adults could have an autoimmune basis came initially from studies in the early 1980s (26,27). Later, Groop et al. (28) in 1986 reported a high frequency of islet cell antibodies (ICAs) in adult Finnish patients with what was thought to be type 2 diabetes, but was then termed latent type 1 diabetes. They selected 102 cases from the register of the Helsinki Diabetic Association and the outpatient clinic of the Helsinki University Hospital, and their sera were available 7 years later for study in our laboratory for antibodies to GAD (12). For this group, the entry criteria included >35 years of age at diagnosis, nonketotic diabetes without insulin treatment over at least 6 months of observation, and an initial diagnosis of type 2 diabetes. They were studied according to 1) serological markers of autoimmunity, including anti-GAD, ICA, and antibodies to thyroid and gastric antigens and 2) postglucagon stimulated C-peptide levels to distinguish insulin-deficient and non–insulin-deficient subjects. Markers of autoimmunity, and particularly anti-GAD, were found to cluster significantly with insulin deficiency. In addition, such cases showed the typical high-susceptibility HLA alleles characteristic of type 1 diabetes (29). A frequency of anti-GAD positivity of 75% was found in the insulin-deficient group compared with 12% in the non–insulin-deficient group (Table 2) (12). Notably, anti-GAD was more useful than ICA in predicting insulin deficiency. From these results, we suggested that in a proportion of adults who present with type 2 diabetes, the actual pathology resembles that of type 1 diabetes, namely a slowly evolving autoimmune insulitis, accordingly designated as LADA.
It is with the LADA group that problems exist in classification between type 1 and type 2 diabetes in adults. Our initial reports on LADA (12,30) have now been confirmed in populations, so that clearly, the presentation of autoimmune type 1 diabetes in adult life is much more common than formerly believed (6). As many as 10–15% of all adults with diabetes may have LADA, and LADA may constitute up to 50% of cases of nonobese type 2 diabetes (6). This figure may be even higher because positivity for anti-GAD may not be the sole marker of autoimmunity in this group, given that about 25% may have markers other than anti-GAD (12). Thus, not all those who show the LADA phenotype will be anti-GAD positive, and other markers of autoimmune diabetes, including ICA, insulin autoantibody, or anti-ICA512/IA2 may be present, although the frequency of anti-GAD is almost double that of ICA in this age-group (12,31). More recent reports show that in adults, testing for anti-ICA512 and insulin autoantibody actually adds very little. Thus, Elbein et al. (24) found a much lower frequency of anti-ICA512 in LADA than in childhood type 1 diabetes, confirming findings from our laboratory (32). Whittingham et al. (32) convincingly showed the long latency of seropositivity of anti-GAD and the predominance of anti-GAD over anti-ICA512 and ICA as serological markers of autoimmune insulitis in adults. One of the most convincing arguments for the
importance of LADA comes with the recent publication by Turner et al. (31) on the results of testing for ICA and anti-GAD in the U.K.
Prospective Diabetes Study (UKPDS). Here, ICA and anti-GAD were measured at diagnosis in
3,672 patients of Europid background selected by family physicians in the U.K. as having
"typical" type 2 diabetes. The proportion overall of these patients who had ICA
was 6% and anti-GAD 10%; 12% of patients had either ICA or anti-GAD, and 4% had both
(Table 3). The presence of autoantibodies in this cohort correlated particularly with a
younger age and phenotypic features consistent with type 1 diabetes, i.e., early age at
diagnosis, lower BMI, and reduced
In another study utilizing the Tasmanian Insulin-Treated Diabetes Register consisting of patients with type 1 diabetes and type 2 diabetes receiving insulin (33,34), we investigated the association of anti-GAD with early commencement of insulin treatment in adult-onset diabetes to ascertain whether this association is stronger than phenotypic characteristics often used for classification of diabetes (35). In the Tasmanian cohort, 36% of male subjects and 39% of female subjects were found to be positive for anti-GAD. Male subjects (64%) were more likely than female subjects (41%) to be treated with insulin within a year of diagnosis. For male subjects, univariate factors significantly associated with early insulin treatment included positivity for anti-GAD, a positive family history of diabetes, and a low BMI at diagnosis (35). For female subjects, the univariate factors significantly associated with early insulin treatment included positivity for anti-GAD and lack of obesity. Age at diagnosis was not associated with early insulin treatment for either male or female subjects (35). In multivariate models, anti-GAD positive status was the only variable associated with early insulin treatment for both sexes (35). Scatterplots (Fig. 1) of age at diagnosis by period from diagnosis to commencement of insulin therapy showed that anti-GAD negative subjects had a large degree of variation in the time from diagnosis to insulin treatment. However, it is apparent that most anti-GAD positive subjects started insulin soon after diagnosis.
The UKPDS (31)
and Tasmanian (35) studies add weight to data from our earlier
studies (12,22,30)
that measurement of anti-GAD is a useful marker for classifying individuals with
adult-onset diabetes, even more so than traditional characteristics such as BMI and age at
diagnosis. Accordingly, a routine test for anti-GAD is a realistic recommendation for
virtually all adults presenting with type 2 diabetes, particularly those with the nonobese
form of the disease (6). There are now available several
commercially developed assays, both radioimmunoassays (23,36) and an enzyme-linked immunosorbent assay (37)
with established reliability. The anti-GAD assay can provide important information to
clinicians on the possibility of future insulin dependency. Earlier treatment of diabetes
with insulin may improve their immediate well-being and, moreover, provides a chance of
preserving remaining IMPLICATIONS OF LADA FOR CLASSIFICATION OF HYPERGLYCEMIA— It is well recognized that the earlier classifications devised by the WHO (5,14) and the NDDG (4) were based predominantly on phenotypic characteristics rather than genotype or etiology and failed to discriminate between adults with type 1 diabetes and adults with insulin-treated type 2 diabetes. Although "dependence on insulin for survival" may be easy to establish in the setting of acute-onset diabetes seen in children, the commencement of insulin treatment in adults usually depends more on poor glycemic control rather than absolute insulin deficiency; hence, the use of insulin as a classification criterion has little value. New serological markers, such as anti-GAD, are now available to help classify adult-onset diabetes cases, although these markers still require evaluation using population-based data. In an attempt to consolidate recent advances, the American Diabetes Association and WHO have convened expert groups to review again the classification of diabetes. The American Diabetes Association report has recently been published (7), and the WHO recommendations are likely to be almost identical. The newly suggested classification is different from the 1979–1985 versions, as it accommodates both clinical stages of hyperglycemia as well as presumed etiological types. The classification by etiological type results from new knowledge of the causes of hyperglycemia, including diabetes (7,40). The actual staging proposed reflects that any etiological type of diabetes can pass or progress through several clinical phases, both asymptomatic and symptomatic, during its natural history (41). Moreover, individuals may move in either direction, from stage to stage of glycemia. Under what is termed the type 1 process in the newly proposed classification, there will be both acute- and slow-onset autoimmune forms, which recognizes the research discussed earlier with respect to LADA. Antibodies to GAD indicate an underlying autoimmune process and have a high positive predictive value for type 1 diabetes in adults (19). An interesting example of the dilemmas of classification is the case of African Americans from Flatbush, a borough of New York. In adults presenting with diabetic ketoacidosis (typical of type 1 diabetes), yet subsequently having a natural history of diabetes akin to type 2 diabetes and usually only requiring treatment with diet alone, ICA and anti-GAD negativity was found (41). This form, now called "Flatbush diabetes," clearly does not fit into the type 1 process category and would fit into the type 2 process until such a time that the actual etiological defect is defined. In our experience, levels of anti-GAD remain stable in adults with autoimmune diabetes over many years (12,30). Tuomi et al. (12) particularly noted this long persistence of anti-GAD, whereas ICA usually disappears shortly after diagnosis (24). Moreover, in adult cases, Tuomi et al. (12) found that anti-GAD had a sensitivity for the diagnosis of diabetes in excess of 60%. This allows the anti-GAD status at the time of diagnosis of diabetes to be determined retrospectively. Additionally, anti-GAD assays are easy to standardize and are relatively inexpensive, making them ideal for population-based studies and clinical use. The misdiagnosis and misclassification hitherto
of adult-onset type 1 diabetes may have been attributable partially to the shortcomings in
the current WHO (14) and NDDG (4)
classification systems, which were based on observation of the phenotype and consideration
of insulinopenia, which are often difficult to demonstrate in adults. Some individuals
with type 2 diabetes can be distinguished from those with type 1 diabetes using C-peptide
measurements (4), but there will still be a proportion of subjects
with equivocal results. Such subjects can have either of the major type of diabetes,
particularly in type 2 diabetes if the patient is tested when insulin secretion may have
started to decline in accordance with the "Starling curve" of the pancreas (6). Conversely, there may be residual The Tasmanian population-based study (35) and our UKPDS data (31) indicate that
measurement of anti-GAD has particular utility for classifying adult-onset diabetes and
predicting future insulin dependency. From a clinical perspective, it is important that
adults with type 1 diabetes have their type of diabetes identified, as this can prompt the
appropriate treatment. Failure to commence insulin treatment in these individuals may mean
that several months of unnecessarily poor control may ensue. Despite the clear findings of
the Diabetes Control and Complications Trial that tight glycemic control is beneficial (42), it may be argued that a few extra months of poor control would
only minimally increase the risk of complications. Against this, there are data that
suggest prompt insulin therapy preserves CONCLUSIONS— Two major types of diabetes have been recognized from the late 1930s to the present, and yet there have been vast changes in perception of these types in the intervening 60 years. One obvious change has been a better understanding of the intermediate types, including "precocious" type 2 diabetes due to identified mutations relating to impaired insulin secretion (8–11) and latent type 1 diabetes in adults due to slowly evolving islet cell autoimmunity (12,13). The newly proposed classification (7) accommodates these in a two-dimensional manner by specifying both cause and time frame as descriptive indices. Newer classifications will certainly evolve over periods as short as 5 to 10 years as the actual causes of type 1 and type 2 diabetes are pinpointed even more clearly. The pathogenic elements of type 1 and type 2 diabetes will be better understood, with autoimmunity accounting predominantly for type 1 diabetes and genetic enzymatic/metabolic disorders of insulin secretion and glucose disposal accounting for type 2 diabetes. One problem that will continue to vex classifiers is the allocation of the relative degree of genetic and environmental contributions to these pathogenetic elements. However, perhaps we can find consolation and hope in a biblical context with St. Paul's reassurance to the Corinthians that our knowledge is imperfect and our prophecy is imperfect, but when the perfect comes, the imperfect will pass away (43). Acknowledgments— UKPDS was supported by the U.K. Medical Research Council, the British Diabetic Association, the U.K. Department of Health, the National Eye Institute, the British Heart Foundation, the National Institute of Digestive, Diabetes, and Kidney Disease in the National Institutes of Health, and by pharmaceutical companies, chiefly Bayer, Novo-Nordisk, and Bristol Myers Squibb. We wish to thank Wellcome Trust for a grant for the ICA and anti-GAD assays and Ray Spark for technical performance of the anti-GAD assays. We also thank Dr. Irene Stratten for statistical analyses of the UKPDS. References 2. Zimmet P: The challenge of diabetes. In The Medical Challenge: Complex Traits. Fisher EP, Möller G, Eds. Zurich, Piper, 1997, p. 55–110 3. Bornstein J, Lawrence RD: Plasma insulin in human diabetes mellitus. Br Med J 2:1541–1542, 1951 4. National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039–1057, 1979 5. World Health Organization: Diabetes Mellitus: Second Report. Geneva, World Health Org., 1980, p. 8–12 (Tech. Rep. Ser., no. 646) 6. Zimmet P: The pathogenesis and prevention of diabetes in adults: genes, autoimmunity, and demography. Diabetes Care 18:1050–1064, 1995 7. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1197, 1997 8. Froguel P, Vaxillaire M, Sun F, Velho G, Zouali H, Butel MO, Lesage S, Vionnet N, Gement K, Fougerousse F, Tanizawa Y, Weissenbach-Beckman JS, Lathrop GM, Passa P, Permutt MA, Cohen D: Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356:162–164, 1992 9. Yamageta K, Oda N,
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Wild T, Scherbaum WA, Gleichmann H, Landt M, Santiago J, Endl J, Landgraf R, Cavallo MG, Ganz M, Pozzilli P: Comparison of a new anti-glutamic acid decarboxylase (GAD) enzyme-linked immunosorbent assay (ELISA) with radioimmunoassay methods: a multicenter study. Horm Metab Res 29:403–406, 1997 38. Skyler J, Marks J: Immune intervention in type I diabetes mellitus. Diabetes Rev 1:15–42, 1993 39. Schatz D: The Diabetes Prevention Trial—Type 1 Diabetes (DPT-1) design and implementation of the oral antigen (insulin) protocol (Abstract). Diabetes 44 (Suppl. 1):A230, 1995 40. Kuzuya T, Matsuda A: Classification of diabetes on the basis of etiologies versus degree of insulin deficiency. Diabetes Care 20:219–220, 1997 41. Banerji MA, Chaiken R, Huey H, Tuomi T, Norin AJ, Mackay IR, Rowley MJ, Zimmet PZ, Lebovitz HE: GAD antibody negative NIDDM in adult black subjects with diabetic ketoacidosis and increased frequency of HLA DR3 and DR4. Diabetes 13:741–745, 1994 42. Diabetic Control and Complications Trial Research Group: The effect of intensive treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986, 1993 43. St. Paul: First Epistle to the Corinthians. Chapter 13:9,10 From the International Diabetes Institute (P.Z., D.M.) and the Department of Biochemistry and Molecular Biology (M.R., I.M.), Monash University, Melbourne, Australia; and the Diabetes Research Laboratories (R.T.), Radcliffe Infirmary, Oxford, U.K. Address correspondence and reprint requests to Paul Zimmet, MD, PhD, International Diabetes Institute, 260 Kooyong Road, Caulfield South, 3162, Australia. E-mail: pzimmet@idi.org.au. Received for publication 27 May 1998 and accepted in revised form 6 October 1998. P.Z. serves as a member of the scientific advisory board for Autogen, an unlisted biotechnology company. Abbreviations: ICA, islet cell antibody; LADA, latent autoimmune diabetes in adults; NDDG, National Diabetes Data Group; UKPDS, U.K. Prospective Diabetes Study; WHO, World Health Organization. This article is based on a presentation at a satellite symposium of the 16th International Diabetes Federation Congress. The symposium and the publication of this article were made possible by educational grants from Hoechst Marion Roussel AG. Copyright © 1999 American Diabetes Association For Technical Issues contact webmaster@diabetes.org |
-cell function). Overall, of patients requiring
insulin by 6 years, 38% were anti-GAD+ at baseline compared with 5.3% of those
not on insulin at 6 years. Antibodies to GAD indicate an underlying autoimmune process and
have a high positive predictive value for type 1 diabetes and future insulin dependency in
adults.
(
-cells
in adults is usually slower than in childhood-onset cases (
