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Type 1 diabetes is characterized by immune-mediated destruc-tion of pancreatic β-cells resulting in insulin deficiency. This results in a common biochemical end-point of hyperglycaemia and risk of ketoacidosis, but the clinical presentation varies widely depending on the rate and degree of β-cell failure. As a consequence, there has been increasing recognition of type 1 diabetes presenting in adulthood, and a blurring of the margins between type 1 and type 2 diabetes. These points are reflected in the most recent report on the diagnosis and classification of diabetes from the American Diabetes Association (ADA).

Classification of diabetes mellitus

An expert committee of the ADA presented a report on the diagnosis and classification of diabetes mellitus in 1998. It made a number of recommendations.• Diabetes mellitus is classified on an aetiological basis.• 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 have often resulted in classification of patients on the basis of treatment rather than aetiology.• The terms ‘type 1’ and ‘type 2’ diabetes are retained (with arabic rather than roman numerals). The diagnosis of type 2 diabetes is essentially one of ex-clusion, and hence strict diagnostic criteria for type 1 diabetes assume greater importance. Type 1 diabetes encompasses

Paul Lambert is Clinical Research Fellow in the Department of Diabetes and Metabolism at Southmead Hospital, Bristol, UK. He qualified from the University of Oxford, and is training as a specialist registrar in diabetes and endocrinology in Bristol. His research interest is the genetics of type 1 diabetes.

Polly J Bingley is Reader in Diabetic Medicine at the University of Bristol, UK. She qualified from University College London, and trained in diabetes at St Bartholomew’s Hospital, London. Her research interests are the aetiology and pathogenesis of type 1 diabetes, particularly prediction and prevention of the disease.

What is Type 1 Diabetes?Paul Lambert

Polly J Bingley

most cases that are primarily caused by pancreatic islet β-cell destruction and in which patients are prone to ketoacidosis. This includes cases currently ascribed to an autoimmune pro-cess and those in which the cause is unknown. Most cases are characterized by autoantibody markers of β-cell destruc-tion and strong HLA gene associations. Those that are not are classified as type 1 idiopathic. Classification of diabetes as type 1 therefore relies on evi-dence of an autoimmune pathogenesis. What is the evidence for autoimmunity?

Evidence of autoimmunity

Type 1 diabetes is a T cell-mediated autoimmune disorder. Recognition that onset of the disease was associated with in-filtration of the islets of Langerhans by mononuclear cells was the first evidence for this. This infiltrate was termed ‘insulitis’ (Figure 1). The autoimmune pathogenesis of the condition was further defined in terms of an array of auto-antibodies specifically associated with the disease. These are as follows.• Islet cell antibodies (ICA), detected by indirect immuno-fluorescence, were the first autoantibodies to be discovered, and are directed against various islet autoantigens. ICA are the most sensitive autoantibody markers of risk of future type 1 diabetes. Antibodies to other autoantigens (glutamic acid decarboxylase (GAD), IA-2 and IA-2β (phogrin)) constitute part of the ICA staining.• GAD antibodies are the best characterized autoantibodies. The antigen is a 64KD isoform of the enzyme found in the β-cell and the cerebellum. The role of GAD in the islet has not been clarified.• Insulin autoantibodies (IAA) are directed against the insu-lin molecule and are indistinguishable from the antibodies produced in response to exogenous insulin. The prevalence of IAA decreases rapidly with increasing age of onset of dia-betes, and thus they are most useful in predicting early-onset diabetes.• IA-2 and IA-2β antibodies are directed against trans-membrane protein tyrosine phosphatases in islet cells. The

1 Insulitis. The human islet (centre) is infiltrated with mononuclear cells. These are macrophages and CD8+ lymphocytes.

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Classical type 1 diabetesThe classical, well-described picture of type 1 diabetes is:• onset in childhood/adolescence• lean body habitus• acute onset of osmotic symptoms• ketosis-prone• high levels of islet autoantibodies• high prevalence of genetic susceptibility alleles.This clinical picture is seen in its purest form when the dis-ease occurs in the very young. A comparison of the character-istics of Finnish children diagnosed with diabetes before and after age 2 years (Komulainen et al.) revealed the following characteristics associated with younger age at diagnosis:• more severe clinical decompensation (as demonstrated by

more frequent and more severe ketoacidosis)• lower C-peptide levels (C-peptide is the cleavage product

remaining after insulin has split from its precursor, pro-insulin; it has no known biological activity)

• higher levels of ICA and IAA• higher prevalence of high-risk HLA susceptibility geno-

types.

Adult-onset diseaseIt is increasingly recognized that type 1 diabetes can present with a more indolent course, typically in adulthood. Data from the Belgian Diabetes Registry showed that the inci-dences of type 1 diabetes in 0–15-year-olds and 15–39-year-olds were identical; 60% of cases occurred after the age of 15 years. It has also been observed that type 1 diabetes is not uncommon in the elderly (Mølbak et al.). The incidence of the disease is stable from age 30 years, and thus the lifetime risk of developing type 1 diabetes is likely to be higher than previously recognized. Studies comparing onset in childhood with onset in adult-hood have shown that the following features are associated with adult onset:• lower levels of autoantibodies• fewer HLA susceptibility factors• longer duration of symptoms• less weight loss• lower incidence of ketoacidosis.Data from a study of Finnish patients (Sabbah et al.) are shown in Figure 3.

role of these proteins is unknown. It is suggested that they may have a role in intracellular signalling. The decrease in the prevalence of IAA and IA-2 antibodies with age of onset of diabetes means that GAD antibodies and ICA are the most useful markers of late-onset autoimmune diabetes. Use of combined autoantibodies maximizes the sensitivity and specificity for prediction of type 1 diabetes. In first-degree relatives of patients with type 1 diabetes, autoantibodies are not present at birth, but often appear before 1 year of age. Most individuals who develop type 1 diabetes have multiple autoantibodies (three in 33–60%), but 5% have none. Relatives with three or more antibodies have a 70–100% risk of developing diabetes over a 5–8-year period. This group accounts for most of those who will ever develop diabetes within the cohort of first-degree relatives (Bingley et al.) Thus, autoimmunity is established early in life, and there follows a dynamic period in early childhood during which autoantibody combinations become established (Ziegler et al.) After this period, however, antibody profiles tend to remain stable. Relatives who have not developed autoantibodies by age 5–10 years seem unlikely to do so subsequently. The natural history of autoantibody production in the pathology of type 1 diabetes is well described, but it is likely that anti-islet autoantibodies do not directly contribute to the β-cell destruction that leads to type 1 diabetes. This β-cell destruction is a cell-mediated process orchestrated by T cells. The islets of children with newly diagnosed diabetes show histological features consistent with cell-mediated immunity. There is a marked mononuclear cell infiltrate of predominantly CD8+ cytotoxic T cells and macrophages, with immune complex and complement deposition. Cells show MHC class I hyperexpression. The interaction between the humoral and the cell-mediated autoimmune processes remains uncertain.

Clinical spectrum of type 1 diabetes

The classical picture of type 1 diabetes is acute onset of symptoms caused by rapid β-cell failure. This process can occur slowly, however, leading to a clinical spectrum of dis-ease. The basic pathophysiology is the same (Figure 2), but occurs over widely varying time courses.

2

Clinical spectrum of type 1 diabetes

Glycaemic status

Normoglycaemia Impaired glucose tolerance

Frank diabetes

Pathology Autoimmunity Insulitis β-cell failure

Not insulin-requiring

Insulin for control

Insulin for survival

In type 1 diabetes, individuals may lie at any point on the continuum shown by the arrows, and can progress along the continuum at widely varying rates.

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Latent autoimmune diabetes in adultsIn the UK Prospective Diabetes Study (UKPDS), ICA and GAD antibodies were measured in 3672 patients diagnosed with ‘typical’ type 2 diabetes (Turner et al.); 12% had at least one antibody, and the presence of antibodies correlated with younger age, lower body mass index and reduced β-cell func-tion. At all ages, the presence of autoantibodies was associ-ated with an increased need for insulin treatment. In studies of Finnish patients with adult-onset diabetes, markers of autoimmunity (particularly GAD antibodies) clustered with biochemical evidence of insulin deficiency and classical high-risk HLA susceptibility alleles for type 1 diabetes. In a population-based study of adults with diabetes in New Zealand (Scott et al.), 14.4% were insulin-treated, and 83% of these required insulin within 1 year of diagnosis. Presence of GAD antibodies in patients with adult-onset diabetes is high-ly predictive of a need for insulin treatment within 3 years. Adult-onset type 1 diabetes may be misclassified as type 2 diabetes because of the relatively slow destruction of β-cells. Development of symptoms is often insidious, without pathognomonic osmotic symptoms or ketoacidosis. Patients can be of any weight, and with a high degree of β-cell re-serve. This is termed ‘latent autoimmune diabetes of adult-hood’ (LADA). The clinical features of LADA are thus:• age ≥ 25 years• clinical presentation masquerading as non-obese type 2

diabetes• initial control achieved with diet alone or with diet and

oral hypoglycaemic agents• usually rapid insulin requirement (months), but may take

up to 10 years• β-cell autoantibodies (principally GAD)• HLA susceptibility alleles• low fasting and post-glucagon-stimulated C-peptide.Early identification of patients with LADA is important, to prompt appropriate treatment and to avoid periods of un-necessary poor control soon after diagnosis. Measurement of GAD antibodies in adults with newly diagnosed diabetes may by useful in this respect.

Patients with type 2 diabetes are presenting at an increas-ingly younger age, and though young-onset type 2 diabetes was previously seen only in genetically enriched groups (e.g. Pima Indians), it is now being seen in European popu-lations. These two facts have lead to the increasing problem of ‘unclassifiable’ diabetes, which confounds the diagnosis and treatment of diabetes in obese young adults.

Epidemiology

In the UK, the cumulative risk of developing type 1 diabetes by the age of 20 years is 0.3–0.4%, with a peak incidence in 10–14-year-olds. The incidence is increasing in all age groups, but the increase is most marked in the youngest (0–4 years); the reasons for this are unclear. The incidence varies between population groups (EURODIAB) – there is a tenfold variation within Europe, and a 350-fold variation worldwide. The highest known incidences are in Finland and Sardinia (40/100,000/year) and the lowest in China (0.1/100,000/year).

Aetiology

Type 1 diabetes results from a complex interaction of genetic and environmental factors.

GeneticThe evidence for a genetic influence on the disease is as follows.• Familial clustering of disease occurs. (The risk of develop-ing type 1 diabetes before age 20 years is 6% in the sibling of an affected patient, compared with a population back-ground risk of 0.4%.)• The concordance is 30–50% in monozygotic twins and 10% in dizygotic twins.• There is an association between HLA class II genes and susceptibility to type 1 diabetes. (HLA DR and DQ are the principal determinants of susceptibility; DR3 and DR4, DQ2 and DQ8 are the high-risk alleles.)

Features of childhood-onset and adult-onset type 1 diabetes

Childhood onset Adult onsetAutoantibodies• Islet cell antibodies 84% 45%

• Insulin autoantibodies 54% 20%

• GAD antibodies 68% 51%

• IA-2 antibodies 79% 48%

• Multiple antibodies 70% 34%

High-risk genotype• DQB1*02/0302 23% 9%

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could occur, probably by the interaction of multiple immuno-logical mediators. This would not guarantee development of diabetes, however, because this immunological process is subject to regulation. This regulation would have to be dys-functional in some manner. Activation of T cells and regu-lation of the T cell response would involve non-HLA genes. Thus, this model does include all the factors thought to be involved in the aetiology of type 1 diabetes.

Prevention

The long prodrome of type 1 diabetes before the develop-ment of frank β-cell failure raises the possibility of inter-vening to delay or prevent clinical onset. Two central require-ments for successful prevention are:• tools to predict which individuals will develop diabetes• methods to slow or halt disease progression before the on-

set of hyperglycaemia.Risk of future diabetes can be assessed using genetic and autoantibody markers and measures of β-cell function (e.g. oral glucose tolerance test, first-phase insulin secretion). Detection of genetic predisposition allows identification of individuals at risk before the onset of the autoimmune pro-cess, but many individuals, even those with the highest levels of risk markers, will not develop the disease. Use of auto-antibody markers can achieve accurate prediction but, by definition, only once the autoimmune process has begun. Evidence of β-cell dysfunction is highly predictive, but is detected only when β-cell destruction is well advanced. There is therefore a trade-off between ability to predict disease

• Genome-wide screens have shown associations between other chromosomal regions and risk of type 1 diabetes (re-gions are designated IDDM2–18). (At present, only the vari-able number of tandem repeats upstream of the insulin gene on chromosome 11 (IDDM2) has been conclusively shown to confer risk.)

EnvironmentalEvidence for the role of environmental factors is more in-direct, and is based on:• low concordance in monozygotic twins• changes in the incidence of the disease in migrants from

low-incidence to high-incidence regions• the increasing incidence of the disease in many popu-

lations despite a stable genetic background (incidence in-creased by 4%/year in 1985–1996 in 0–14-year-olds in the Oxford region, and by 11%/year in 0–4-year-olds (Gardner et al.).

The environmental triggers are poorly defined, but there is evidence for cows’ milk protein and virus infection (Figure 4).

Pathophysiology

Nepom proposed a multi-step model (Figure 5) in which susceptibility-associated DQ molecules are inefficient at interacting with self-peptide from β-cells, and consequently autoreactive T cells are not deleted in the thymus. In the periphery, these T cells may be amplified by environmental factors acting via direct, bystander or molecular mimicry mechanisms. Activation of these T cells by β-cell antigens

Evidence for environmental factors in type 1 diabetes

Cows’ milk protein• Removal of cows’ milk protein from the diet of animal models of type 1 diabetes is protective

• Ecological studies have shown a correlation between cows’ milk consumption and the incidence of type 1 diabetes

• Meta-analyses show that the odds ratio for the developmentof type 1 diabetes is 1.6 for cows’ milk consumption beforeage 3 months, and 1.2–1.4 for a short duration ofbreast-feeding

• The effects are small, however, and have not always beenreproduced, and there are limitations to many of the studies

concerned

Viral infection• Clustering of cases and seasonality of diagnosis

• Congenital rubella syndrome is associated with diabetes

• Evidence of recent coxsackievirus B infection in cases of newly diagnosed type 1 diabetes

• Sequence homology and evidence of molecular mimicry between enterovirus proteins and islet cell proteins

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and the stage to which the disease has progressed when it is detected. A number of trials of prevention strategies are under way; most are recruiting patients at the highest risk of disease (i.e. relatives of patients with type 1 diabetes who have islet antibodies). The Diabetes Prevention Trial-1 has two arms, one using oral insulin and the other using parenteral insulin to prevent onset of clinical disease. Use of parenteral insulin has already been shown not to influence disease progression. The European Nicotinamide Diabetes Intervention Trial is using high-dose nicotinamide as a preventive strategy. To date, no intervention has been shown to prevent the onset of clinical disease. u

REFERENCESAkerblom H K, Knip M. Putative Environmental Factors in Type 1

Diabetes. Diabetes Metab Rev 1998; 14: 31–67.Bingley P J, Williams A J, Gale E A. Optimized Autoantibody-based

Risk Assessment in Family Members. Implications for Future Intervention Trials. Diabetes Care 1999; 22: 1796–801.

Practice points

• There is increasing recognition that type 1 diabetes can be diagnosed at all ages and has a spectrum of presentation depending on the rate of β-cell destruction• There may be diagnostic confusion between slow-onset adult type 1 diabetes and young-onset type 2 diabetes, leading to inappropriate treatment decisions• The classification of diabetes has recently been changed, with an emphasis on classification according to aetiology and a ‘tightening-up’ of terminology

DPT-1 Study Group. The Diabetes Prevention Trial Type 1 Diabetes (DPT-1): Implementation of Screening and Staging of Relatives. Transplant Proc 1995; 27: 337.

EURODIAB ACE Study Group. Variation and Trends in Incidence of Childhood Diabetes in Europe. Lancet 2000; 355: 873–6.

Gale E A M. Theory and Practice of Nicotinamide Trials in Pre-type 1 Diabetes. J Pediatr Endocrinol Metab 1996; 9(3): 375–9.

Gardner S G, Bingley P J, Sawtell P A, Weeks S, Gale E A. Rising Incidence of Insulin Dependent Diabetes in Children Aged Under 5 Years in the Oxford Region: Time Trend Analysis. BMJ 1997; 315: 713–17.

Komulainen J, Kulmala P, Savola K et al. Clinical, Autoimmune and Genetic Characteristics of Very Young Children with Type 1 Diabetes. Diabetes Care 1999; 22: 1950–5.

Mølbak A G, Christau B, Marner B, Borch-Johnsen K, Nerup J. Incidence of Insulin-treated Diabetes Mellitus in Age Groups Over 30 Years in Denmark. Diabetic Med 1994; 11: 650–5.

Nepom G T, Kwok W W. Molecular Basis for HLA-DQ Associations with IDDM. Diabetes 1998; 47: 1177–84.

Sabbah E, Savola K, Ebeling T et al. Genetic, Autoimmune and Clinical Characteristics of Childhood- and Adult-onset Type 1 Diabetes. Diabetes Care 2000; 23: 1326–32.

Scott R S, Brown L J. Prevalence and Incidence of Insulin-treated Diabetes Mellitus in Adults in Canterbury, New Zealand. Diabetic Med 1991; 8: 1–8.

Turner R, Stratton I, Manley S et al. UKPDS2. Autoantibodies to Islet-cell Cytoplasm and Glutamic Acid Decarboxylase for Prediction of Insulin Requirement in Type 2 Diabetes. Lancet 1997; 350: 1288–93.

Ziegler A G, Hummel M, Schenker M, Bonifacio E. Autoantibody Appearance and Risk for Development of Childhood Diabetes in Offspring of Parents with Type 1 Diabetes: The 2-year Analysis of the German BABYDIAB Study. Diabetes 1999; 48: 460–8.

FURTHER READINGAtkinson M A, Eisenbarth G S. Type 1 Diabetes: New Perspectives on

Disease Pathogenesis and Treatment. Lancet 2001; 358: 221–9.Expert Committee on the Diagnosis and Classification of Diabetes

Mellitus. Diabetes Care 1998; 21: (Suppl. 1): S5–19. (Explains the new classification and diagnostic criteria for diabetes.)Zimmet P, Turner R, McCarty D, Rowley M, Mackay I. Crucial Points at

Diagnosis. Type 2 Diabetes or Slow Type 1 Diabetes. Diabetes Care 1999; 22: (Suppl. 2): B59–64.

(Describes potential confusion and means of distinguishing between these two conditions.)

Hypothetical mechanism of the interaction between MHC genes, non-MHC genes and the environment in the aetiology of type 1 diabetes

Source: Nepom G T, Kwok W W. Diabetes 1998; 47: 1177–84.

MHC genesAutoreactive T cells

Bystandereffect

Amplification

MHC-driven β-cell antigen recognition

T cell activationTh1 vs Th2

No regulation

Autoimmunediabetes

Regulation

No diseaseAutoimmune markers

Direct effect – viral infection of β-cells

Molecular mimicry

MHC genes and environment

MHC genes and non-MHC genes

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