[IPp] Age-Dependent Influences on the Origins of Autoimmune Diabetes: Evidence and Implications
- To: Rachel A <email @ redacted>
- Subject: [IPp] Age-Dependent Influences on the Origins of Autoimmune Diabetes: Evidence and Implications
- From: Rachel A <email @ redacted>
- Date: Sat, 29 Jan 2005 13:16:20 -0800 (PST)
- Comment: DomainKeys? See http://antispam.yahoo.com/domainkeys
- Reply-To: email @ redacted
http://www.rednova.com/news/display/?id=122936Age-Dependent Influences on the
Origins of Autoimmune Diabetes: Evidence and Implications
IA2, insulinoma-associated 2; IAA, insulin autoantibody; ICAA, islet cell
autoantibody; LADA, latent autoimmune diabetes of adults.
2004 by the American Diabetes Association.
A decade ago we proposed that environmental factors operating in early life
lead to type 1 diabetes, outlining the evidence and the implications if the
hypothesis was true (1). Today we can be confident that environmental factors
can indeed operate in childhood to cause type 1 diabetes, but we now review
evidence that this is unlikely to be true in the generality of cases of type 1
diabetes. Indeed, type 1 diabetes presenting in adult life is remarkably
distinct from diabetes presenting in children in terms of its genetic, immune,
metabolic, and clinical features. If the mechanism and timing of disease
induction is also distinct in adult-onset, compared with childhood-onset, type 1
diabetes, then these differences would have implications for our understanding
of the disease pathogenesis, prediction, and prevention. The aim of this article
is to explore the different influences of genetic and nongenetic factors on type
1 diabetes according to the age of clinical disease onset!
potential consequences of such differences.
Type 1 diabetes is caused by the destruction of 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 that affect ~10% of the population in the developed
AGE-DEPENDENT ROLE FOR GENETIC FACTORS
Type 1 diabetes is genetically determined as shown by family, twin, and genetic
studies. The frequency of type 1 diabetes is higher in siblings of diabetic
patients (e.g., 6% by age 30 years in the U.K.) than in the general population
(0.4% by age 30 years) (6). Familial clustering could be caused by shared
genetic or environmental factors, and to distinguish between them, twin studies
have been used. Higher concordance rates for autoimmune diseases in identical
compared with nonidentical twins is consistent with a genetic influence on these
diseases (7). Of genes implicated in the genetic susceptibility to type 1
diabetes, the most important are in the histocompatibility (HLA) region of
chromosome 6 (6,8).
Age-related genetic factors not only influence the risk of type 1 diabetes, but
also the presence of diabetes-associated autoantibodies, the rate of progression
to clinical diabetes, and the severity of reduced insulin secretory capacity.
Not only is the age incidence of type 1 diabetes lower than in children, but the
range of incidence across European countries is also reduced (9). Furthermore,
there is a male excess in disease incidence that becomes evident during puberty
and is most striking in the agegroup 25-29 years (9). Survival analysis
estimated that nondiabetic identical twins of probands diagnosed with type 1
diabetes <25 years of age had, in one study, a 38% probability of developing
diabetes compared with 6% for twins of probands diagnosed later (10-12) (Table
1). Such a remarkably low twin concordance rate for adult- onset type 1
diabetes, lower than that for influenza, implies that the genetic impact in
adult-onset diabetes is limited (7).
HLA alleles associated with diabetes susceptibility include HLA DR3, DQB1*0201
and DR4, DQB1*0302, whereas others are associated with disease protection, e.g.,
HLA DR2, DQB1*0602 (2,6). Type 1 diabetic children show an increased prevalence
of the heterozygous alleles HLA DR3, DQB1*0201 and DR4, DQB1*0302, with the
proportion of heterozygotes declining with age at diagnosis (13-15) (Table 2).
Children with the diabetes-protective HLA DR2, DQB1*0602 are unlikely to develop
diabetes, whereas in adult-onset diabetes the same alleles carry less protection
(13,14). Patients with HLA DR4, DQB1*0302 are at particular risk of having
insulin autoantibodies (IAAs), and these HLA alleles and IAAs are more prevalent
in children with type 1 diabetes (15,16).
Despite the limited genetic risk implied by twin studies, adult- onset type 1
diabetes shows HLA genetic susceptibility, which is also found in adults
presenting with non-insulin-requiring diabetes who have diabetes-associated
autoantibodies to GAD (17-19). Such patients, mistakenly diagnosed initially
with type 2 diabetes, have autoimmune non-insulin-requiring diabetes, designated
latent autoimmune diabetes of adults (LADA), with a reduced frequency of
metabolic syndrome compared with other cases of non-insulin- requiring diabetes
(17,18). This form of autoimmune diabetes affects ~10% of recently diagnosed
non-insulin-requiring European adults, implying that it is more prevalent than
childhood type 1 diabetes (18). Moreover, ~90% of LADA patients progress to
insulin dependence within 6 years, so that, rates of progression to insulin
dependence apart, it is difficult to distinguish between adult-onset type 1
diabetes and LADA (18,19) (Table 2). Even in LADA, older patients p!
to insulin dependence more slowly (19). Strikingly, adults with
non-insulin-requiring diabetes without GAD autoantibodies have an excess of
diabetes-associated HLA alleles and are relatively young and lean (16,17).
Concordance for type 1 diabetes in identical twins according to age at clinical
onset in the index twin
AGE-DEPENDENT ROLE FOR NONGENETIC FACTORS
The incidence of autoimmune diseases has increased notably over the last 3
decades (5). The current low selection density and relative stability of HLA
polymorphisms indicate that this increasing incidence cannot be caused by
genetic selection pressures, at least operating through HLA genes, and is most
likely the result of nongenetic factors (5,8). Nongenetic 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.
Population studies are of limited value in identifying the impact of nongenetic
factors because it is difficult to segregate genetic from environmental
influences. However, changes in disease incidence within a genetically stable
population-or in migrants-are important when disease incidence rises rapidly
(5,20). In the U.S. the reported death rates from diabetes in children aged <15
years (by implication the type 1 diabetes incidence because this was before
insulin therapy) in 1890 and 1920 were 1.3/100,000 and 3.1/100,000 per year,
respectively (21), rising by 1959-1961 in Erie County, New York, to 11.3/100,000
per year, a substantial change within four generations (22). Such changes have
been most striking in children diagnosed at <5 years of age, as in Switzerland,
where the incidence rose from 4.5/100,000 in 1965 to 10.5/100,000 in 2000 (23).
Distinction between childhood-onset and adult-onset type 1 diabetes and LADA
Migration studies also support a role for environmental factors influencing
disease incidence (3,5). Type 1 diabetes incidence in Asian children who
migrated to Britain increased from 3.1/100,000 per year in 1978-1981 to 11.7/
100,000 per year in 1988-1990, much higher than in their native Karachi
(1/100,000 per year) (24,25). There are no comparable studies of adults.
Increases in disease risk in young children could be caused by an accelerated
progression to type 1 diabetes (a proposal encompassed in the accelerator
hypothesis and the early spring harvest hypothesis) or to an increased disease
risk or both. In support of an increased disease risk, there has been a recent
shift in Finland in the HLA genetic susceptibility to include more cases with
low- or moderate-risk HLA genotypes (26). In support of accelerated disease
progression, the disease incidence rose in the young (age 0-14 years) with a
coincident fall later (15-34 or 39 years) (27,28). So perhaps both factors
explain the increasing disease incidence in young children. Acceleration of the
disease process, or of metabolic decompensation, could result from reduced
insulin sensitivity, due either to increased linear growth, which has been
linked to diabetes risk, or increased childhood obesity, which has been
correlated with age at presentation (29-31). We have previously argued !
these non-genetically determined factors are likely to be environmental
DISEASE INDUCTION BY ENVIRONMENTAL FACTORS
Environmental factors have been implicated in the etiology of autoimmune
diseases. These factors include: temperate climate, increased hygiene and
decreased rates of infection, vaccinations and antibiotics, and increasing
wealth (possibly all relevant for most autoimmune and atopic diseases); however,
for type 1 diabetes, factors also include overcrowding in childhood and virus
infections, early exposure to cow's milk, reduced rates or duration of breast-
feeding, and vitamin D and nitrite consumption (1,5,32-50).
The qualitative age-specific pattern of incidence of type 1 diabetes is similar
worldwide, with a peak incidence in childhood and declining sharply thereafter
(1) (Fig. 1A). The striking postpubertal decline in disease incidence could be
caused by a loss of a genetic or environmental effect. The latter is most likely
because there is also a fall in disease risk in identical twins of young
diabetic patients, though notably not in older twins (1,10) (Fig. 1B). Such a
declining disease risk in c\hildhood-onset, but not adult-onset, diabetes
implies that those critical environmental events causing childhood-onset type 1
diabetes operate preferentially within a limited period in early childhood. Put
simply, if two events or "hits" widely separated in time led to diabetes, then
the longer the time of follow-up, the more likely would susceptible individuals
be to encounter both hits, as happens with cancer, in which the disease risk
rises with time, in contrast with childhood-onset!
diabetes after 15 years of age (1,45) (Fig. 1A and B). No such claim can be
made currently for adult- onset autoimmune diabetes.
FIG. 1. A: Age of onset of type 1 diabetes compiled from several sources to
estimate age-specific incidence, but only before 35 years of age (1,85). Note
the sharp decline in disease incidence during adolescence. It is important to
note that ~25% of type 1 diabetic patients develop the disease after 35 years of
age, and a further substantial proportion develop adult-onset
non-insulin-requiring autoimmune diabetes, so-called LADA. B: Diabetes incidence
for the twin cohort from the time of diagnosis of the index twin, according to
the age at diagnosis in the index twin when aged 0-6 years (n = 38) (solid line)
and !]24 years (n = 40) (dashed line). Note the sharp decline in diabetes
incidence in the cotwins of young diabetic twins, but a lower and more stable
diabetes incidence in co- twins of adult-onset diabetic twins, and compare this
decline with the decline shown in Fig. 1A.
Factors associated with increased risk of type 1 diabetes
Maternal-related events influence diabetes risk. Disproportionate maternal
influences on risk of type 1 diabetes suggests that critical disease-inducing
environmental events operate very early, even in utero. A number of
maternal-related events are associated with an increased disease risk in
children but not in adults (Table 3).
Children of diabetic mothers are less likely to develop type 1 diabetes than
children of diabetic fathers, and the risk in mothers is less than the expected
risk based on their HLA status (46,47). The mean life table risk of diabetes in
offspring of diabetic mothers and fathers in one study was 1.3 and 6.1%,
respectively (46). This low disease risk is confined to offspring of mothers who
had become diabetic after the age of 8 years, perhaps because of reduced
transmission of genetic risk. The risk of offspring developing diabetes
increases with maternal age at birth, whereas the effect of paternal age is
smaller (48). The first born has the highest risk of diabetes, the risk falling
thereafter by 15% per child born. Blood group incompatibility between mother and
child may also predispose to diabetes, although the cause remains obscure (49).
Whereas the size of these studies is limited, a more comprehensive analysis has
been made of viral infections during pregnancy and of ea!
cessation of breast-feeding.
Exposure to viruses. Extensive epidemiological, histological, and immunologic
data, largely derived from studies of patients aged <15 years at diagnosis,
support the role for a virus or viruses in the pathogenesis of type 1 diabetes
(33,38). Attention has focused on enteroviruses, specifically on members of the
picornavirus family, which are nonenveloped RNA viruses; for example, coxsackie
B virus infection was detected in 64% of young diabetic children as compared
with only 4% of control subjects (34).
Maternal viral infections during pregnancy could increase disease risk: levels
of group-specific enteroviral IgG and IgM antibodies during pregnancy were
higher in 57 mothers of pre-diabetic children than in 203 mothers of control
subjects (35), although HLA-DR disease risk alleles were associated with
increased humoral responsiveness to enteroviral antigens (36). Two further
observations support a viral etiology for type 1 diabetes: there is both
seasonality in the appearance of diabetes-associated autoantibodies, which peak
in the autumn and winter (50), and a temporal relationship between
diabetes-associated autoantibodies appearing and enterovirus infections
occurring in the preceding 6 months (37).
Nature of weaning diet. Early infant diet affects type 1 diabetes development.
Non-breast-fed children have a greater risk of developing diabetes than
breast-fed children, and breast-feeding for >3 months protects from diabetes
(38). This proposed protective effect could operate by providing immune factors,
e.g., secretory immunoglobulin A, or it could delay the early introduction of
foreign antigens such as cow's milk proteins (38). In either event there appears
to be an association between a short period (<2 months) of breast-feeding and
the development of diabetes- associated autoantibodies, especially when infants
carried the high- diabetes risk HLA DQ*0302 allele (39). Furthermore, the
association between milk consumption and diabetes risk may not be confined to
early life because the quantity of cow's milk intake in adults is related to
disease risk (32,38).
In summary, epidemiological evidence favors the induction of childhood-onset
type 1 diabetes by an environmental event, possibly a virus or dietary factor,
operating over a finite period in early childhood. This environmental effect
probably operates in the context of various disease susceptibility genes to
determine disease outcome. There is no evidence for such environmental effects
in patients with adult-onset type 1 diabetes.
ACTIVATION OF THE DIABETES-ASSOCIATED IMMUNE RESPONSE
If the critical event that induces the destructive immune process operates in
early childhood, it follows that diabetes-associated immune changes, which
reflect that process, may also be detected at an early age. Timing of the onset
of autoimmunity is a prerequisite for unmasking triggers in the pathogenesis of
this disease. At birth, children of diabetic mothers often have islet cell
autoantibodies (ICAAs), IAAs, and GAD autoantibodies. But these autoantibodies
can also be found in the maternal serum and are probably placentally transferred
to the child because autoantibody specificities are similar in mother and cord
blood and are not usually detected in the infants of mothers without such
autoantibodies (51-53). Passively acquired maternal autoantibodies disappear
after birth, as expected, but they can subsequently be replaced by the infant's
own autoantibodies. In one study, 3 of 58 infants of diabetic mothers developed
IAAs, ICAAs, and GAD autoantibodies de novo by 2 ye!
age, and only then were autoantibodies associated with diabetes risk (51).
Cumulative risk of type 1 diabetes in 1,353 offspring of diabetic parents was
18% at age 5 years but 50% in those with more than one diabetes-associated
Although cord blood autoantibodies are mainly transplacentally acquired,
diabetes-associated autoantibodies can appear at a very young age. For example,
85% of New Zealand schoolchildren who seroconverted to ICAA did so before 5
years of age (1). Of 137 children with ICAAs from a prospective Finnish study of
4,590 consecutive newborns with the disease risk HLA-DQB1 allele, IAAs and GAD
autoantibodies usually appeared before ICAAs, whereas insulinoma- associated 2
(IA2) autoantibodies usually appeared afterward (54). Strikingly, 95% of
seroconversions to IAAs or GAD or IA2 autoantibodies occurred in a cluster (-12
to +8 months) around the time of ICAA seroconversion. Children at high genetic
risk seroconverted steadily at approximately twice the rate of those at moderate
risk (54). Thus, induction and activation of diabetes- associated autoantibodies
is not confined to early childhood, and seroconversion may be detected up to at
least 10 years of age.
Taken together, these observations suggest that activation, possibly by
viruses, of the diabetes-associated immune process can occur in early childhood.
However, seroconversion is not confined to early childhood, so neither, by
implication, is activation of the diabetes-associated immune response.
DESTRUCTION BY THE DIABETES-ASSOCIATED IMMUNE RESPONSE
Loss of insulin secretory capacity is variable and age dependent, being more
rapid in childhood-onset diabetes than in adults. Variation in rates of disease
progression appears to be substantially genetically determined and associated
Variable rate of disease progression. If the critical initiating environmental
event were to operate exclusively in childhood, then the subsequent rate of
progression to clinical disease would be rapid in patients presenting at <5
years of age and slow in those presenting much later (1). Histological evidence
supports this contention; islet &B-cells tend to be absent within 12 months of
diagnosis in patients aged <7 years, but they are detected for longer periods in
older patients (55). Even when immune changes are activated in very young
children, there can be variability in progression to clinical diabetes;
remarkably, of children identified between 1 and 5 years of age with
diabetes-associated autoantibodies and subnormal insulin responses, half of them
progressed rapidly to diabetes, whereas the remainder were not diabetic up to 4
years later (56). This observation implies variable disease progression even
among very young children with similar HLA genetic susceptibility!
of diabetes-associated autoantibodies, and degree of metabolic disturbance.
Other studies have emphasized such variable progression being more rapid in
children in the presence of diabetes-associated autoantibodies but being
independent of autoantibody type and the degree of insulin secretory loss and
being more rapid in obese than lean children (31,57,58).
Genetic factors affect disease rate. Genetic factors determine when type 1
diabetes presents. Identical twins develop the disease at a similar age, which
is for them also at a similar time, with a heritability for age at diagnosis of
74% (12,59). Family studie\s comparing affected siblings show a correlation in
them with age at diagnosis, and not with time of diagnosis (59). Lack of
correlation between siblings for time of diagnosis argues against a common
environmental exposure precipitating diabetes and favors a distinct
environmental event (59). Given clustering in time between siblings for immune
activation, as judged by autoantibody seroconversion, as well as clustering by
age at time of diagnosis, the rate of progression of the destructive process
during the intervening pre- diabetic period is probably, to a degree,
genetically determined in both children and adults.
IMPLICATIONS FOR DISEASE PATHOGENESIS
Complex disorders tend to present clinically in adult life, whereas ~80% of
Mendelian disorders present in childhood (60). Thus, the diverse ages at which
autoimmune diabetes presents clinically could reflect differences in the disease
pathogenesis. We have already noted differences in the impact of genetic and
nongenetic factors with age at diagnosis in autoimmune diabetes. From these
observations it follows that there should be a spectrum in rates of metabolic
decompensation during the pre-diabetic period. Such a metabolic spectrum has
been well documented.
Age-dependent variation in disease progression. Insulin secretory capacity is
less compromised in adults at diagnosis than in children, and after diagnosis it
deteriorates less rapidly. A study of 235 consecutive cases with newly diagnosed
type 1 diabetes found that those aged <7 years had the lowest baseline residual
insulin secretion and required the highest insulin dose for optimal control,
whereas the older the age at diagnosis, the higher the basal C- peptide level
(61). Decreased insulin sensitivity in puberty and in adulthood could also be
relevant to metabolic decompensation, leading to frank diabetes (Fig. 1A).
Postdiagnosis, there is a decline in both fasting and stimulated C-peptide;
however, persistent C-peptide secretion, implying less aggressive disease, is
detected in more adults than adolescents and in more adolescents than
prepubertal diabetic children (62-64).
Pre-diabetic individuals pass through a stage of impaired glucose tolerance or
even non-insulin-requiring diabetes before becoming frankly insulin dependent.
DPT-1 (Diabetes Prevention Trial of Type 1 Diabetes) detected 585 relatives of
type 1 diabetic patients who had ICAAs plus either IAAs or low first-phase
insulin response to intravenous glucose; of them, 427 had normal glucose
tolerance, 87 had impaired glucose tolerance, and 61 were diabetic-yet
asymptomatic-on glucose tolerance testing (65). 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). It follows that some patients
with autoimmune diabetes (i.e., with diabetes-associated autoantibodies) pass
through a phase of non-insulin-requiring diabetes before becoming insulin
dependent. Numerous studies worldwide have identified such cases as LADA
patients and have shown that they have a similar clinical and immunogene!
profile to adult-onset type 1 diabetes (Table 2) (17- 19). Of these LADA
patients, 94% required insulin treatment by 6 years as compared with only 14%
without either GAD autoantibodies or ICAAs. Consistent with an age effect on
rates of disease progression, even in adults progression to insulin dependence
in LADA is more rapid in those aged <45 years than in older cases (19).
Furthermore, patients of a similar age with LADA and adult-onset type 1 diabetes
have similar C-peptide levels at clinical onset, although C-peptide levels fall
more rapidly in the latter after diagnosis (66).
It remains to be established whether LADA has the same disease process as adult
type 1 diabetes, but the argument could be semantic and in the present context
only serves to illustrate the wide clinical spectrum associated with the
immunogenetic features of autoimmune diabetes and the age at which it presents.
How broad that spectrum could be remains uncertain, but, as described earlier, a
proportion of non-insulin-requiring patients who do not have GAD autoantibodies
may have a disease process similar to LADA in that they also show an association
with diabetes-associated HLA alleles, just as for others with
diabetes-associated autoantibodies, clinical diabetes many never develop (1,2).
This observation is in keeping with other studies identifying an increased risk
of diabetes- associated HLA alleles in patients with non-insulin-requiring
Age-dependent variation in growth. Changes in growth and weight gain can occur
shortly before the onset of type 1 diabetes. However, these clinical changes are
distinct in early- and late-onset cases. Although identical twins normally grow
at the same rate and to approximately the same final height (70), a diabetic
twin aged !]9 years at diagnosis is often shorter than their nondiabetic cotwin,
probably because of growth delay in the pre-diabetic period (71). On the other
hand, twins and siblings of diabetic patients aged <9 years at diagnosis are not
shorter, suggesting a more rapid disease process (72,73). Decreasing insulin
sensitivity during puberty could be relevant to the increased disease incidence
at this time (Fig. 1A).
Age-dependent variation in disease outcome. Once diabetes is established, age
at onset is associated with the microvascular complication rate. The EURODIAB
Prospective Complications Study found that diabetes developing before puberty
(arbitrarily taken at 12 years of age) was associated with a higher risk of
progression to proliferative diabetic retinopathy and diabetic nephropathy
independent of diabetes duration (74,75).
It follows that there is a broad spectrum of immunogenetic, metabolic, and
clinical features associated with autoimmune diabetes, and many aspects of that
spectrum are age dependent (Table 2). Current studies, focusing on events early
in childhood, may well miss those events inducing adult-onset type 1 diabetes
IMPLICATIONS FOR PREDICTION
Accurate disease prediction is vital for secondary disease prevention, so that
therapy is only given to individuals who are otherwise likely to develop
diabetes. Strategies for disease prevention involve identification of high-risk
individuals, using both genetic markers and disease-associated immune and
metabolic changes. If the immune process associated with the development of type
1 diabetes is sometimes initiated in early childhood, but later in others,
population screening will have to be performed at different ages to detect
induction of diabetes-associated autoantibodies in the pre-diabetic period
(54,76). Indeed, GAD or IA2 autoantibodies at birth may protect against future
autoimmunity or diabetes (77). Furthermore, current studies to either detect
critical environmental factors (e.g., DIPP [Diabetes Prediction and Prevention],
DAISY [Diabetes Autoimmunity Study of the Young]) or prevent diabetes by
reducing critical exposure (e.g., TRIGR [Trial to Reduce IDDM in the
Genetically at Risk]) each confine themselves to children and may not be
relevant to autoimmune diabetes presenting in adults (50,78,79). A search for
autoantibody seroconversion in families with adultonset autoimmune diabetes
could be valuable.
Maximal predictive sensitivity and specificity in population screening will
require testing of different sets of autoantibodies at different ages (80); for
example, a study of recently diagnosed type 1 diabetic patients detected
multiple autoantibodies in 60% of patients aged <16 years but in only 37% of
older cases (81). Identification of combinations of diabetes-associated
autoantibodies will therefore be less valuable in screening adults compared with
infants, whereas testing for GAD autoantibodies as disease predictors in the
former will be more valuable than testing for IAAs, and vice versa. Because
autoantibodies to different antigens appear sequentially, disease risk based on
autoantibody combinations requires repeated screening with different
combinations, given that the predictive value of an autoantibody combination
varies with age (15,80). Thus, screening strategies need to be flexible.
IMPLICATIONS FOR PREVENTION
The aim of disease prediction is disease prevention. Type 1 diabetes could be
prevented by avoiding those environmental factors that cause the disease process
(primary prevention) or modulating the destructive process before the onset of
clinical diabetes (secondary prevention). A primary prevention strategy for type
1 diabetes requires that critical environmental factors such as diet or viruses
are recognized and removed, or their effect negated, while remembering that
infections could be protective (79,82,83). Intervention at an early age is
therefore imperative for some; for example, the TRIGR study is assessing the
prevention of type 1 diabetes by introducing different supplemental formula
feeds in the first 6 months of infant life (79). However, if environmental
factors causing diabetes can operate later, then these factors might be
different and could induce a different type of destructive immune process. In
that case, primary and secondary prevention strategies might !
differ from those that are used for childhood-onset diabetes (79,84). Given
the differences between childhood- and adult- onset autoimmune diabetes, therapy
to modify the disease process could also differ; for example, antigen-specific
therapy might involve insulin-related compounds in children, whereas in adults
GAD- or IA2-related strategies could be more relevant. Future strategies may
benefit from incorporating the patient's age at diagnosis into the study design.
We have come a long way since the possibility was first discussed that type 1
diabetes could be induced early in life. Recent developments are bringing us
close to determining the utility of this concept. In time, we must move t\oward
a more sophisticated understanding of this disease, including the relationship
between clinical diabetes, HLA-mediated genetic susceptibility, and the presence
of serum GAD autoantibodies, which in children at diagnosis are together
associated with insulin dependence but in adults are probably more frequently
associated with diabetes that does not initially require insulin therapy. To
this end we will have to consider the relevance of disease induction through
environmental events at different ages, as well as the impact such events can
have on the dynamic stability of our physiology. Only then will we understand
how inappropriate cell destruction can arise and lead to clinical diabetes, and
only then will we be able to clarify decisions about !
when, and whom we should treat to prevent autoimmune diabetes.
Rachel - email @ redacted/jracheln
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