Clinical Chemistry 45: 1331-1338, 1999;
(Clinical Chemistry. 1999;45:1331-1338.)
© 1999 American Association for Clinical Chemistry, Inc.
Type 1 Diabetes
Åke Lernmark
R.H. Williams Laboratory, University of Washington, 1959 N.E. Pacific St., Room K-165, HSB, Seattle, WA 98195. Fax 206-543-3169; e-mail ake{at}u.washington.edu
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Abstract
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Type 1 (insulin-dependent) diabetes occurs worldwide and can appear at
any age. The genetic susceptibility is strongly associated with
HLA-DQ and DR on chromosome 6, but
genetic factors on other chromosomes such as the insulin gene on
chromosome 11 and the cytotoxic T-lymphocyte antigen gene on chromosome
2 may modulate disease risk. Numerous studies further support the view
that environmental factors are important. Gestational infections may
contribute to initiation, whereas later infections may accelerate islet
ß-cell autoimmunity. The pathogenesis is strongly related to
autoimmunity against the islet ß cells. Markers of autoimmunity
include autoantibodies against glutamic acid decarboxylase, insulin,
and islet cell antigen-2, a tyrosine phosphatase-like protein.
Molecular techniques are used to establish reproducible and precise
autoantibody assays, which have been subject to worldwide
standardization. The diagnostic sensitivity (40–80%) and specificity
(99%) of all three autoantibodies for type 1 diabetes are high, and
double or triple positivity among first-degree relatives predicts
disease. Combined genetic and antibody testing improved prediction in
the general population despite the transient nature of these
autoantibodies. Classification of diabetes has also been improved by
autoantibody testing and may be used in type 2 diabetes to predict
secondary failure and insulin requirement. Islet autoantibodies do not
seem to be related to late complications but rather to metabolic
control, perhaps because the presence of islet cell autoantibodies
marks different residual ß-cell function. Combined genetic and
autoantibody screening permit rational approaches to identify subjects
for secondary and tertiary intervention trials.© 1999 American
Association for Clinical Chemistry
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Introduction
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Diabetes mellitus is a heterogeneous group of disorders, all
characterized by increased plasma glucose. In the majority of patients
with diabetes, the etiology of the disease is not understood. Expert
panels have recommended one set of criteria for diagnosis and another
set for classification (1)(2). The criteria
serve two purposes. One is to secure optimal treatment of the patient.
The other is to support research aimed at understanding the etiology
and pathogenesis of diabetes syndromes. Recently, new guidelines (Table 1
) have been suggested for the concentrations of blood glucose to
be used to diagnose diabetes (3). Normal fasting plasma
glucose
(FPG)1
is <6.1 mmol/L (110 mg/dL). Impaired fasting
glucose is >6.1 mmol/L (110 mg/dL) and <7.0 mmol/L (126
mg/dL). Provisional diagnosis of diabetes is made at a FPG >7.0 mmol/L
(126 mg/dL). It is recommended that the test is repeated on a different
day for the final diagnosis of diabetes.
Many recent investigations, therefore, support the view the diabetes
mellitus syndrome is very heterogeneous. The most common type of
diabetes is type 2 diabetes. The etiology is still unclear. The major
recent advances in understanding the etiology of diabetes have come
from genetic investigations of monogenic types of diabetes, most
prominently the primary genetic diabetes classified as MODY 1–5
(4)(5)(6). Gestational diabetes is still a major problem
affecting ~4% of all pregnancies. Mothers with gestational diabetes
have a markedly increased risk of developing postpartum diabetes. Type
1 diabetes is the most severe type of diabetes, leading to life-long
dependency on daily insulin injections. In adults, type 1 may often
masquerade as type 2 diabetes (7)(8). Diabetes
is sufficiently common that it is possible that the genetic risk for
one type may contribute to the risk of developing another type of
diabetes. The importance of modifying factors is again exemplified by
patients, often referred to as having latent autoimmune diabetes in the
adult, who seem to have a slow-onset type 1 autoimmune diabetes.
In the present short review, the current progress in understanding the
etiology and pathogenesis of diabetes will be discussed along with
recent evaluation of assays to determine diagnostic sensitivity and
specificity as well as the usefulness of combined genetic and antibody
tests to predict type 1 diabetes. The possible role of autoimmunity in
type 1 diabetes in relation to long-term complications will also be
discussed briefly. The reader is referred to more extensive reviews of
recent progress made in research to understand the development and
possible future prevention of type 1 diabetes
(4)(9)(10)(11)(12)(13)(14).
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Etiology
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We are far from understanding the etiology of type 1 diabetes
(Table 2
). Several genetic factors have been identified that indicate
the presence of strong susceptibility genetic factors
(9)(15). It is well known that studies in
identical twins demonstrate a concordance rate below 50%, supporting
the view that although genes are important, environmental factors may
be even more important. It has been known for the past 150 years
that type 1 diabetes may develop in conjunction with certain viral
infections (16). It is, therefore, often speculated that the
combinations of susceptibility genes with environmental factors are
important to the development of type 1 diabetes.
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Genetic Factors
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Many studies have shown that regardless of the ethnic background,
type 1 diabetes is strongly genetically linked and associated with
HLA on chromosome 6 (Table 2
). Molecular cloning and
sequencing of HLA genes and class II proteins have made it
possible to study genetic loci that may explain the strong association
and linkage to type 1 diabetes. Recent studies have indicated that
HLA-DQB10302-A10301 is more important than any of the
12 or more HLA-DRB104 subtypes (17)(18)(19).
However, to complicate the understanding of the role of HLA
class II molecules in disease, it is also demonstrated that the
HLA-DRB104 subtype, DRB10401 confers a risk
that is additive to that of DQB10302-A10301
(20)(21). In other words, it may be argued that
the DR0401 allele confers a risk for diabetes that is
independent of DQ. Similarly, on the HLA DQB10201-A10501
DRB103 extended haplotype, the DRB103 haplotype
seems to provide an equal risk or slightly higher risk for type 1
diabetes than DQB10201-A10501 (22).
Although molecular combinations in cis and trans may explain possible
ways by which class II molecules are formed and are able to present
antigen (23), further studies are warranted to explain the
mechanisms of disease susceptibility. HLA-DQ6 is negatively
associated with type 1 diabetes. It is speculated that the HLA DR or DQ
class II molecules associated with type 1 diabetes provide antigen
presentations that generate T-helper cells that initiate an immune
response to specific islet cell autoantigens. This immune response
includes the formation of cytotoxic T cells, which kill the
insulin-producing cells in the islets of Langerhans, and also leads to
the formation of autoantibodies. In the absence of reliable
T-cell assays, the above possibility remains difficult to test.
It has been estimated that 60% of the genetic susceptibility to
type 1 diabetes is conferred by HLA (24). Several
approaches to identify other susceptibility genes have therefore been
taken. Families with multiple affected members have been collected
(25) and used by several laboratories to carry out complete
genome scans to identify other type 1 diabetes genes
(26)(27). Currently, there are >15 such
candidate loci identified. It is possible that a combination of
HLA with other genetic factors may either enhance or
decelerate the type 1 diabetes process. Some prominent candidate
factors are the insulin gene on chromosome 11
(28)(29) and the cytotoxic T-lymphocyte
antigen (CTLA-4) gene on chromosome 2 (30). Upstream
of the insulin gene are variable numbers of tandem repeats
(28). Class I alleles (26–63 repeats) predispose in a
recessive way to type 1 diabetes, whereas class III alleles (140 to
>200 repeats) seem dominantly protective. The protective effect may be
explained by higher concentrations of proinsulin mRNA in the thymus,
perhaps to enhance immune tolerance to preproinsulin, a key autoantigen
in type 1 diabetes pathogenesis (31)(32). The
linkage to the CTLA4 gene is not understood; however, it has
been speculated that a gene polymorphism involving a AT repeat at the C
terminus at the 3' end of the gene may affect the mRNA stability of
CTLA-4 mRNA. The longer the repeat, the less stable the CTLA-4 mRNA.
Because CTLA-4 is critical to T-cell apoptosis, it has been speculated
that long AT repeats may lead to T-cell survival because the CTLA-4
protein is not formed. Further experiments will be necessary to uncover
the importance and role of other type 1 diabetes genes.
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Environmental Factors
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Studies in both dizygotic and monozygotic twins are consistent
with the fact that the environment is important to the risk of type 1
diabetes (33)(34). Numerous case-control studies
on the association of recent outbreaks of virus infection mumps,
Coxsackie B, Echo virus, and the onset of type 1 diabetes have been
published. The most compelling evidence is congenital rubella, which is
strongly associated with appearance in the affected child
(35)(36)(37). More recent studies have provided evidence that
maternal enterovirus infections increase the risk for type 1 diabetes
in the offspring (38)(39). Recently it has been
demonstrated that intrauterine exposure to enterovirus (Table 3
) is also associated with an increased risk of the offspring
developing type 1 diabetes (38)(39). It has been
speculated that a combination between susceptibility genes and
environmental factors may initiate a disease process that is associated
with a formation of an autoimmune response to the insulin-producing
cells.
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Pathogenesis
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This autoimmune reaction is reflected by the presence of
antibodies against prominent antigens in the pancreatic ß cell. The
HLA type of the individual may control the recognition of certain
autoantigens. The most important markers for ß-cell autoimmunity are
autoantibodies against insulin (40)(41),
glutamic acid decarboxylase (GAD65) (41)(42),
and islet cell antigen-2 (IA-2)
(41)(43)(44). All three molecules
are available as recombinant molecules, which has made development of
highly sensitive and reproducible assays for autoantibodies against
these autoantigens possible (41). Radioligand binding assays
using in vitro transcribed and translated GAD65 and IA-2 demonstrate
high diagnostic sensitivity and specificity for type 1 diabetes (Table 4
). Monoiodinated insulin is used in a radiobinding assay
(45)(46). ELISA tests are not appropriate to
detect these autoantibodies, which are shown to be dependent on
conformational epitopes (47)(48).
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Diagnostic Sensitivity and Specificity
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The Immunology of Diabetes Workshop and Immunology of Diabetes
Society have organized antibody standardization workshops since 1985
(49)(50). The recent Combinatorial Islet
Autoantibody Workshop (41) demonstrated that GAD65Ab and
IA-2Ab have a high diagnostic sensitivity and specificity for type 1
diabetes (Table 4
) and can be measured consistently by most
laboratories. The diagnostic sensitivity of insulin autoantibodies is
age dependent and decreases with increasing age. The assay concordance
for insulin autoantibodies in different laboratories was markedly less
than for IA-2Ab and GAD65Ab, respectively. The Combinatorial Islet
Autoantibody Workshop, however, demonstrated that the use of a
combination of autoantibody assays made it possible for several
laboratories to achieve excellent discrimination between diabetic and
control sera (Table 5
). Many laboratories achieved a sensitivity of up to 80% with a
false-positive rate of 0%. This international workshop standardization
effort demonstrated that a combination of three assays might be used
not only to identify new onset patients with type 1 diabetes but also
to define criteria for inclusion in immune intervention and other
trials. Apart from selecting subjects for immune intervention trials,
the islet cell autoantibody tests may find use in the clinical routine
to better classify adult patients with diabetes.
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Diabetes Classification
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Islet cell autoantibody assays, in particular the quantitative
radioligand binding assays for GAD65Ab and IA-2Ab, have also been
important to diabetes classification (Table 1
). Many patients with type
2 diabetes are antibody positive
(7)(8)(13)(51). It has
been demonstrated that plasma C-peptide concentrations as a measure of
residual ß-cell function are decreased in patients classified with
type 2 diabetes but positive for GAD65Ab
(7)(8)(52). As many as 10% of
new-onset patients with diabetes but classified with type 2 diabetes
may have either GAD65Ab or IA-2Ab. These patients have substantially
less plasma C-peptide than the antibody-negative type 2 diabetes
patients (52). Follow-up studies on patients with type 1
diabetes in relation to C-peptide concentrations have also demonstrated
that fewer younger individuals have residual ß-cell function at
follow-up compared with patients who are older than 15 years of age
when diagnosed and classified with type 1 diabetes. These observations
support the notion that some individuals develop a milder form of type
1 diabetes that is reflected by the presence of autoantibodies and
clinical classification in type 2 diabetes
(13)(53). It was therefore tested whether
GAD65Ab was related to an abnormal glucose tolerance test in healthy
adult subjects (54). Approximately 1% and 0.8% of
subjects exceeded the 99th percentile of GAD65Ab and IA-2Ab,
respectively. In individuals with diabetic oral glucose tolerance test
results, GAD65Ab and IA-2Ab were significantly higher (about threefold)
than in individuals with normal oral glucose tolerance test results.
GAD65Ab and IA-2Ab are, therefore, associated with impaired or diabetic
glucose tolerance in the adult population. This observation together
with the association between GAD65Ab concentrations and body mass index
may indicate a possible relationship between islet autoimmunity and
ß-cell function abnormalities with obesity and insulin resistance
(54). Studies are therefore warranted to determine the
predictive value of these islet cell autoantibodies as a predictor for
the appearance of diabetes in the healthy population.
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Prediction
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Several studies have been carried out in first-degree relatives of
type 1 diabetic patients (55). It should be noted that these
studies may not be fully representative of type 1 diabetes in the
general population because numerous epidemiological studies have
demonstrated that only 10% of new-onset type 1 diabetes children have
a first-degree relative with the disease
(10)(56). However, it has not been possible to
screen for islet cell antibodies in the general population until
recently. The many family studies, which currently are being evaluated,
are difficult to interpret because the subjects were identified in
follow-up studies that used the indirect immunofluorescence test for
islet cell antibodies (55)(57). It
recently has been shown, however, that the combination the three
autoantibody assays seems to be sufficient to replace the
immunofluorescence assay (58)(59). Several
studies have shown that the presence of three antibodies predicts
diabetes (60)(61). The presence of any one of
the autoantibodies alone may not be predictive of disease; hence,
long-term family studies have identified GAD65Ab-positive subjects who
have remained normoglycemic, although some of these individuals have
reduced ß-cell function (62). It is possible that these
individuals have a very high sensitivity to insulin, which precludes
them from developing hyperglycemia. The data suggest, however, that
there may be other factors in marker-positive first-degree relatives
that decelerate the pathogenetic process despite a major loss of ß
cells. It is therefore clear that antibodies alone do not have a high
predictive value for type 1 diabetes. Current research is focused on
the possibility of combining genetic markers with antibody testing
(63). The genetic markers DBQ10201-A10501
and DQB10302-A10301 are both often used as inclusion
criteria, whereas the presence of HLA DQ6 is used as an exclusion
criterion for participation in follow-up studies with or without
intervention treatment. The possible utility of other genetic factors
is yet to be determined.
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Intervention
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Type 1 diabetes is approached by primary, secondary, and tertiary
intervention (Table 6
). Primary intervention would include a treatment of all
individuals. The possibility of using autoantigens as a type of
vaccination is currently being explored not only in animal experiments
but also in human tests. The selection of children on the basis of HLA
type is being used to treat newborns with either oral or nasal insulin
(11). Animal experiments have shown that treatment of
spontaneously diabetic nonobese diabetic mice with GAD as a peptide,
protein, or expressed in potatoes reduced diabetes
(64)(65). Vaccination studies of children and
adults remain a future possibility to test whether type 1 diabetes can
be prevented.
Secondary intervention (Table 6
) involves screening for genetic,
autoantibody, and other possible markers at birth, in school children,
or in adults (61). Individuals classified with type 2
diabetes but positive for islet autoantibodies (representing slow-onset
type 1 diabetes, latent autoimmune diabetes in the adult, or type 1.5
diabetes) are also being tested to determine whether they are suitable
for immune intervention to preserve their ß-cell function.
Recent studies in GAD65Ab-positive patients in Japan suggested that
early insulin treatment preserves ß-cell function (66).
Several intervention trials are pending, including the use of
subcutaneous or oral insulin in the Diabetes Prevention Trial for Type
1 Diabetes (67), milk formula or nasal insulin in Finland
(11), aerosol insulin in Melbourne (68), or
nicotinamide in the European Nicotinamide Diabetes Intervention
Trial (69). In the next few years we will learn
important lessons concerning to what extent such intervention trials
preserve ß-cell function in subjects at risk for type 1 diabetes.
Finally, tertiary intervention (Table 6
) involves the treatment
of newly diagnosed patients with type 1 diabetes. Previous studies have
demonstrated that immunosuppression with cyclosporin and other agents
has not been able to stop the pathogenetic process in new-onset
patients (14). A future novel treatment is envisioned that
represents an antigen-specific immune intervention. Animal experiments
have demonstrated that administration of antigen, be it GAD65 or
insulin, at the time of clinical onset may slow the disease process
(12)(70)(71).
Pancreas and islet transplantation is being used in attempts to replace
insulin production in patients. Until recently, patients have mostly
been selected for pancreas as well as islet transplantation after a
prior kidney transplantation. Islet transplantation has not yet been
very successful, although recent studies with highly purified human
islets show prolonged function (72)(73).
Allograft rejection despite long-term immunosuppression as well as
recurrence of diseases (73) often explains the failure. In
one study, the islet graft-specific cellular auto- and alloreactivity
in peripheral blood from patients with failing islet allografts were
compared to the reactivities in patients with functional grafts. The
patients who remained C-peptide-positive for >1 year exhibited no
signs of alloreactivity, and their autoreactivity to islet autoantigens
was only marginally increased. In contrast, rapid failure was
accompanied by increases in graft-specific alloreactive T cells and
sometimes in autoreactivity to islet autoantigens. T-cell reactivities
in peripheral blood may therefore also be important influences on the
survival of ß-cell allografts (74).
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Long-Term Complications
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Retinopathy, nephropathy, and neuropathy are the three major
long-term complications of type 1 diabetes. Currently, no relationship
has been observed between type 1 immune markers and development of
nephropathy. Retinopathy on the other hand has shown increased risk
among DQB10201-A10501 and
DBQ10302-A10301 individuals and a inverse correlation
to GAD65 antibodies (75)(76). Neuropathy is
highly controversial. It was reported that GAD65Ab may be present in
type 1 diabetes patients with neuropathy (77), but numerous
subsequent studies have failed to confirm this early demonstration
(78)(79)(80).
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Future Control of Type 1 Diabetes
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The Diabetes Control and Complications Trial lesson of
diabetes control is a question of success of implementation (Table 7
). It has been clearly demonstrated that good diabetes
control is important for preventing or delaying the onset of late
complications (81). A major effort is being made to
implement the Diabetes Control and Complications Trial principles.
Ongoing studies that involve subcutaneous or oral insulin treatment of
individuals with ß-cell loss and with autoimmune markers should
provide new information on the possibility of using insulin before the
clinical onset of hyperglycemia (67). The mechanisms
may be either ß-cell rest (82) or the possibility that the
administration of insulin would alleviate the immune response in
individuals who are not yet diabetic (Table 7
). A total of >75 years
of experience with insulin therapy in relatively large dosages at the
time of clinical diagnosis have, however, failed to prolong the
"honeymoon" period. The common view is, therefore, that
antigen-specific immunosuppression will be needed in addition to
insulin to halt the pathogenetic process.
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Acknowledgments
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The research in my laboratory is supported by the National
Institutes of Health (Grants DK42654, GK26190, AI42380, DK53384, and
DK53004), the Juvenile Diabetes Foundation International, and the
American Diabetes Association.
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Footnotes
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1 Nonstandard abbreviations: FPG, fasting plasma glucose; CTLA-4, cytotoxic T-lymphocyte antigen-4; GAD65, glutamic acid decarboxylase; and IA-2, islet cell antigen-2. 
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Abstract
Introduction
