Key words: type 1 diabetes, LADA, islet cell antibodies, HLA Dept Endocrinology & Diabetes, University Campus Bio-Medico, Rome, Italy …
J Clin Endocrin Metab First published February 14, 2006 as doi:101210/jc2005-1623
Type 1 diabetes and latent autoimmune diabetes in adults LADA : one end of the rainbow
Short title: type 1 diabetes and LADA Key words: type 1 diabetes, LADA, islet cell antibodies, HLA
R David G Leslie, Rhys Williams and Paolo Pozzilli
Institute of Cell and Molecular Science Queen Mary College, University of London London, UK The School of Medcine, University of Wales Swansea, UK Dept Endocrinology Diabetes, University Campus Bio-Medico, Rome, Italy
Address for correspondence: Professor David Leslie Department of Diabetes, St Bartholomews Hospital, West Smithfield, London EC1A 7BE, UK Tel 44 207 6017453 Fax 44 207 6017449 e-mail: rdgleslie@qmulacuk
Copyright C 2006 by The Endocrine Society
Abstract
Context: the aim of this review is to explore the pathogenic and clinical spectrum of type 1 diabetes which includes a form of adult onset autoimmune diabetes usually referred to as latent autoimmune diabetes in adults LADA We look at this entire range of forms of autoimmune diabetes as a spectrum of genetic and non-genetic environmental influences, of diabetes-associated immune responses and of
metabolic changes Evidence Acquisition: we assessed epidemiological, genetic, immunological and clinical data from major articles on autoimmune diabetes, including LADA and type 1 diabetes, published since 1992 Evidence Synthesis: data analysis of autoimmune diabetes indicate that type 1 diabetes and LADA occupy different poles of the same spectrum Conclusion: evidence is presented that LADA represents one end of a rainbow encompassing type 1 diabetes The clinical nature and management of autoimmune diabetes poses important therapeutic questions regarding conventional therapy for hyperglycaemia as well as therapy aiming to protect residual beta cell function Limiting loss of endogenous insulin secretion using immunomodulation could be valuable, not only for LADA, but also for type 1 diabetes
2
Type 1 diabetes results from the destruction of the insulin secreting islet cells by an immune mediated process This adverse immune response is induced and promoted by the interaction of genetic and environmental factors and is one of a group of autoimmune diseases which affect about 10 of the population in the developed world Type 1 diabetes used to be defined in terms of the absolute need
for insulin therapy insulin-dependent diabetes or, prior to that, the age at onset of the disease juvenile onset diabetes These defining features were then abandoned in favour of the term type 1 diabetes 1 when it became apparent that not everyone with autoimmune diabetes is either a juvenile or necessarily exhibits an absolute insulin requirement
Individuals diagnosed with autoimmune diabetes - that is diabetes associated with diabetesassociated autoantibodies - when they are adults may not initially require insulin treatment and have been classified as having latent autoimmune diabetes of adults LADA 2,3; latent because without testing for diabetes-associated autoantibodies it would not be possible to identify these patients as having autoimmune diabetes; adult because, at that time, it was suggested that this form of diabetes was not present in juveniles This form of diabetes has also been called slowly progressing insulin dependent diabetes SPIDM 4 or type 15 diabetes 5 The aim of this article is to explore the clinical and pathogenic spectrum of autoimmune diabetes which extends into and includes LADA LADA is defined by three features including: adult age at diagnosis, the
presence of diabetesassociated autoantibodies and delay from diagnosis in the need for insulin therapy to manage hyperglycaemia However, the first and last are not categorical traits being dependent on the mode of ascertainment and decision making by physicians The second feature lacks disease-specificity as it is based on positivity for autoantibodies found in T1DM In a recent review 6 it was suggested that LADA patients should be diagnosed with non-insulin requiring diabetes at age 30 years or more and that age range 30-70 years was also used in a major European Union initiative wwwactionlada; in addition, both defined LADA to include patients who had six months without insulin treatment post-diagnosis 6 Other large studies of autoimmune non-insulin requiring patients have included selected cases, cases not taking any pharmacological agent, or avoided a definition entirely 7-9 Difficulties with the performance of islet cell and insulin autoantibody assays precluded them from being used routinely in defining LADA Since insulinoma-associated antigen IA-2 autoantibodies are usually found with glutamic acid decarboxylase GAD autoantibodies, but rarely in LADA, this condition is
broadly defined by the presence of GAD autoantibodies However, GAD autoantibodies are also found in T1DM, so it follows that using 3
them in the definition of LADA lacks disease specificity 10 The epidemiology of LADA is also influenced by geography, genetic susceptibility, environmental factors, gender and age at diagnosis In Northern Europe and North America, about 5-10 of newly-diagnosed non-insulin requiring diabetes patients have LADA, according to the mode of ascertainment, the sourced population, the age of the patient frequency is higher in younger age groups and the definition of the disease 5, 6,10
LADA at one end of a spectrum of genetic susceptibility The epidemiology of autoimmune diabetes including type 1 diabetes is influenced by genetic susceptibility which modifies age at onset 6 There is evidence in autoimmune diabetes for a continuum of genetic susceptibility which extends from a marked effect in childhood onset type 1 diabetes to the relatively limited effect detected in LADA Table 1 Survival analysis estimates that non-diabetic identical twins of probands diagnosed with type 1 diabetes under 25 years of age have a 38 probability of developing diabetes
compared with only 6 for twins of probands diagnosed later 11-13 Table 2 Such a remarkably low twin concordance for adult-onset type 1 diabetes implies that the genetic impact in adult-onset diabetes is limited 14,15, favouring a substantial impact of environmental factors There is an age-related continuum in diminishing twin concordance suggesting that the decline in genetic influence is gradual, consistent with a phased influence on a single disease, type 1 diabetes, rather than an age-related step-wise effect resulting from two distinct diseases There are, as yet, no twin studies of LADA Of genes implicated in the genetic susceptibility to type 1 diabetes and LADA, the most important, for both, are in the histocompatibility HLA region of chromosome 6 14
HLA alleles associated with type 1 diabetes susceptibility, include HLA DR3, DQB10201 and DR4, DQB10302, while others are associated with disease protection, eg HLA DR2, DQB10602 16-19 Children with type 1 diabetes show an increased prevalence of the heterozygous alleles HLA DR3, DQB10201 and DR4, DQB10302, the proportion of heterozygotes declining with age at diagnosis 19 Children with the diabetes-protective HLA DR2, DQB10602
are unlikely to develop diabetes 20, while in type 1 diabetes of adult onset and LADA the same alleles carry less protection 21-22 Table 1 Nevertheless, both the latter and LADA show HLA genetic susceptibility with little or no HLA genetic protection 19-21
Strikingly, even adults with non-insulin requiring diabetes without the diabetes-associated autoantibody to glutamic acid decarboxylase GAD have an excess of diabetes-associated HLA 4
alleles and are relatively young and lean 7,23-25 Age-related genetic factors also influence the risk of type 1 diabetes Not only is the age incidence of type 1 diabetes lower in adults than in children, the range of incidence across European countries is also reduced in adults 26 Furthermore, there is a male excess in incidence which becomes evident during puberty and is most striking in the age group 25 to 29 years 26
A recent, albeit small, genetic study found similar HLA susceptibility genes in both type 1 diabetes and LADA 8 Other genes have been linked to type 1 diabetes and these genes, including TNFalpha, TNF-beta, IL-10, IL-6 gene polymorphisms and IL-18 gene promoter polymorphism, but they have yet to be studied comprehensively in LADA
27, 28 Other gene polymorphisms within the CTLA4, PTPN22, IRS-1, ICOS and SUMO4 genes confer a substantial risk to type 1 diabetes with Odds Ratios OR between 18 and 25 but have not been studied in LADA 29
In the light of these observations it remains possible that LADA represents one end of a rainbow of autoimmune diabetes, which is only distinguished from classic type 1 diabetes because it is diagnosed in adulthood and presents with some clinical, anthropometric and metabolic features more commonly associated with type 2 diabetes
LADA in a spectrum of non-genetic influences Non-genetic factors play a major role in causing type 1 diabetes as shown by studies of populations that have migrated, of populations with changing disease incidence, and of twins We know little of the current incidence of autoimmune diabetes in adults and of LADA The incidence of a range of autoimmune diseases, including diabetes, has increased notably over the last three decades 30 The current low selection density and relative stability of HLA gene polymorphisms indicates that this increasing incidence cannot be due to genetic selection pressures, and is most likely the result of non-genetic factors
10,15
Unfortunately, population studies are of limited value in identifying the impact of non-genetic factors since it is difficult to segregate genetic from environmental influences However, changes in disease incidence within a genetically stable population are important when disease incidence rises rapidly or changes abruptly as in migrants 31, 32 Migrant studies support a role for environmental factors influencing disease incidence 32, 33 Type 1 diabetes incidence in Asian children in families who have migrated to Britain increased from 31/100,000 per year in 1978-81 to 117/100,000 per year in 1988-90, much higher than in their native Karachi 1/100,000 per year 5
29,30 However, Sardinian migrants moving to continental Italy retained the high incidence of the ancestry region suggesting that is the genetic susceptibility that determines the prevalence of the disease in response to the environmental factors 34 There are no comparable migration studies of adults with type 1 diabetes or of LADA patients On the other hand the identical twin concordance for adult-onset type 1 diabetes is slow, implying that the genetic impact on this form of diabetes is limited, which in turn
suggests a major impact of environmental factors 10 The declining identical twin concordance rate for type 1 diabetes with increasing age appears to be a continuum and not a categorical phenomenon, in line with an age-related spectrum of environmental impact on the aetiology of autoimmune diabetes However, there are no twin studies in LADA so it is unclear whether this spectrum extends into that form of autoimmune diabetes
LADA at one end of a spectrum of diabetes-associated immune responses At birth, children of mothers with diabetes may have islet cell autoantibodies ICA, insulin autoantibodies IAA and GAD autoantibodies But these autoantibodies can also be found in the maternal serum and are probably placentally transferred to the child since autoantibody specificities are similar in mother and cord blood and are not usually detected in the infants of mothers without such autoantibodies 35-37 Passively acquired maternal autoantibodies disappear after birth as expected, but can subsequently be replaced by the infants own autoantibodies
Diabetes-associated autoantibodies can appear at a later stage In one study, 3 out of 58 infants of diabetic mothers developed IAA, ICA and GAD
de novo by two years of age and only then were autoantibodies associated with diabetes risk 35and in another study,137 children with ICA from a prospective Finnish study of 4,590 consecutive newborns with the disease-risk HLA-DQB1, IAA and GAD autoantibodies usually appeared in childhood before ICA, while insulinoma-associated-2 IA-2 autoantibodies usually appeared later when IAA are uncommon 38 In contrast to LADA and adult onset type 1 diabetes, children often have IAA at diagnosis and, in them, IAA is highly predictive of the disease 39 Since seroconversion continued up to at least age 10 years of age, it follows that the induction event with activation of immune response to produce diabetes-associated autoantibodies is not confined to early childhood It remains unclear whether the age at clinical diagnosis is in part dependent on the age at which an environmental event activates the immune response If this is the case, then the immune process which leads to adult onset type 1 diabetes and LADA would be induced later in them than in childhood onset type 1 diabetes
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Taken together these observations suggest that activation of the diabetes-associated immune process can occur in
early childhood when it is more likely to be associated with IAA in those who progress to childhood onset type 1 diabetes But the induction of diabetes-associated autoantibodies is not confined to early childhood Currently we have no clear evidence identifying the age of induction of diabetes-associated autoantibodies in those subjects who develop either adult-onset type 1 diabetes or LADA However, we know that these diabetes associated autoantibodies, when detected in adult life, are predictive of an ongoing beta cell destructive process
In this respect the prevalence of autoantibodies to protein tyrosine phosphatase isoforms IA-2 and IA-2beta/phogrin has been recently examined in a cohort of adult UKPDS patients thought to have type 2 diabetes, to determine whether these autoantibodies predict a requirement for insulin therapy 37 In this cohort the presence of IA-2A was infrequent about 2, associated with the HLADR4 haplotype as is the case in classic type 1 diabetes, and highly predictive of insulin therapy positive predictive value 60 The measurement of IA-2betaA does not provide additional information 40
LADA at one end of a spectrum of metabolic changes There is evidence in
autoimmune diabetes for a continuum of metabolic changes, predominantly decreased insulin secretory capacity but also insensitivity to insulin These extend from the severe changes seen in childhood onset type 1 diabetes to the relatively minor changes initially detected in LADA
Some individuals pass through a pre-diabetic stage of impaired glucose tolerance or even noninsulin requiring diabetes before becoming frankly insulin-dependent 41 Diabetes Prevention Trial of Type 1 Diabetes DPT-1 detected 585 relatives of type 1 diabetic patients who had ICA plus either IAA or low first-phase insulin response to intravenous glucose 42 Of them, 427 had normal glucose tolerance, 87 impaired glucose tolerance and 61 were diabetic, yet asymptomatic 39 Of these latter, those with impaired fasting glucose were significantly older mean age 21 years than those with normal fasting glucose mean age 12 years These subjects with asymptomatic autoimmune diabetes resemble LADA but their age is less than 30 years precluding the diagnosis It follows that some patients with autoimmune diabetes, pass through a phase of altered glucose levels including non-insulin requiring diabetes before becoming
insulin-dependent and the frequency of this phase, to a degree, is age dependent It remains to be determined whether all children with diabetes-associated autoantibodies will progress to diabetes, let alone insulin7
dependent diabetes The rate of progression to clinical diabetes is more rapid in patients presenting under 5 years of age than in those presenting much later 43 Histological evidence supports this contention: islet beta cells tend to be absent within 12 months of diagnosis in patients aged less than 7 years, but detected for longer periods in older patients 44 Variability in progression to clinical diabetes can even be detected in very young children; for example, of children identified between 1 to 5 years of age with diabetes-associated autoantibodies and subnormal insulin responses, half of them progress rapidly to diabetes while the remainder are free from diabetes up to 4 years later 45 Other studies have noted such variable progression to type 1 diabetes, which is more rapid in obese than lean children 46 and in children than adults 47-50 From these observations it follows that there is a spectrum in the rate of metabolic decompensation during the pre-diabetic
period in autoimmune type 1 diabetes, but no data is available, as yet, in LADA
Insulin secretory capacity is less in children than in adults at the onset of type 1 diabetes, and following diagnosis deteriorates more rapidly A study of 235 consecutive cases with newlydiagnosed type 1 diabetes found that those aged less than 7 years had the lowest baseline residual insulin secretion and required the highest insulin dose for optimal control, while the older the age at diagnosis the higher was the basal C-peptide level 51 Patients with LADA also have reduced fasting and stimulated C-peptide at diagnosis though the levels of C-peptide are higher than those found in children and similar to those found in adult-onset type 1 diabetes 8 However, postdiagnosis, the C-peptide levels have been reported to fall more rapidly in childhood onset type 1 diabetes than in adult onset type 1 diabetes and in the latter more rapidly than in LADA 52-55 Furthermore, persistent C-peptide secretion, implying less aggressive disease, is detected in more adults than adolescents after diagnosis of type 1 diabetes, and in more adolescents than pre-pubertal children with diabetes 52-54 Other studies report a
quite rapid loss of C-peptide even in LADA, which argues against a chronic destructive process in that condition 6, 55, 56 In summary, there is a continuous spectrum of loss of insulin secretory capacity, the severity of which can be agerelated, being more severe in children than adults with type 1 diabetes, and more severe in the latter than in LADA subjects, though some patients with LADA may show a rapid loss of insulin secretory capacity
The metabolic decompensation which leads to frank diabetes could result either from increased linear growth, which has been linked to diabetes risk, or from increased childhood obesity, which has been correlated with age at presentation 10, 46 People with LADA may well have more severe loss of insulin sensitivity than in childhood-onset type 1 diabetes but there are only two 8
small studies considering insulin sensitivity in LADA and both used the homeostasis model of assessment HOMA, while no studies have employed the gold-standard euglycaemic hyperinsulinaemic clamp 57,58 Certainly in LADA the frequency of the metabolic syndrome, usually associated with insulin resistance, while less prevalent than in type 2 diabetic patients of similar
age, is more prevalent than in the general population 9 In a recent report, the metabolic syndrome, which is found in approximately 22 of the North American population was identified in 74 of those with LADA but in significantly more subjects with type 2 diabetes 84 9
It is likely, therefore, that within autoimmune diabetes, including both type 1 diabetes and LADA, there is an age-related spectrum of decreasing insulin secretory capacity and increasing insulin insensitivity associated with the metabolic syndrome The distinction between LADA and adult onset classical type 1 diabetes is a matter of debate It is possible that the distinction between the two is one of degree, with the classical type 1 diabetes being at one end of the spectrum and LADA, when it remains insulin-independent, being at the other end
A spectrum of clinical management in LADA Type 1 diabetes progresses to insulin dependence usually within two years of the clinical diagnosis as noted in the pre-insulin era Before two years some patients may have a partial or complete remission when insulin therapy is not required 59 Of LADA patients, in one study, 94 required insulin treatment by 6 years as compared with
only 14 in those initially non-insulin requiring diabetes patients without either GAD autoantibodies or ICA 7 Progression to insulin dependence in LADA patients was more rapid in those aged less than 45 years than in older cases 7 It follows that patients with autoimmune diabetes, including both type 1 diabetes and LADA, are at high risk of progression to insulin dependence but that risk declines with age at diagnosis
It is well established that insulin is the treatment of choice for type 1 diabetes but there is no established management strategy for patients diagnosed with LADA 60-65 The European Union, therefore, funded a major initiative ACTION-LADA to study the characteristics of LADA and report on how to treat it In considering how to treat LADA some important questions arise as to our broad management of autoimmune diabetes Since the predominant defect in autoimmune diabetes is loss of insulin secretion, should we treat the disease with insulin irrespective of the level of dependency on insulin? Autoantibody positive, initially non-insulin requiring, diabetic patients initially treated with sulphonylureas have been found to require insulin earlier than
autoantibody-
9
negative patients but sulphonyloureas did not impact on the need for insulin treatment or the time to progression to insulin therapy 41
Metformin is routinely offered to patients with non-insulin requiring diabetes but its specific role in LADA is unclear and the drug may be contraindicated in those with LADA as there is a theoretical risk of severe metabolic disturbance in individuals who progress to insulin dependency whilst on it Intriguingly, however, there is limited evidence that metformin could be of value even in patients with type 1 diabetes For example, in one study, adolescent type 1 insulin dependent diabetes patients given metformin subsequently showed a significantly lower HbA1c and reduced insulin requirements compared with those not taking metformin 62
Thiazoledinediones also might theoretically be of value since they not only improve insulin sensitivity but have an anti-inflammatory effect and protect non obese diabetic mice, a well established model of autoimmune diabetes, from developing diabetes 63 In a small study of LADA patients in China there was a significant improvement in C-peptide but not HbA1c in patients receiving rosiglitazone plus
insulin compared with insulin alone 64
Since the primary defect in autoimmune diabetes is loss of insulin secretion, treatment should aim to restore islet insulin secretion Therapy to prevent progression towards insulin dependency could include insulin, or immunomodulation, given the inflammatory nature of the disease process thought to cause insulin secretory cell destruction The optimal insulin regimen is unclear; given the broad loss of insulin secretory capacity it might be argued that the early introduction of a longacting insulin could be beneficial Alternatively, the loss of rapid insulin release in LADA patients suggests that replacement with a fast-acting insulin would be more valuable
One study in Japan of patients with LADA compared early treatment with insulin given as multiple injections with sulphonylureas 61 Whilst of limited power, this study did show a statistically significant persistence of C-peptide in the insulin treated group as compared with the sulphonylurea group with the proviso that the insulin treated group had preserved insulin secretory capacity and a high titre of GAD autoantibodies at the start of the study 61 An alternative interpretation of this
study is that sulphonylureas are disadvantageous, in support of which sulphonylureas could theoretically promote apoptosis, apoptosis being one mechanism whereby insulin secreting cells could be destroyed in autoimmune diabetes
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A pilot phase 2 trial in LADA patients found that a tolerance induction plan using alum formulated whole GAD Diamyd had a significant effect on the C-peptide response to a mixed meal consistent with modulation of the aggressive process 65 Another phase 2 trial in LADA patients using the peptide analogue of heat shock protein 60 Diapep 277 has been completed following initial positive results in protecting residual beta cell function in adult-onset type 1 diabetes patients 66 and in experimental models of the disease 67 These immunomodulatory studies, although small and preliminary, pioneer a novel approach towards the maintenance of islet cell function, itself a new field in the management of autoimmune diabetes
In conclusion, LADA, whether viewed genetically, immunologically, metabolically or clinically, occupies one end of a rainbow of features associated with autoimmune diabetes The management and prevention of LADA need to be investigated in order
to define the best strategy for treating this most prevalent form of autoimmune diabetes
Acknowledgments We wish to thank all our collaborators, in particular Drs Mohammed Hawa, Huriya Beyan, Chiara Guglielmi, Marta Vadacca, Sinead Brophy and Mark Airey for their contribution to the work in our laboratories and in the field The research groups in London, Swansea and Rome are supported by grants from the Juvenile Diabetes Research Foundation, Develogen, Diabetes UK, Diabetes Twin Research Trust and the European Union
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TABLE 1 Genetic, immunological and metabolic differences between childhood-onset, adult-onset type 1 diabetes and LADA Children T1DM Age at diagnosis Identical twin concordance rate Childhood Moderate eg 38 Adults T1DM Adulthood Very Low eg6 LADA Adulthood ?
HLA-DR3/ DR4
Moderate eg37
Low eg13
Low-Moderate eg22
Protective HLA genotype HLADR2
Very Low eg 9
Low eg 15
Moderate eg 22
Autoantibodies Plasma insulin
IAA GAD IA-2 Very low
GAD
IA-2
GAD low
IA-2
Low
Note that the children, compared with the others, have a higher identical twin concordance rate, frequency of HLA genetic susceptibility heterozygosity and insulin autoantibodies, and lower
serum insulin levels HLA DR3/4 is found in about 6 of North American and European control populations Data compiled from different sources 6, 11, 17, 19, 20, 21, 22
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TABLE 2 Concordance for type 1 diabetes in identical twins according to age at clinical onset in the index twin Note the substantially lower concordance rates in the older-onset twins consistent with a marked non-genetically determined effect causing diabetes in them
Young-onset years
Older-onset years
UK / USA ref11 USA ref 12 Finland ref 13
38 25 44 15 50 10
6 25 13 15 23 10
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