Pathogenesis of Type 1 Diabetes Mellitus PDF

Pathogenesis of type 1 diabetes mellitus
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Author
Massimo Pietropaolo, MD
Section Editor
Irl B Hirsch, MD
Deputy Editor
Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2015. | This topic last updated: Jun 30, 2014.
INTRODUCTION Type 1A diabetes mellitus results from autoimmune destruction of the insulin-producing beta cells
in the islets of Langerhans [1]. This process occurs in genetically susceptible subjects, is probably triggered by one or
more environmental agents, and usually progresses over many months or years during which the subject is
asymptomatic and euglycemic. Thus, genetic markers for type 1A diabetes are present from birth, immune markers are
detectable after the onset of the autoimmune process, and metabolic markers can be detected with sensitive tests
once enough beta cell damage has occurred, but before the onset of symptomatic hyperglycemia [2]. This long latent
period is a reflection of the large number of functioning beta cells that must be lost before hyperglycemia occurs (figure
1). Type 1B diabetes mellitus refers to non-autoimmune islet destruction (Type 1B diabetes). (See "Classification of
diabetes mellitus and genetic diabetic syndromes".)
The pathogenesis of type 1A diabetes is quite different from that of type 2 diabetes mellitus, in which both decreased
insulin release (not on an autoimmune basis) and insulin resistance play an important role. Genome-wide association
studies indicate that type 1 and type 2 diabetes genetic loci do not overlap, although inflammation (eg, interleukin-1
mediated) may play a role in islet beta cell loss in both types [3]. (See "Pathogenesis of type 2 diabetes mellitus".)
The pathogenesis of type 1 diabetes mellitus will be reviewed here. The diagnosis and management of type 1 diabetes
are discussed separately. (See "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and
adolescents" and "Prevention of type 1 diabetes mellitus" and "Management of type 1 diabetes mellitus in children and
adolescents" and "Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus".)
GENETIC SUSCEPTIBILITY Polymorphisms of multiple genes are reported to influence the risk of type 1A diabetes
(including, HLA-DQalpha, HLA-DQbeta, HLA-DR, preproinsulin, the PTPN22 gene, CTLA-4, interferon-induced helicase,
IL2 receptor (CD25), a lectin-like gene (KIA0035), ERBB3e, and undefined gene at 12q) [4-10]. A meta-analysis of
data from genome-wide association studies confirmed the above associations and identified four additional risk loci
(BACH2, PRKCQ, CTSH, C1QTNF6) associated with an increased risk of type 1 diabetes [11].
In addition, some loci conferring shared risk for celiac disease (RGS1, IL18RAP, CCR5, TAGAP, SH2B3, PTPN2) have
been identified [12]. Most loci have small effects, and the variants studied are common. The CCR5 association is of
interest in that a 32-base pair insertion deletion in a chemokine receptor, CCR5, results in a loss of function and, when
homozygous, a twofold decrease in risk of type 1 diabetes. (See 'MHC genes' below and 'Non-MHC genes' below and
'Association with other autoimmune diseases' below.)
Genes in both the major histocompatibility complex (MHC) and elsewhere in the genome influence risk, but only human
leukocyte antigen (HLA) alleles have a large effect, followed by insulin gene polymorphisms and PTPNN22. Although
the association of certain HLA alleles with type 1 diabetes is strong, this genetic locus is estimated to account for less
than 50 percent of genetic contributions to disease susceptibility. The associations of other loci are of a magnitude that
do not contribute to prediction of disease but may implicate important pathways, such as CCR5.
In particular, it is estimated that 48 percent of the familial aggregation can now be ascribed to known loci, and the MHC
contributes 41 percent [6]. As an example, siblings with the highest risk HLA DR and DQ alleles (eg, DR3/DR4
heterozygotes), who inherit both HLA regions identical by descent to their diabetic sibling, may have a risk of
developing anti-islet autoimmunity as high as 80 percent and a similar long-term risk of diabetes [13].
The lifelong risk of type 1 diabetes is markedly increased in close relatives of a patient with type 1 diabetes, averaging
about 6 percent in offspring, 5 percent in siblings, and 50 percent in identical twins (versus 0.4 percent in subjects with
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no family history) [1,14,15]. A monozygotic twin of a patient with type 1 diabetes has a higher risk of diabetes than a
dizygotic twin, and the risk in a dizygotic twin sibling is similar to that in non-twin siblings [14].
MHC genes The major susceptibility genes for type 1 diabetes (called IDDM1 for the MHC locus) are in the HLA
region on chromosome 6p [16,17]. This region contains genes that code for MHC class II molecules expressed on the
cell surface of antigen-presenting cells such as macrophages. These MHC molecules consist of alpha and beta chains
that form a peptide-binding groove in which antigens involved in the pathogenesis of type 1 diabetes are bound. MHC
binding of antigen allows it to be presented to antigen receptors on T cells, which are the main effector cells of the
destructive autoimmune process (figure 2). (See "Major histocompatibility complex (MHC) structure and function".)
The ability of these class II molecules to present antigens is dependent in part upon the amino-acid composition of their
alpha and beta chains. Substitutions at one or two critical positions can markedly increase or decrease binding of
relevant autoantigens and therefore the susceptibility to type 1 diabetes [18,19]. In particular, more than 90 percent of
patients with type 1 diabetes carry either HLA-DR3,DQB1*0201 (also referred to as DR3-DQ2) or -DR4,DQB1*0302
(also referred to as DR4-DQ8), versus 40 percent of controls with either haplotype; furthermore, about 30 percent of
patients have both haplotypes (DR3/4 heterozygotes), which confers the greatest susceptibility [17].
The prevalence of this high-risk genotype is remarkably high in some populations. As an example, 8.9 percent of
healthy white teenagers in Washington state have the DR4,DQB1*0302/DR3,DQB1*0201 genotype and 2.4 percent of
the general population of Denver, Colorado. Approximately 5 percent of children with this genotype develop type 1A
diabetes versus approximately 0.3 percent of children overall [19,20]. A subset of DR4 alleles, such as DRB1*0403 and
DPB1*0402, decrease the risk of development of diabetes, even with the high risk DQB1*0302 allele [21,22].
In addition, the HLA allele DQB1*0602 confers protection against the development of type 1 diabetes. This allele is
present in approximately 20 percent of the general US population, but only 1 percent of children developing type 1A
diabetes. One prospective study evaluated 72 relatives with islet-cell antibodies (ICA), 75 percent of whom carried the
high-risk alleles DQB1*0302 and/or *0201 [23]. Diabetes developed in 28 of the 64 subjects who did not have the
DQB1*0602 allele versus none of the eight with it. No other common DQ allele provides such dramatic protection.
The prevalence of these genes varies with ethnicity, and explains to a large degree why type 1 diabetes is relatively
common in Scandinavia and Sardinia, but uncommon in China (figure 3).
Non-MHC genes Although important, the MHC susceptibility genes are not sufficient to induce type 1 diabetes,
suggesting polygenic inheritance in most cases [16]. An important component of the susceptibility to type 1 diabetes
resides in certain non-MHC genes that have an effect only in the presence of the appropriate MHC alleles.
In particular, polymorphisms of a promoter of the insulin gene and an amino acid change of a lymphocyte-specific
tyrosine phosphatase (termed lyp, PTPN22) are associated with the risk of type 1 diabetes in multiple populations
[24-27]. A repeat sequence in the 5' region of the insulin gene is associated with greater insulin expression in the
thymus and it is hypothesized that this contributes to decreasing the development of diabetes [28]. The polymorphism
of the protein tyrosine phosphatase (PTP) gene influences T cell receptor signaling, and the same polymorphism is a
major risk factor for multiple autoimmune disorders [29,30].
A polymorphism in the cytotoxic T-lymphocyte-associated antigen-4 gene was shown to be associated with the risk of
type 1 diabetes in a meta-analysis of 33 studies involving over 5000 patients [31].
Additional evidence for the role of non-MHC genes comes from studies in NOD mice (non-obese diabetic mice, a major
model of type 1A diabetes). These mice develop spontaneous autoimmune diabetes with striking similarities to type 1
diabetes in humans [32]. Autoimmune infiltration of the islets of Langerhans (insulitis) begins at about 50 days of age
and clinical diabetes appears at about 120 days.
Interferon gamma-positive T cells (Th1 cells) appear to be an important mediator of the insulitis in NOD mice, and
destruction of the islet cells can be slowed by the administration of anti-interferon gamma antibodies. Interferon
gamma-inducing factor (IGIF; also called interleukin-18) and interleukin-12 are potent inducers of interferon gamma,
and the progression of insulitis begins in parallel with increased release of these two cytokines [33].
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It was initially thought that, in contrast to Th1 cells, Th2 cells (which produce interleukin-4, -5, -10, and -13) protected
against the onset and progression of type 1 diabetes. However, Th2 cells also are capable of inducing islet-cell
destruction and, therefore, the onset and progression of type 1 diabetes are probably under the control of both Th1 and
Th2 cells [34].
A more generalizable concept is that type 1A diabetes is prevented by a balance between pathogenic and regulatory T
lymphocytes [35]. A major subset of regulatory T lymphocytes have the markers CD4 and CD25 on their surface and
lack the IL7 receptor, and are dependent for development upon a transcription factor termed foxP3. Mutations of foxP3
lead to lethal neonatal autoimmunity, including type 1 diabetes in neonates. This condition, though extremely rare (see
"IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked"), is important to recognize as bone marrow
transplantation can reverse it [36]. (See "Overview of autoimmunity", section on 'Pathogenetic mechanisms'.)
AUTOIMMUNITY Islet cell autoantibodies (ICAs) were first detected in serum from patients with autoimmune
polyendocrine deficiency; they have subsequently been identified in 85 percent of patients with newly diagnosed type 1
diabetes and in prediabetic subjects [1]. Radioassays are available to detect autoantibodies which react with specific
islet autoantigens. (See "Prediction of type 1 diabetes mellitus".)
Children with type 1 diabetes who do not have islet-cell or other autoantibodies at presentation have a similar degree of
metabolic decompensation as do children who have these antibodies, although those with more of the different types of
antibodies appear to have the most accelerated islet destruction and a higher requirement for exogenous insulin during
the second year of clinical disease [37]. A few patients from Japan without obvious evidence of islet autoimmunity have
been described in whom the onset of hyperglycemia was abrupt, A1C (glycosylated hemoglobin values) were normal,
and serum pancreatic enzyme concentrations were high [38]. It is not clear whether these patients had an unusually
abrupt onset of autoimmune type 1A diabetes or non-autoimmune islet destruction (type 1B diabetes), though with
studies indicating high-risk human leukocyte antigen (HLA) alleles in these individuals, rapid type 1A diabetes in the
absence of islet autoantibodies is a possibility.
Target autoantigens An ongoing search has identified several autoantigens within the pancreatic beta cells that
may play important roles in the initiation or progression of autoimmune islet injury (table 1) [1,39]. Studies on the NOD
(non-obese diabetic) mouse model indicate that proinsulin/insulin itself is the likely primary target for the autoantibodies
[40,41]. The autoimmune response to proinsulin subsequently spreads to other autoantigens, such as islet-specific
glucose-6-phosphatase catalytic-subunit-related protein (IGRP), which is downstream of the immune response to insulin
[41]. Diabetes in the NOD mouse can be eliminated by changing a specific amino acid of insulin [40].
Other important autoantigens are glutamic-acid decarboxylase (GAD), insulinoma-associated protein 2 (IA-2 and IA-2
beta), and the autoantigen ZnT8, a zinc transporter of islet beta cells [42-45]. (See "Prediction of type 1 diabetes
mellitus", section on 'Immunologic markers'.)
Insulin The early appearance of anti-insulin antibodies suggests that insulin is an important autoantigen [46,47].
Direct confirmation of this hypothesis has come from studies in NOD mice. Pathogenic CD8+ T cell clone recognizes an
epitope on the insulin B chain [48] and a major target autoantigen for CD4 T cells of NOD mice is insulin peptide B chain
amino acids 9 to 23 [40]. Similar T cell responses are found in peripheral lymphocytes obtained from patients with
recent-onset type 1 diabetes and from subjects at high risk for the disease have also been reported [49].
Also consistent with the importance of insulin as an autoantigen is the demonstration that knockouts of the insulin genes
in NOD mice greatly influence progression to disease [50], and the administration of insulin or its B chain during the
prediabetic phase can prevent or delay diabetes in susceptible mice and perhaps in humans. (See "Prevention of type 1
diabetes mellitus", section on 'Insulin'.)
Insulin autoantibodies are often the first to appear in children followed from birth and progressing to diabetes, and are
the highest in young children developing diabetes. Of note, once insulin is administered subcutaneously, essentially all
individuals develop insulin antibodies, and thus insulin autoantibody measurements after approximately two weeks of
insulin injections cannot be used as a marker of immune mediated diabetes (type 1A) [47].
Glutamic acid decarboxylase Another important autoantigen against which antibodies are detected is the
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enzyme GAD, which is present in the islets as well as in the central nervous system and testes [42]. Antibodies to GAD
(a 65-kD protein) are found in about 70 percent of patients with type 1 diabetes at the time of diagnosis.
Autoantibodies reacting with GAD (anti GAD65 antibodies) are prominent in humans with type 1 diabetes. In contrast,
the NOD mouse does not appear to express GAD autoantibodies [51] but does express insulin autoantibodies [52].
NOD mice rendered tolerant to GAD develop diabetes. This coupled with lack of GAD expression by mouse islets has
cast doubt on its importance as a pathogenic autoantigen in this model, although injections of GAD peptides slow
progression to diabetes [53].
Insulinoma-associated protein 2 Another autoantigen is a neuroendocrine protein called insulinoma-associated
protein 2 (IA-2), which is a protein tyrosine phosphatase-related protein [43,44]. IA-2 is granule membrane protein,
whose cytosolic domain binds beta 2-syntrophin, an F-actin-associated protein, and is cleaved upon granule exocytosis.
The resulting cleaved cytosolic fragment, ICA512-CCF, reaches the nucleus and upregulates the transcription of granule
genes, including insulin and ICA512 [54]. In one study, antibodies to this antigen were found in the serum of 58 percent
of patients with type 1 diabetes at the time of diagnosis [55]. Autoantibodies to IA-2 usually appear later than
autoantibodies to insulin and GAD, and are highly associated with expression of multiple anti-islet autoantibodies and
progression to diabetes. One of the best predictors of progression to type 1A diabetes is expression of two or three
autoantibodies: GAD, IA-2 or insulin autoantibodies [56].
Zinc transporter ZnT8 The cation efflux zinc transporter (ZnT8) has also been identified as a candidate type 1
diabetes autoantigen [45]. Sixty to 80 percent of patients with newly diagnosed type 1 diabetes have ZnT8
autoantibodies. In addition, 26 percent of subjects with antibody negative (insulin, GAD, IA-2 and ICA) type 1 diabetes
have ZnT8 autoantibodies. In children followed from birth to the development of diabetes in the Diabetes Autoimmunity
Study in the Young (DAISY) study, ZnT8 autoantibodies appear later than insulin autoantibodies [45], and the antibody
is typically lost very early after the onset of diabetes [57].
Other type 1 diabetes-related autoantigens As autoimmunity in type 1 diabetes progresses from initial
activation to a chronic state, there is often an increase in the number of islet autoantigens targeted by T cells and
autoantibodies. This condition is termed epitope spreading. Several observations indicate that islet autoantibody
responses directed to multiple islet autoantigens are associated with progression to overt disease [56]. A number of
additional type 1 diabetes-related autoantigens have been identified, which include islet cell autoantigen 69 kDa
(ICA69), the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), chromogranin A (ChgA), the
insulin receptor, heat shock proteins, the antigens jun-B,16, CD38, peripherin and glial fibrillary acidic protein (GFAP)
[58].
It has been hypothesized that early autoimmunity in spontaneous type 1 diabetes can also target nervous system tissue
elements, raising the concept that in type 1 diabetes pathogenetic immune responses may also be non-beta cell
exclusive [59]. However, it remains to be established as to whether or not the presence of serologic responses to
putative neuronal antigens are predictive of the development of small fiber neuropathy (autonomic and/or somatic) and
for the progression to clinical type 1 diabetes.
Role of cellular immunity The existence of IgG immunoglobulins directed to epitopes of islet autoantigens implies
the influence of T cell participation in the autoimmune response. While the role of autoimmunity in the pathogenesis of
type 1 diabetes and the frequent development of autoantibodies are not in question, there is increasing evidence for a
major role of cellular immunity. The occurrence of type 1 diabetes in a 14-year-old boy with X-linked
agammaglobulinemia suggests that B cells are not required for the development of the disorder and that the destruction
of pancreatic beta cells is mediated principally by T cells [60].
The observation that this boy did not develop the disorder until age 14 years might imply that normal B cells facilitate
the development of diabetes, but are not absolutely necessary. This is supported by a study of NOD mice, which found
that when the mice were rendered absolutely deficient in B cells, the incidence of diabetes in female mice dropped from
80 percent to 30 percent, and the disease developed later in life [61]. Other groups have reported almost complete
protection if autoantibodies are absent [62].
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Naturally-processed epitopes of islet cell autoantigens represent the targets of effector and regulatory T cells in
controlling pancreatic beta cell-specific autoimmune responses [63]. In particular, naturally processed HLA class II
allele-specific epitopes recognized by CD4+ T cells, corresponding to the intracellular domain of IA-2, were identified
after native IA-2 antigen was delivered to EBV-transformed B cells and peptides eluted and analyzed by mass
spectrometry [64]. Furthermore, dendritic cell subsets can process and present soluble IA-2 to CD4+ T cells after
short-term culture, but only plasmacytoid dendritic cells enhance (by as much as 100 percent) autoantigen presentation
in the presence of IA-2 autoantibody patient serum [65]. The plasmacytoid subset of dendritic cells is overrepresented
in the blood close to type 1 diabetes onset and shows a distinctive ability to capture islet autoantigenic immune
complexes and enhance autoantigen-driven CD4+ T cell activation. This suggests a synergistic proinflammatory role for
plasmacytoid dendritic cells and IA-2 autoantibodies in type 1 diabetes. Taken together, these observations may lead to
identification of novel naturally-processed epitopes recognized by CD4+ T cells, which may represent potential
therapeutic agents, either in native form or as antagonistic altered peptide ligands, for the treatment of type 1 diabetes.
Molecular mimicry Initiating factors of the immune response are not well understood. One possibility is molecular
mimicry due to homology between GAD and an infectious agent such as Coxsackie B virus (see 'Role of viruses'
below). A study of the expression of a beta cell specific 38 kDa protein in rats provides an alternative model for how
this might occur [66]. This protein is expressed in the islets at birth and at all times thereafter in strains that are
resistant to the development of diabetes, but is not expressed until day 30 in diabetes-prone biobreeding (BB) rats.
Delayed expression of this protein may lead to loss of self-tolerance and the initiation of an anti-beta cell autoimmune
response.
The role of the thymus and lymphoid organs There is evidence to suggest that self-antigens are naturally
expressed in the thymus and peripheral lymphoid organs [67-69]. Tolerance to tissue-restricted self-molecules is
believed to begin at the level of the thymus with negative selection where the deletion of thymocytes with T cell
receptors (TCR) exhibiting strong affinity towards self-molecules are expressed during maturation of the immune
system [70-72]. The insulin gene is one of the most widely studied genes in both humans and mice exhibiting thymic
expression as well as a beta cell expression-dependent association with type 1 diabetes susceptibility [40,68,73-75].
For instance, in humans the IDDM2 susceptibility locus of the insulin gene (INS) is a region associated with type 1
diabetes and has been finely mapped to reveal Variable Number of Tandem Repeat (VNTR) polymorphisms upstream
of the INS promoter. The length of these repeats has been directly implicated in the control of the expression levels of
insulin mRNA in the thymus [75-78]. In addition to insulin, islet cell autoantigen 69 kDa (ICA69), a neuroendocrine
protein targeted by autoimmune responses in human T1D and in nonobese diabetic (NOD) mice [79-81], is also
expressed in the thymus, and the likelihood that thymic levels of ICA69 will affect susceptibility to T1D through a
mechanism similar to that shown for the insulin VNTRs has been suggested [68,82]. This hypothesis is primarily based
on previous studies indicating that IA-2, GAD, and ICA69 are transcribed in the human thymus throughout fetal life and
childhood [68,76,83,84], and that the existence of DNA sequence variation in NOD mice with the potential for
functionally relevant effects on Ica1 gene expression in the thymus. Such variations in the Ica1 promoter might lead to
an increased probability of failure to negatively select ICA69-reactive T cell clones of developing thymocytes [84].
Reversal of diabetes in animal models Reversal of type 1 diabetes with administration of complete Freund's
adjuvant, an immune modulator, has been reported in up to 32 percent of treated diabetic mice [85-87]. This recovery is
believed to be due to immunomodulation of an underlying autoimmune condition, allowing proliferation of small numbers
of surviving islet cells and restoration of the beta cell mass in the mouse pancreas. A related adjuvant regimen used in
human trials did not delay loss of C-peptide secretion and other immune modulators. The immunosuppressant
mycophenolate mofetil, anti-CD3 antibody, and anti-CD20 monoclonal antibody are under investigation [88,89]. (See
"Prevention of type 1 diabetes mellitus", section on 'Prevention and reversal strategies'.)
Association with other autoimmune diseases Patients with type 1 diabetes are at increased risk for developing
other autoimmune diseases, most commonly autoimmune thyroiditis and celiac disease. This association is reviewed
briefly below and in more detail separately. (See "Associated autoimmune diseases in children and adolescents with
type 1 diabetes mellitus".)
Thyroid autoimmunity is particularly common among patients with type 1A diabetes, affecting more than
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one-fourth of individuals, and 2 to 5 percent of patients with type 1 diabetes develop autoimmune hypothyroidism.
(See "Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus", section on
'Thyroid screening'.)
Transglutaminase autoantibodies are present in approximately 10 percent of patients, and half of these patients
have high levels of the autoantibody and celiac disease on biopsy [90,91]. In addition, certain alleles (eg, PTPN2,
CTLA4, RGS1) confer a genetic susceptibility to both type 1 diabetes and celiac disease, suggesting a common
biologic pathway [12]. (See "Associated autoimmune diseases in children and adolescents with type 1 diabetes
mellitus", section on 'Celiac screening' and "Pathogenesis, epidemiology, and clinical manifestations of celiac
disease in adults", section on 'Genetic factors' and "Diagnosis of celiac disease in adults", section on 'Anti-tissue
transglutaminase antibodies'.)
Fewer than 1 percent of children with type 1 diabetes have autoimmune adrenalitis. In one report, 11 of 629
patients (1.7 percent) with type 1 diabetes but none of 239 normal subjects had antibodies directed against
21-hydroxylase, a common autoantigen in primary adrenal insufficiency [92]. Three of eight patients with anti-21hydroxylase antibodies had adrenal insufficiency. (See "Pathogenesis of autoimmune adrenal insufficiency".)
Type 1 diabetes can be seen with polyglandular autoimmune disease, especially type II, in which adrenal
insufficiency, autoimmune thyroid disease, and gonadal insufficiency are the other major components. (See
"Causes of primary adrenal insufficiency (Addison's disease)".)
Rare syndromes associated with type 1 diabetes have shed important light on pathogenesis. The immune
dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is associated with neonates developing type
1 diabetes. These infants usually die of overwhelming autoimmunity, in particular, severe enteritis. They have a mutation
of a gene termed foxp3, a "master-switch" for the development of regulatory T cells. Studies of the syndrome and the
related animal model provide dramatic evidence that regulatory T cells (formerly termed suppressor T cells) have a
major physiologic role. The APS-I syndrome (Autoimmune Polyendocrine Syndrome type 1) is caused by a mutation of
the AIRE gene (autoimmune regulator). This gene controls expression of a series of "peripheral" antigens in the thymus,
including insulin. It is thought that the gene provides protection from autoimmune disorders, including type 1 diabetes,
via its influence on central T cell tolerance [93].
ENVIRONMENTAL FACTORS Environmental influences are another important factor in the development of type 1
diabetes. The best evidence for this influence is the demonstration in multiple populations of a rapid increase in the
incidence of type 1A diabetes [94,95]. The etiology of the increase is unknown. One hypothesis, termed the hygiene
hypothesis, relates improved "sanitation" to increasing immune mediated disorders [96]. Twin studies indicate that not
all monozygotic twins of probands with type 1 diabetes develop diabetes, although the cumulative prevalence increases
with long-term follow-up [14,15,97].
Perinatal factors Several pregnancy-related and perinatal factors were associated with a small increase in risk of
type 1 diabetes in a study of 892 children with diabetes and 2291 normal children in Europe [98]. They were maternal
age >25 years, preeclampsia, neonatal respiratory disease, and jaundice, especially that due to ABO blood group
incompatibility; protective factors were low birth weight and short birth length. One cohort study found a relatively weak
but significant direct association between birth weight and risk of type 1 diabetes [99]; in a second study, the
association was limited to cases with disease onset prior to age 10 [100]. Postnatal dietary factors, such as vitamin D
and omega-3 fatty acid ingestion may also be important [101]. (See 'Role of diet' below.)
Role of viruses Viruses can cause diabetes in animal models either by directly infecting and destroying beta cells or
by triggering an autoimmune attack against these cells [102]. Although isolated case reports have suggested direct viral
destruction of beta cells [103], this is probably extremely rare. A careful autopsy study found no evidence for acute or
persisting infection from Coxsackie, Epstein-Barr virus, mumps, or cytomegalovirus in the pancreatic tissue of 75
patients who died within a few weeks of developing type 1 diabetes [104]. However, some unusual forms of diabetes
have been associated with the presence of Coxsackie virus in a large number of beta cells [105].
The importance of autoimmune activation is also uncertain. Coxsackie B virus-specific immunoglobulin M (IgM)
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responses have been found in 39 percent of children with newly diagnosed type 1 diabetes, compared with only 6
percent of normal children [106]. Two additional findings were noted in another report [107]:
Coxsackie virus antibody titers were significantly higher in pregnant women whose children subsequently
developed type 1 diabetes, compared with pregnant women whose children did not become diabetic.
Enteroviral infections were almost two times more common in siblings who developed type 1 diabetes than in
siblings who remained nondiabetic.
These observations suggest that exposure to enteroviruses, both in utero and in childhood, can induce beta cell
damage and lead to clinical diabetes. Significant homology has been found between human glutamic-acid
decarboxylase (GAD) and the F2C protein of Coxsackievirus B4, suggesting a possible role for molecular mimicry
[108,109].
The possibility of viral-induced autoimmunity or molecular mimicry is supported by long-term follow-up of infants with the
congenital rubella syndrome. Autoimmune diabetes and other autoimmune diseases may occur 5 to 20 years after
infection, especially in those subjects who have HLA-DR3 [110,111]. Unfortunately, the long latent period between peak
immunologic activity and clinical disease means that measuring viral titers at the onset of hyperglycemia is unlikely to be
helpful.
The clearest association of viral infection with the development of spontaneous autoimmune diabetes comes from the
observation that biobreeding diabetes-resistant (BB-DR) rats, a diabetes resistant strain of rats related to BB rats but
without the severe lymphopenia of BB rats, develop diabetes when infected with the Kilham rat virus [112]. Studies
suggest a role for innate immune system activation in this model. In a similar manner, polyinosinic:polycytidylic acid
(poly-IC) injections (a mimic of double stranded RNA viruses that induces interferon alpha secretion) can induce
diabetes in this model and in a mouse model, where induction of interferon alpha is essential for diabetes development
[113].
In contrast to the above reports, there are data that refute the role of viruses in the pathogenesis of type 1 diabetes
[114,115]. In one report, Coxsackie B virus infections in childhood were associated with transient production of
antibodies to GAD, but not type 1 diabetes [115].
To further confuse the issue, there is evidence that viruses may protect against type 1 diabetes. In NOD mice and BB
rats inoculation with lymphocytic choriomeningitis virus at an early age reduced the incidence of diabetes [116,117].
Also supporting a protective role for viruses is the observation that raising non-obese diabetic (NOD) mice and BB rats
in pathogen-free environments leads to an increased incidence of type 1 diabetes [118].
Childhood immunization There has been concern that childhood vaccination may be associated with later
development of chronic diseases, including type 1 diabetes. However, immunization of genetically predisposed infants
(siblings with type 1 diabetes) with viral (and bacterial) antigens does not appear to be associated with an increased
risk of developing type 1 diabetes [119]. (See "Autism and chronic disease: No evidence for vaccines as a contributing
factor", section on 'Type 1 diabetes mellitus'.)
Role of diet Several dietary factors may influence the development of type 1 diabetes, with most attention having
been paid to cow's milk [120].
Cow's milk It has been proposed that some component of albumin in cow's milk (bovine serum albumin), the
basis for most infant milk formulas, may trigger an autoimmune response [121]. As an example, epidemiologic data
from Finland suggest that there is an increased risk of type 1 diabetes associated with introduction to dairy products at
an early age and with high milk consumption during childhood [121]. However, a cross-sectional study found no
evidence of an association between early exposure to cow's milk and the development of type 1 diabetes [122], and
some prospective studies have found no association between the duration of breast feeding or introduction of cow's
milk and the development of islet autoimmunity in children at high risk of type 1 diabetes [114,123].
It has also been suggested that a cell-mediated response to a specific cow's milk protein, beta-casein, may be involved
in the pathogenesis of type 1 diabetes. In one report, 36 patients with recent-onset type 1 diabetes were compared
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with 36 normal subjects [124]. Exposure to bovine beta-casein led to proliferation of peripheral blood T cells in 51
percent of the patients with type 1 diabetes versus only one (3 percent) of the normal subjects. In addition, an
epidemiological study of children from 10 countries revealed a strong correlation between the incidence of type 1
diabetes and the consumption of beta-casein [125].
A more detailed understanding of the complex protein composition of early cow's milk exposure is necessary to
understand its putative effect upon the development of type 1 diabetes. Randomized trials of early nutritional
intervention with formulas containing less complex dietary proteins are reviewed separately. (See "Prevention of type 1
diabetes mellitus", section on 'Avoidance of cow's milk'.)
Vitamin D supplements Although cow's milk may be associated with an increase of risk for type 1 diabetes,
one component, vitamin D, may be protective. (See "Prevention of type 1 diabetes mellitus", section on 'Vitamin D
supplements'.)
Cereals In infants at high risk for type 1 diabetes, the timing of initial exposure to cereals may affect the risk of
developing islet cell autoantibodies. In two large prospective cohort studies of newborns at high risk for type 1 diabetes
(either a first degree relative [126,127] or a high risk human leukocyte antigen (HLA) genotype [126]), first exposure to
cereal before age three months [126,127] or after seven months [126] was associated with an increased risk of
developing islet cell autoantibodies [126,127] and type 1 diabetes (adjusted hazard ratio [HR] 3.33, 95% CI 1.54-7.18
for age at first exposure to any cereal 6 months) compared with infants whose first exposure was between ages four
to six months [128]. The increased risk was associated with gluten-containing cereals in one study [127], but with either
gluten or rice-containing cereals in the other [126]. Early introduction of gluten (<3 months of age) increases the risk of
celiac disease [129].
Based upon these data, we do not recommend changing current infant feeding guidelines, which state that cereal
should be introduced between ages four and six months. (See "Introducing solid foods and vitamin and mineral
supplementation during infancy", section on 'Optimal timing'.)
Omega-3 fatty acids Omega-3 fatty acids may be involved in the development of autoimmunity and type 1
diabetes. Preliminary studies in animals support a protective role of omega-3 fatty acids in the inflammatory response
associated with autoimmune islet cell destruction [130,131]. In a case-control study from Norway, children with type 1
diabetes were less likely to be given cod liver oil (containing omega-3 fatty acids and vitamin D) during infancy than
children without diabetes [101]. In addition, a longitudinal observational study of children at increased risk for type 1
diabetes reported an inverse association between omega-3 fatty acid intake and development of islet autoimmunity
(adjusted HR 0.45, 95% CI 0.21-0.96) [132]. A clinical trial of omega-3 fatty acid supplementation in infants with high
genetic risk of type 1 diabetes is underway. (See "Prevention of type 1 diabetes mellitus", section on 'Omega-3
polyunsaturated fatty acids'.)
The role of polyunsaturated fatty acids in the prevention of other diseases is discussed separately. (See "Dietary fat",
section on 'Polyunsaturated fatty acids'.)
Nitrates Studies in Colorado and in Yorkshire (UK) have found that the incidence of type 1 diabetes correlates
with the concentration of nitrates in the drinking water [133]. The incidence is about 30 percent higher in areas with
nitrate concentrations above 14.8 mg/L compared with areas with concentrations below 3.2 mg/L.
DETERMINANTS OF INSULIN DEFICIENCY Although glucose tolerance can remain normal until near the onset of
clinical type 1 diabetes, measurement of pancreatic beta cell function usually shows substantial reduction in insulin
secretion during the preclinical period [134,135]. Impaired glucose tolerance frequently precedes the onset of overt
diabetes [136]. The most widely used test to estimate functioning beta cell mass is measurement of the acute insulin
response to an intravenous injection of glucose (AIRg). This test [137,138] is used, along with immunologic
measurements, to identify subjects at high risk for type 1 diabetes. (See "Prediction of type 1 diabetes mellitus".)
It has been thought in the past that about 90 percent of the beta cell mass needs to be destroyed before
hyperglycemia occurs; however, this is probably not true. As an example, the administration of streptozotocin in
increasing doses to adolescent baboons can induce complete insulin dependency (with no detectable AIRg) at a time
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when 30 to 50 percent of the beta cell mass is still viable [139]. The profound insulin deficiency in this setting is out of
proportion to the loss of functioning cells and may be due in part to the inhibitory action of cytokines released from
inflammatory cells in the islets. The following observations are consistent with the importance of such external factors:
When severely inflamed islets are removed from 12- to 13-week-old NOD mice and studied in culture, insulin
secretion on day 0 is very low, but there is almost complete recovery of function by day seven (figure 4) [140].
Histologic and in vitro physiologic studies of the pancreas of a patient who died soon after the onset of type 1
diabetes revealed that a substantial mass of beta cells were still viable [141].
In a mouse model of diphtheria toxin-induced beta cell apoptosis (characterized by the absence of an
inflammatory reaction), cessation of diphtheria toxin expression was associated with beta cell proliferation,
recovery of beta cell function, and subsequent normalization of glucose homeostasis, even in a hyperglycemic
environment [142]. These findings are in contrast to those observed in autoimmune and pharmacologic
(streptozotocin) models of diabetes, in which beta cells have demonstrated a poor ability to regenerate.
These findings are of potential clinical importance, because they suggest that severe hyperglycemia does not
necessarily imply irreversible loss of almost all functioning beta cells. Thus, stopping the autoimmune process, even at
this late stage, may allow substantial recovery of beta cell function.
Insulin-like growth factor 1 (IGF-1) is thought to play a role in islet development and function. In transgenic mice, local
expression of IGF-1 in beta cells resulted in regeneration of pancreatic islets and reversal of type 1 diabetes [143].
However, in another study, beta cell-specific deletion of the IGF-1 receptor did not affect beta cell mass, but resulted in
hyperinsulinemia and glucose intolerance [144]. This suggests that the IGF-1 receptor may not be critical for beta cell
development, but is important for beta cell function.
CLINICAL RESEARCH The National Institutes of Health has established a program termed Trialnet whose goal is
the prevention of type 1A diabetes and prevention of further beta cell destruction in patients with recent-onset diabetes.
Relatives of patients with type 1A diabetes can be screened for expression of islet autoantibodies and trials are
available to study agents to halt beta cell destruction in multiple centers throughout the United States and the world
(www.diabetestrialnet.org).
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and
Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition. These articles are
best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade
reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics
to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info
and the keyword(s) of interest.)
Basics topics (see "Patient information: Type 1 diabetes (The Basics)")
Beyond the Basics topics (see "Patient information: Diabetes mellitus type 1: Overview (Beyond the Basics)")
SUMMARY
Type 1A diabetes mellitus results from autoimmune destruction of the insulin-producing beta cells in the islets of
Langerhans [1]. This process occurs in genetically susceptible subjects, is probably triggered by one or more
environmental agents, and usually progresses over many months or years during which the subject is
asymptomatic and euglycemic. This long latent period is a reflection of the large number of functioning beta cells
that must be lost before hyperglycemia occurs (figure 1). (See 'Introduction' above.)
Polymorphisms of multiple genes are known to influence the risk of type 1A diabetes (HLA-Dqalpha; HLA-Dqbeta;
HLA-DR, preproinsulin, the PTPN22 gene, and CTLA-4), with whole genome analysis providing additional genes
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and loci, such as KIAA0035 (a lectin). Genes in both the major histocompatibility complex (MHC) and elsewhere in
the genome influence risk, but only human leukocyte antigen (HLA) alleles have a large effect. (See 'Genetic
susceptibility' above.)
There are a number of autoantigens within the pancreatic beta cells that may play important roles in the initiation
or progression of autoimmune islet injury including glutamic acid decarboxylase (GAD), insulin, insulinomaassociated protein 2 (IA-2), and zinc transporter ZnT8. It is not certain, however, which of these autoantigens is
involved in the initiation of the injury and which are secondary, being released only after the injury, though in the
non-obese diabetic (NOD) mouse model and man increasing evidence points to insulin as the primary immune
target. (See 'Target autoantigens' above and "Prediction of type 1 diabetes mellitus".)
Environmental factors that may affect risk include pregnancy-related and perinatal influences, viruses, and
ingestion of cows milk and cereals. (See 'Environmental factors' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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nonobese diabetic mice during the phase preceding insulin-dependent diabetes mellitus. J Clin Invest 1990;
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Topic 1800 Version 13.0
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GRAPHICS
Time course of type 1 diabetes mellitus
Time course of the development of type 1 diabetes. Genetic markers are present
from birth, immune markers first appear at the time of the environmental
triggering events, and sensitive metabolic markers of deficient insulin secretion
begin to appear soon after the onset of beta-cell dysfunction. However, clinically
evident type 1 diabetes does not occur until there has been a much greater loss
of functioning beta-cell mass.
Graphic 66417 Version 1.0
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Representation of T cell activation
Schematic representation of initiation of the immunologic response to an

antigen. The antigen binds to a groove in MHC class II molecules on antigenpresenting cells (such as macrophages). This binding allows the antigen to
be presented to antigen receptors on autoreactive CD4 inducer or helper T
cells which, in type 1 diabetes mellitus, initiate autoimmune injury to the
pancreatic beta cells. In addition, the respective binding of B7 proteins and
LFA-3 on antigen-presenting cells to CD28 and CD2 on T cells are important
costimulatory pathways that further increase T cell activation. Other
molecules also can participate in the immune response, such as the binding
of interleukin-2 to its receptor (IL-2R).
MHC: major histocompatibility complex; LFA-3: lymphocyte functional antigen-3;
IL-2R: interleukin-2 receptor.
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Association of type 1 diabetes with diabetogenic

genes
Direct correlation in different populations between the gene frequency of

"diabetogenic" HLA-DQ genotypes (which lack aspartate at position 57
on the beta chain) and the predicted and observed incidence of type 1
diabetes mellitus (per 100,000 population).
Data from: Dorman JS, LaPorte RE, Stone RA, Trucco M, Worldwide
differences in the incidence of type I diabetes are associated with amino acid
variation at position 57 of the HLA-DQ beta chain. Proc Natl Acad Sci USA
1990; 87:7370.
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Confirmed targets of autoantibodies in type 1 diabetes of man

Insulin
Glutamic acid decarboxylase
Insulinoma associated antigens 2 (alpha and beta)
ZnT8 (zinc transporter)
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Recovery of insulin secretion in NOD mice
Insulin release from isolated pancreatic islets from in 12 to 13 week-old

nonobese diabetic (NOD) mice and normal mice on day 0 and day 7 in culture.
Measurements were made at baseline during incubation with low glucose
medium (B) and after incubation in high glucose medium (G). Insulin release
from the islets from NOD mice in response to glucose was low on day 0
(second panel) but above normal by day 7 (fourth panel), suggesting the
importance of in vivo inhibitory factors such as locally released cytokines.
Data from: Strandell E, Eizirik DL, Sandler S. Reversal of beta-cell suppression in
vitro in pancreatic islets isolated from nonobese diabetic mice during the phase
preceding insulin-dependent diabetes mellitus. J Clin Invest 1990; 85:1944.
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Disclosures
Disclosures: Massimo Pietropaolo, MD Nothing to disclose. Irl B Hirsch, MD Grant/Research/Clinical Trial Support: Sanofi [Diabetes
(Glargine, glulisine)]; NovoNordisk [Diabetes (Detemir, aspart, liraglutide)]. Consultant/Advisory Boards: Abbott [Diabetes (Glucose test strips)];
Roche [Diabetes (Glucose test strips)]; Valeritas [Diabetes (Insulin pumps)]. Jean E Mulder, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
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