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DM Tipo 1, Patogenia. Up To Date
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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 nonautoimmune 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 "Overview of the management of type 1 diabetes mellitus in children and
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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 (KIAA0035), 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 approximately 6 percent in offspring, 5 percent in siblings, and 50 percent
in identical twins (versus 0.4 percent in subjects with 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].
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MHC genes — The major susceptibility genes for type 1 diabetes (called IDDM1 for the major
histocompatibility complex [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, approximately 30 percent of patients have both haplotypes (DR3/4
heterozygotes), which confers the greatest susceptibility [17].
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 (ICAs), 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.
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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].
Additional evidence for the role of non-MHC genes comes from studies in NOD mice (nonobese
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 approximately 50 days of age and
clinical diabetes appears at approximately 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].
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].
STAT3 mutations have been identified as a monogenic cause of autoimmunity, including type 1
diabetes [37]. De novo germline activating STAT3 mutations are associated with a spectrum of
early-onset autoimmune disease, such as type 1 diabetes, autoimmune thyroid dysfunction,
and autoimmune enteropathy. These findings emphasize the critical role of STAT3 in
autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in
hyperimmunoglobulin E (IgE) syndrome. (See "Autosomal dominant hyperimmunoglobulin E
syndrome".)
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 [38]. A few patients from Japan without obvious evidence of islet
autoimmunity have been described in whom the onset of hyperglycemia was abrupt, glycated
hemoglobin (A1C) values were normal, and serum pancreatic enzyme concentrations were high
[39]. It is not clear whether these patients had an unusually abrupt onset of autoimmune type
1A diabetes or nonautoimmune 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) [1,40]. Studies on the NOD (nonobese diabetic) mouse
model indicate that proinsulin/insulin itself is the likely primary target for the autoantibodies
[41,42]. The autoimmune response to proinsulin subsequently spreads to other autoantigens,
such as islet-specific glucose-6-phosphatase catalytic-subunit-related protein (IGRP), which is
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downstream of the immune response to insulin [42]. Diabetes in the NOD mouse can be
eliminated by changing a specific amino acid of insulin [41].
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 [51], 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) [48].
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 [52] but
does express insulin autoantibodies [53]. 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 [54].
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Zinc transporter ZnT8 — The cation efflux zinc transporter (ZnT8) has also been identified as
a candidate type 1 diabetes autoantigen [46]. 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
[46], and the antibody is typically lost very early after the onset of diabetes [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 [60]. 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.
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 [61].
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 [62]. Other groups have reported almost
complete protection if autoantibodies are absent [63].
Naturally processed epitopes of islet cell autoantigens represent the targets of effector and
regulatory T cells in controlling pancreatic beta cell-specific autoimmune responses [64]. 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 Epstein-Barr virus (EBV)-transformed B cells and peptides eluted and analyzed by
mass spectrometry [65]. 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 [66]. 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 [67]. 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 it 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.
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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 [68-70].
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
[71-73]. 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 [41,69,74-76]. 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 [76-79]. In addition to insulin, islet cell autoantigen 69 kDa
(ICA69), a neuroendocrine protein targeted by autoimmune responses in human type 1
diabetes and in NOD mice [80-82], is also expressed in the thymus, and the likelihood that
thymic levels of ICA69 will affect susceptibility to type 1 diabetes through a mechanism similar
to that shown for the insulin VNTRs has been suggested [69,83]. 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 [69,77,84,85] 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
[85].
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● 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 [93]. Three of eight patients with anti-21-hydroxylase
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
(Tregs, formerly termed suppressor T cells) have a major physiologic role. The autoimmune
polyendocrine syndrome type 1 (APS-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 [94].
ENVIRONMENTAL FACTORS
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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 [95,96]. The etiology of the increase is unknown.
One hypothesis, termed the hygiene hypothesis, relates improved "sanitation" to increasing
immune-mediated disorders [97]. 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 [14,15,98].
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 [103]. Although
isolated case reports have suggested direct viral destruction of beta cells [104], 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 [105]. However, some unusual forms
of diabetes have been associated with the presence of Coxsackie virus in a large number of
beta cells [106].
● 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.
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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 Coxsackie virus B4,
suggesting a possible role for molecular mimicry [109,110].
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 [113]. Studies suggest a role for
innate immune system activation in this model. In a similar manner, polyinosinic-to-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 [114].
In contrast to the above reports, there are data that refute the role of viruses in the
pathogenesis of type 1 diabetes [115,116]. In one report, Coxsackie B virus infections in
childhood were associated with transient production of antibodies to GAD, but not type 1
diabetes [116]. Thus far, there is also no evidence to support that COVID-19 infection plays a
role in the pathogenesis of type 1 diabetes [117]. (See "COVID-19: Issues related to diabetes
mellitus in adults".)
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 [118,119]. Also supporting a protective role for viruses is the
observation that raising nonobese diabetic (NOD) mice and BB rats in pathogen-free
environments leads to an increased incidence of type 1 diabetes [120].
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diabetes [121]. (See "Autism spectrum disorder and chronic disease: No evidence for vaccines or
thimerosal 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 [122].
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
[123]. 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 [123]. 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
[124], and some prospective studies have found no association between the duration of
breastfeeding or introduction of cow's milk and the development of islet autoimmunity in
children at high risk of type 1 diabetes [115,125].
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 with 36 normal subjects [126]. 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 [127].
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 [128,129] or a
high-risk HLA genotype [128]), first exposure to cereal before age three months [128,129] or
after seven months [128] was associated with an increased risk of developing islet cell
autoantibodies [128,129] and type 1 diabetes (adjusted hazard ratio [HR] 3.33, 95% CI 1.54-7.18
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for age at first exposure to any cereal ≥6 months) compared with infants whose first exposure
was between ages four to six months [130]. The increased risk was associated with gluten-
containing cereals in one study [129], but with either gluten- or rice-containing cereals in the
other [128]. Early introduction of gluten (<3 months of age) increases the risk of celiac disease
[131].
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'.)
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 (United Kingdom) have found that the
incidence of type 1 diabetes correlates with the concentration of nitrates in the drinking water
[135]. The incidence is approximately 30 percent higher in areas with nitrate concentrations
above 14.8 mg/L compared with areas with concentrations below 3.2 mg/L.
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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 [141,142]. Impaired glucose tolerance frequently
precedes the onset of overt diabetes [143]. 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 [144,145] 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 approximately 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 when 30 to 50 percent of the
beta cell mass is still viable [146]. 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 7 ( figure 4) [147].
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● 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
[148].
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 [150]. 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 [151]. 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 (NIH) 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.
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
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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.)
● Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the
Basics)")
SUMMARY
● Overview – 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.)
● Genetic susceptibility – Polymorphisms of multiple genes are known to influence the risk
of type 1A diabetes (human leukocyte antigen [HLA]-DQalpha; HLA-DQbeta; HLA-DR,
preproinsulin, the PTPN22 gene, and CTLA-4), with whole-genome analysis providing
additional genes and loci, such as KIAA0035 (a lectin). Genes in both the major
histocompatibility complex (MHC) and elsewhere in the genome influence risk, but only
HLA alleles have a large effect. (See 'Genetic susceptibility' above.)
● Target autoantigens – 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, insulinoma-associated 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 nonobese diabetic (NOD) mouse model and in human type 1
diabetes, increasing evidence points to insulin as the primary immune target. (See 'Target
autoantigens' above and "Prediction of type 1 diabetes mellitus".)
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● Environmental factors – Environmental factors that may affect risk include pregnancy-
related and perinatal influences, viruses, and ingestion of cow's milk and cereals. (See
'Environmental factors' above.)
REFERENCES
2. McCulloch DK, Palmer JP. The appropriate use of B-cell function testing in the preclinical
period of type 1 diabetes. Diabet Med 1991; 8:800.
3. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2
diabetes mellitus. N Engl J Med 2007; 356:1517.
4. Smyth DJ, Cooper JD, Bailey R, et al. A genome-wide association study of nonsynonymous
SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region.
Nat Genet 2006; 38:617.
5. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases
of seven common diseases and 3,000 shared controls. Nature 2007; 447:661.
6. Todd JA, Walker NM, Cooper JD, et al. Robust associations of four new chromosome regions
from genome-wide analyses of type 1 diabetes. Nat Genet 2007; 39:857.
7. Hakonarson H, Grant SF, Bradfield JP, et al. A genome-wide association study identifies
KIAA0350 as a type 1 diabetes gene. Nature 2007; 448:591.
8. Lowe CE, Cooper JD, Brusko T, et al. Large-scale genetic fine mapping and genotype-
phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat
Genet 2007; 39:1074.
12. Smyth DJ, Plagnol V, Walker NM, et al. Shared and distinct genetic variants in type 1
diabetes and celiac disease. N Engl J Med 2008; 359:2767.
https://www.uptodate.com/contents/1800/print 18/34
6/19/22, 1:20 PM 1800
13. Aly TA, Ide A, Jahromi MM, et al. Extreme genetic risk for type 1A diabetes. Proc Natl Acad
Sci U S A 2006; 103:14074.
14. Redondo MJ, Rewers M, Yu L, et al. Genetic determination of islet cell autoimmunity in
monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes:
prospective twin study. BMJ 1999; 318:698.
15. Kaprio J, Tuomilehto J, Koskenvuo M, et al. Concordance for type 1 (insulin-dependent) and
type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in
Finland. Diabetologia 1992; 35:1060.
16. Davies JL, Kawaguchi Y, Bennett ST, et al. A genome-wide search for human type 1 diabetes
susceptibility genes. Nature 1994; 371:130.
21. Undlien DE, Friede T, Rammensee HG, et al. HLA-encoded genetic predisposition in IDDM:
DR4 subtypes may be associated with different degrees of protection. Diabetes 1997;
46:143.
22. Baschal EE, Aly TA, Babu SR, et al. HLA-DPB1*0402 protects against type 1A diabetes
autoimmunity in the highest risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY population.
Diabetes 2007; 56:2405.
23. Pugliese A, Gianani R, Moromisato R, et al. HLA-DQB1*0602 is associated with dominant
protection from diabetes even among islet cell antibody-positive first-degree relatives of
patients with IDDM. Diabetes 1995; 44:608.
24. Bell GI, Horita S, Karam JH. A polymorphic locus near the human insulin gene is associated
with insulin-dependent diabetes mellitus. Diabetes 1984; 33:176.
25. Barratt BJ, Payne F, Lowe CE, et al. Remapping the insulin gene/IDDM2 locus in type 1
diabetes. Diabetes 2004; 53:1884.
https://www.uptodate.com/contents/1800/print 19/34
6/19/22, 1:20 PM 1800
30. Kyogoku C, Langefeld CD, Ortmann WA, et al. Genetic association of the R620W
polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet
2004; 75:504.
31. Kavvoura FK, Ioannidis JP. CTLA-4 gene polymorphisms and susceptibility to type 1 diabetes
mellitus: a HuGE Review and meta-analysis. Am J Epidemiol 2005; 162:3.
32. Kolb H. Mouse models of insulin dependent diabetes: low-dose streptozocin-induced
diabetes and nonobese diabetic (NOD) mice. Diabetes Metab Rev 1987; 3:751.
33. Rothe H, Jenkins NA, Copeland NG, Kolb H. Active stage of autoimmune diabetes is
associated with the expression of a novel cytokine, IGIF, which is located near Idd2. J Clin
Invest 1997; 99:469.
34. Almawi WY, Tamim H, Azar ST. Clinical review 103: T helper type 1 and 2 cytokines mediate
the onset and progression of type I (insulin-dependent) diabetes. J Clin Endocrinol Metab
1999; 84:1497.
35. Bluestone JA, Tang Q. Therapeutic vaccination using CD4+CD25+ antigen-specific
regulatory T cells. Proc Natl Acad Sci U S A 2004; 101 Suppl 2:14622.
36. Wildin RS, Freitas A. IPEX and FOXP3: clinical and research perspectives. J Autoimmun 2005;
25 Suppl:56.
37. Flanagan SE, Haapaniemi E, Russell MA, et al. Activating germline mutations in STAT3 cause
early-onset multi-organ autoimmune disease. Nat Genet 2014; 46:812.
https://www.uptodate.com/contents/1800/print 20/34
6/19/22, 1:20 PM 1800
40. Boitard C. The differentiation of the immune system towards anti-islet autoimmunity.
Clinical prospects. Diabetologia 1992; 35:1101.
41. Nakayama M, Abiru N, Moriyama H, et al. Prime role for an insulin epitope in the
development of type 1 diabetes in NOD mice. Nature 2005; 435:220.
42. Krishnamurthy B, Dudek NL, McKenzie MD, et al. Responses against islet antigens in NOD
mice are prevented by tolerance to proinsulin but not IGRP. J Clin Invest 2006; 116:3258.
43. Baekkeskov S, Aanstoot HJ, Christgau S, et al. Identification of the 64K autoantigen in
insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase.
Nature 1990; 347:151.
44. Pietropaolo M, Hutton JC, Eisenbarth GS. Protein tyrosine phosphatase-like proteins: link
with IDDM. Diabetes Care 1997; 20:208.
45. Hawa M, Rowe R, Lan MS, et al. Value of antibodies to islet protein tyrosine phosphatase-
like molecule in predicting type 1 diabetes. Diabetes 1997; 46:1270.
46. Wenzlau JM, Juhl K, Yu L, et al. The cation efflux transporter ZnT8 (Slc30A8) is a major
autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 2007; 104:17040.
47. Ziegler AG, Hillebrand B, Rabl W, et al. On the appearance of islet associated autoimmunity
in offspring of diabetic mothers: a prospective study from birth. Diabetologia 1993; 36:402.
48. Achenbach P, Koczwara K, Knopff A, et al. Mature high-affinity immune responses to
(pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes. J Clin Invest
2004; 114:589.
49. Wong FS, Karttunen J, Dumont C, et al. Identification of an MHC class I-restricted
autoantigen in type 1 diabetes by screening an organ-specific cDNA library. Nat Med 1999;
5:1026.
50. Alleva DG, Crowe PD, Jin L, et al. A disease-associated cellular immune response in type 1
diabetics to an immunodominant epitope of insulin. J Clin Invest 2001; 107:173.
51. Moriyama H, Abiru N, Paronen J, et al. Evidence for a primary islet autoantigen
(preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse. Proc Natl Acad
Sci U S A 2003; 100:10376.
52. Bonifacio E, Atkinson M, Eisenbarth G, et al. International Workshop on Lessons From
Animal Models for Human Type 1 Diabetes: identification of insulin but not glutamic acid
decarboxylase or IA-2 as specific autoantigens of humoral autoimmunity in nonobese
diabetic mice. Diabetes 2001; 50:2451.
https://www.uptodate.com/contents/1800/print 21/34
6/19/22, 1:20 PM 1800
55. Mziaut H, Trajkovski M, Kersting S, et al. Synergy of glucose and growth hormone signalling
in islet cells through ICA512 and STAT5. Nat Cell Biol 2006; 8:435.
56. Ellis TM, Schatz DA, Ottendorfer EW, et al. The relationship between humoral and cellular
immunity to IA-2 in IDDM. Diabetes 1998; 47:566.
57. Verge CF, Gianani R, Kawasaki E, et al. Prediction of type I diabetes in first-degree relatives
using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 1996;
45:926.
58. Wenzlau JM, Walter M, Gardner TJ, et al. Kinetics of the post-onset decline in zinc
transporter 8 autoantibodies in type 1 diabetic human subjects. J Clin Endocrinol Metab
2010; 95:4712.
59. Winer S, Tsui H, Lau A, et al. Autoimmune islet destruction in spontaneous type 1 diabetes
is not beta-cell exclusive. Nat Med 2003; 9:198.
62. Yang M, Charlton B, Gautam AM. Development of insulitis and diabetes in B cell-deficient
NOD mice. J Autoimmun 1997; 10:257.
63. Greeley SA, Katsumata M, Yu L, et al. Elimination of maternally transmitted autoantibodies
prevents diabetes in nonobese diabetic mice. Nat Med 2002; 8:399.
64. Di Lorenzo TP, Peakman M, Roep BO. Translational mini-review series on type 1 diabetes:
Systematic analysis of T cell epitopes in autoimmune diabetes. Clin Exp Immunol 2007;
148:1.
65. Peakman M, Stevens EJ, Lohmann T, et al. Naturally processed and presented epitopes of
the islet cell autoantigen IA-2 eluted from HLA-DR4. J Clin Invest 1999; 104:1449.
66. Allen JS, Pang K, Skowera A, et al. Plasmacytoid dendritic cells are proportionally expanded
at diagnosis of type 1 diabetes and enhance islet autoantigen presentation to T-cells
through immune complex capture. Diabetes 2009; 58:138.
67. Ko IY, Jun HS, Kim GS, Yoon JW. Studies on autoimmunity for initiation of beta-cell
destruction. X. Delayed expression of a membrane-bound islet cell-specific 38 kDa
https://www.uptodate.com/contents/1800/print 22/34
6/19/22, 1:20 PM 1800
autoantigen that precedes insulitis and diabetes in the diabetes-prone BB rat. Diabetologia
1994; 37:460.
68. Jolicoeur C, Hanahan D, Smith KM. T-cell tolerance toward a transgenic beta-cell antigen
and transcription of endogenous pancreatic genes in thymus. Proc Natl Acad Sci U S A
1994; 91:6707.
69. Pugliese A, Zeller M, Fernandez A Jr, et al. The insulin gene is transcribed in the human
thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2
susceptibility locus for type 1 diabetes. Nat Genet 1997; 15:293.
70. Gardner JM, Devoss JJ, Friedman RS, et al. Deletional tolerance mediated by extrathymic
Aire-expressing cells. Science 2008; 321:843.
71. Nitta T, Murata S, Ueno T, et al. Thymic microenvironments for T-cell repertoire formation.
Adv Immunol 2008; 99:59.
72. Hanahan D. Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance
and autoimmunity. Curr Opin Immunol 1998; 10:656.
73. DeVoss JJ, Anderson MS. Lessons on immune tolerance from the monogenic disease APS1.
Curr Opin Genet Dev 2007; 17:193.
74. Palumbo MO, Levi D, Chentoufi AA, Polychronakos C. Isolation and characterization of
proinsulin-producing medullary thymic epithelial cell clones. Diabetes 2006; 55:2595.
75. Fan Y, Rudert WA, Grupillo M, et al. Thymus-specific deletion of insulin induces
autoimmune diabetes. EMBO J 2009; 28:2812.
76. Sabater L, Ferrer-Francesch X, Sospedra M, et al. Insulin alleles and autoimmune regulator
(AIRE) gene expression both influence insulin expression in the thymus. J Autoimmun 2005;
25:312.
77. Vafiadis P, Bennett ST, Todd JA, et al. Insulin expression in human thymus is modulated by
INS VNTR alleles at the IDDM2 locus. Nat Genet 1997; 15:289.
78. Vafiadis P, Bennett ST, Todd JA, et al. Divergence between genetic determinants of IGF2
transcription levels in leukocytes and of IDDM2-encoded susceptibility to type 1 diabetes. J
Clin Endocrinol Metab 1998; 83:2933.
79. Vafiadis P, Ounissi-Benkalha H, Palumbo M, et al. Class III alleles of the variable number of
tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose
to type 1 diabetes. J Clin Endocrinol Metab 2001; 86:3705.
80. Pietropaolo M, Castaño L, Babu S, et al. Islet cell autoantigen 69 kD (ICA69). Molecular
cloning and characterization of a novel diabetes-associated autoantigen. J Clin Invest 1993;
92:359.
https://www.uptodate.com/contents/1800/print 23/34
6/19/22, 1:20 PM 1800
81. Karges W, Pietropaolo M, Ackerley CA, Dosch HM. Gene expression of islet cell antigen p69
in human, mouse, and rat. Diabetes 1996; 45:513.
82. Song A, Winer S, Tsui H, et al. Deviation of islet autoreactivity to cryptic epitopes protects
NOD mice from diabetes. Eur J Immunol 2003; 33:546.
83. Mathews CE, Pietropaolo SL, Pietropaolo M. Reduced thymic expression of islet antigen
contributes to loss of self-tolerance. Ann N Y Acad Sci 2003; 1005:412.
84. Dogra RS, Vaidyanathan P, Prabakar KR, et al. Alternative splicing of G6PC2, the gene
coding for the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP),
results in differential expression in human thymus and spleen compared with pancreas.
Diabetologia 2006; 49:953.
85. Bonner SM, Pietropaolo SL, Fan Y, et al. Sequence variation in promoter of Ica1 gene, which
encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune
regulator (AIRE) to increase its binding and down-regulate expression. J Biol Chem 2012;
287:17882.
86. Chong AS, Shen J, Tao J, et al. Reversal of diabetes in non-obese diabetic mice without
spleen cell-derived beta cell regeneration. Science 2006; 311:1774.
87. Nishio J, Gaglia JL, Turvey SE, et al. Islet recovery and reversal of murine type 1 diabetes in
the absence of any infused spleen cell contribution. Science 2006; 311:1775.
88. Suri A, Calderon B, Esparza TJ, et al. Immunological reversal of autoimmune diabetes
without hematopoietic replacement of beta cells. Science 2006; 311:1778.
89. Melton DA. Reversal of type 1 diabetes in mice. N Engl J Med 2006; 355:89.
90. Decochez K, Truyen I, van der Auwera B, et al. Combined positivity for HLA DQ2/DQ8 and
IA-2 antibodies defines population at high risk of developing type 1 diabetes. Diabetologia
2005; 48:687.
91. Hoffenberg EJ, Emery LM, Barriga KJ, et al. Clinical features of children with screening-
identified evidence of celiac disease. Pediatrics 2004; 113:1254.
92. Jaeger C, Hatziagelaki E, Petzoldt R, Bretzel RG. Comparative analysis of organ-specific
autoantibodies and celiac disease--associated antibodies in type 1 diabetic patients, their
first-degree relatives, and healthy control subjects. Diabetes Care 2001; 24:27.
93. Brewer, KW, Parziale, et al. Screening patients with insulin-dependent diabetes mellitus for
adrenal insufficiency (letter). New Engl J Med 1997; 337:202.
94. Barker JM, Eisenbarth GS. Autoimmune Polyendocrine Syndromes. In: Immunology of Type
1 Diabetes, Eisenbarth GS (Ed), 2003.
https://www.uptodate.com/contents/1800/print 24/34
6/19/22, 1:20 PM 1800
95. Vehik K, Hamman RF, Lezotte D, et al. Increasing incidence of type 1 diabetes in 0- to 17-
year-old Colorado youth. Diabetes Care 2007; 30:503.
96. Gale EA. The rise of childhood type 1 diabetes in the 20th century. Diabetes 2002; 51:3353.
97. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N
Engl J Med 2002; 347:911.
98. Redondo MJ, Yu L, Hawa M, et al. Late progression to type 1 diabetes of discordant twins of
patients with type 1 diabetes: Combined analysis of two twin series (United States and
United Kingdom). Diabetes 1999; 48:780.
99. Dahlquist GG, Patterson C, Soltesz G. Perinatal risk factors for childhood type 1 diabetes in
Europe. The EURODIAB Substudy 2 Study Group. Diabetes Care 1999; 22:1698.
100. Stene LC, Magnus P, Lie RT, et al. Birth weight and childhood onset type 1 diabetes:
population based cohort study. BMJ 2001; 322:889.
101. Dahlquist GG, Pundziūte-Lyckå A, Nyström L, et al. Birthweight and risk of type 1 diabetes
in children and young adults: a population-based register study. Diabetologia 2005;
48:1114.
102. Stene LC, Joner G, Norwegian Childhood Diabetes Study Group. Use of cod liver oil during
the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large,
population-based, case-control study. Am J Clin Nutr 2003; 78:1128.
103. Szopa TM, Titchener PA, Portwood ND, Taylor KW. Diabetes mellitus due to viruses--some
recent developments. Diabetologia 1993; 36:687.
104. Yoon JW, Austin M, Onodera T, Notkins AL. Isolation of a virus from the pancreas of a child
with diabetic ketoacidosis. N Engl J Med 1979; 300:1173.
105. Foulis AK, McGill M, Farquharson MA, Hilton DA. A search for evidence of viral infection in
pancreases of newly diagnosed patients with IDDM. Diabetologia 1997; 40:53.
106. Dotta F, Censini S, van Halteren AG, et al. Coxsackie B4 virus infection of beta cells and
natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A
2007; 104:5115.
107. King ML, Shaikh A, Bidwell D, et al. Coxsackie-B-virus-specific IgM responses in children
with insulin-dependent (juvenile-onset; type I) diabetes mellitus. Lancet 1983; 1:1397.
108. Hyöty H, Hiltunen M, Knip M, et al. A prospective study of the role of coxsackie B and other
enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe)
Study Group. Diabetes 1995; 44:652.
109. Kaufman DL, Erlander MG, Clare-Salzler M, et al. Autoimmunity to two forms of glutamate
decarboxylase in insulin-dependent diabetes mellitus. J Clin Invest 1992; 89:283.
https://www.uptodate.com/contents/1800/print 25/34
6/19/22, 1:20 PM 1800
110. Atkinson MA, Bowman MA, Campbell L, et al. Cellular immunity to a determinant common
to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. J Clin Invest
1994; 94:2125.
111. Menser MA, Forrest JM, Bransby RD. Rubella infection and diabetes mellitus. Lancet 1978;
1:57.
112. Hyöty H, Taylor KW. The role of viruses in human diabetes. Diabetologia 2002; 45:1353.
113. Zipris D, Lien E, Xie JX, et al. TLR activation synergizes with Kilham rat virus infection to
induce diabetes in BBDR rats. J Immunol 2005; 174:131.
114. Devendra D, Jasinski J, Melanitou E, et al. Interferon-alpha as a mediator of
polyinosinic:polycytidylic acid-induced type 1 diabetes. Diabetes 2005; 54:2549.
115. Hummel M, Füchtenbusch M, Schenker M, Ziegler AG. No major association of breast-
feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the
German BABYDIAB Study. Diabetes Care 2000; 23:969.
116. Cainelli F, Manzaroli D, Renzini C, et al. Coxsackie B virus-induced autoimmunity to GAD
does not lead to type 1 diabetes. Diabetes Care 2000; 23:1021.
https://www.uptodate.com/contents/1800/print 26/34
6/19/22, 1:20 PM 1800
125. Couper JJ, Steele C, Beresford S, et al. Lack of association between duration of breast-
feeding or introduction of cow's milk and development of islet autoimmunity. Diabetes
1999; 48:2145.
126. Cavallo MG, Fava D, Monetini L, et al. Cell-mediated immune response to beta casein in
recent-onset insulin-dependent diabetes: implications for disease pathogenesis. Lancet
1996; 348:926.
127. Elliott RB, Harris DP, Hill JP, et al. Type I (insulin-dependent) diabetes mellitus and cow milk:
casein variant consumption. Diabetologia 1999; 42:292.
128. Norris JM, Barriga K, Klingensmith G, et al. Timing of initial cereal exposure in infancy and
risk of islet autoimmunity. JAMA 2003; 290:1713.
129. Ziegler AG, Schmid S, Huber D, et al. Early infant feeding and risk of developing type 1
diabetes-associated autoantibodies. JAMA 2003; 290:1721.
130. Frederiksen B, Kroehl M, Lamb MM, et al. Infant exposures and development of type 1
diabetes mellitus: The Diabetes Autoimmunity Study in the Young (DAISY). JAMA Pediatr
2013; 167:808.
131. Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac disease autoimmunity and timing of
gluten introduction in the diet of infants at increased risk of disease. JAMA 2005; 293:2343.
132. Krishna Mohan I, Das UN. Prevention of chemically induced diabetes mellitus in
experimental animals by polyunsaturated fatty acids. Nutrition 2001; 17:126.
133. Kleemann R, Scott FW, Wörz-Pagenstert U, et al. Impact of dietary fat on Th1/Th2 cytokine
gene expression in the pancreas and gut of diabetes-prone BB rats. J Autoimmun 1998;
11:97.
134. Norris JM, Yin X, Lamb MM, et al. Omega-3 polyunsaturated fatty acid intake and islet
autoimmunity in children at increased risk for type 1 diabetes. JAMA 2007; 298:1420.
135. Parslow RC, McKinney PA, Law GR, et al. Incidence of childhood diabetes mellitus in
Yorkshire, northern England, is associated with nitrate in drinking water: an ecological
analysis. Diabetologia 1997; 40:550.
136. Dougan M, Pietropaolo M. Time to dissect the autoimmune etiology of cancer antibody
immunotherapy. J Clin Invest 2020; 130:51.
137. Akturk HK, Michels AW. Immune Checkpoint Inhibitor-Induced Type 1 Diabetes: An
Underestimated Risk. Mayo Clin Proc 2020; 95:614.
138. Wang DY, Salem JE, Cohen JV, et al. Fatal Toxic Effects Associated With Immune Checkpoint
Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol 2018; 4:1721.
https://www.uptodate.com/contents/1800/print 27/34
6/19/22, 1:20 PM 1800
139. Wright JJ, Salem JE, Johnson DB, et al. Increased Reporting of Immune Checkpoint Inhibitor-
Associated Diabetes. Diabetes Care 2018; 41:e150.
140. Stamatouli AM, Quandt Z, Perdigoto AL, et al. Collateral Damage: Insulin-Dependent
Diabetes Induced With Checkpoint Inhibitors. Diabetes 2018; 67:1471.
141. McCulloch DK, Palmer JP, Benson EA. Beta cell function in the preclinical period of insulin-
dependent diabetes. Diabetes Metab Rev 1987; 3:27.
142. Thai AC, Eisenbarth GS. Natural history of IDDM. Diabetes Reviews 1993; 1:1.
143. Sosenko JM, Palmer JP, Greenbaum CJ, et al. Increasing the accuracy of oral glucose
tolerance testing and extending its application to individuals with normal glucose tolerance
for the prediction of type 1 diabetes: the Diabetes Prevention Trial-Type 1. Diabetes Care
2007; 30:38.
144. Bingley PJ, Colman P, Eisenbarth GS, et al. Standardization of IVGTT to predict IDDM.
Diabetes Care 1992; 15:1313.
145. McCulloch DK, Bingley PJ, Colman PG, et al. Comparison of bolus and infusion protocols for
determining acute insulin response to intravenous glucose in normal humans. The ICARUS
Group. Islet Cell Antibody Register User's Study. Diabetes Care 1993; 16:911.
146. McCulloch DK, Koerker DJ, Kahn SE, et al. Correlations of in vivo beta-cell function tests with
beta-cell mass and pancreatic insulin content in streptozocin-administered baboons.
Diabetes 1991; 40:673.
147. 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.
148. Conget I, Fernández-Alvarez J, Ferrer J, et al. Human pancreatic islet function at the onset of
type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1993; 36:358.
149. Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. J Clin
Invest 2007; 117:2553.
150. George M, Ayuso E, Casellas A, et al. Beta cell expression of IGF-I leads to recovery from
type 1 diabetes. J Clin Invest 2002; 109:1153.
151. Kulkarni RN, Holzenberger M, Shih DQ, et al. beta-cell-specific deletion of the Igf1 receptor
leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat
Genet 2002; 31:111.
Topic 1800 Version 21.0
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GRAPHICS
Genetic predisposing factors are present from birth, environmental factors can trigger the disease process,
immune biomarkers occur years to decades prior to overt disease, and metabolic abnormalities of deficient
insulin secretion begin to appear soon after the onset of beta-cell dysfunction. Individuals with multiple isle
autoantibodies and normal glucose tolerance during formal oral glucose tolerance testing (OGTT) are
considered to be at stage 1, and those with abnormal glucose tolerance are at stage 2 type 1 diabetes.
From: American Diabetes Association. Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: A scientific
statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 2015; 38:1964. American Diabetes
Association, 2015. Copyright and all rights reserved. Material from this publication has been used with the permission of American
Diabetes Association.
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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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Insulin
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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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Contributor Disclosures
Massimo Pietropaolo, MD No relevant financial relationship(s) with ineligible companies to disclose. Irl
B Hirsch, MD Grant/Research/Clinical Trial Support: Beta Bionics [Diabetes]; Insulet Corporation
[Diabetes].
Consultant/Advisory Boards: Abbott [Diabetes]; GWave [Diabetes]; Lifescan [Diabetes]; Roche
[Diabetes].
All of the relevant financial relationships listed have been mitigated. Jean E Mulder, MD No
relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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