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خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 1 مورد

Pathogenesis of type 1 diabetes mellitus

Pathogenesis of type 1 diabetes mellitus
Author:
Irl B Hirsch, MD
Section Editor:
David M Nathan, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Apr 2025. | This topic last updated: Jun 08, 2022.

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 "Type 1 diabetes mellitus: Prevention and disease-modifying therapy" and "Overview of the 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 (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].

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).

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].

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 (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.

The prevalence of these genes varies in different populations (figure 3).

Non-MHC genes — Although important, the major histocompatibility complex (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 (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].

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 termed regulatory T cells (Tregs) express the markers CD4 and CD25 on their surface and lack the IL7 receptor. Tregs generally suppress or downregulate induction and proliferation of effector T cells 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'.)

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 "Type 1 diabetes mellitus: Disease prediction and screening".)

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 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].

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 [43-46]. (See "Type 1 diabetes mellitus: Disease prediction and screening".)

Insulin — The early appearance of anti-insulin antibodies suggests that insulin is an important autoantigen [47,48]. 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 [49], and a major target autoantigen for CD4 T cells of NOD mice is insulin peptide B chain amino acids 9 to 23 [41]. 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 [50].

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 "Type 1 diabetes mellitus: Prevention and disease-modifying therapy".)

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].

Glutamic acid decarboxylase — Another important autoantigen against which antibodies are detected is the enzyme GAD, which is present in the islets as well as in the central nervous system and testes [43]. Antibodies to GAD (a 65-kD protein) are found in approximately 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 [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].

Insulinoma-associated protein 2 — Another autoantigen is a neuroendocrine protein called insulinoma-associated protein 2 (IA-2), which is a protein tyrosine phosphatase (PTP)-related protein [44,45]. 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 [55]. 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 [56]. Autoantibodies to IA-2 usually appear later than autoantibodies to insulin and GAD, and they 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 [57].

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].

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 [57]. 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, CD38, and peripherin; and glial fibrillary acidic protein (GFAP) [59].

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.

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 [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.

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].

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 [86-88]. 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 [89,90]. (See "Type 1 diabetes mellitus: Prevention and disease-modifying therapy".)

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 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 surveillance'.)

●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 [91,92]. 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 surveillance' and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Genetic factors'.)

●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 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 — 

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].

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 [99]. 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 [100]; in a second study, the association was limited to cases with disease onset prior to age 10 [101]. Postnatal dietary factors such as vitamin D and omega-3 fatty acid ingestion may also be important [102]. (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 [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].

The importance of autoimmune activation is also uncertain. Coxsackie B virus-specific immunoglobulin M (IgM) responses have been found in 39 percent of children with newly diagnosed type 1 diabetes, compared with only 6 percent of normal children [107]. Two additional findings were noted in another report [108]:

●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 Coxsackie virus B4, suggesting a possible role for molecular mimicry [109,110].

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 human leukocyte antigen (HLA)-DR3 [111,112]. 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 [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 [117,118]. (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 [119,120]. 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 [121].

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 [122]. (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 [123].

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 [124]. 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 [124]. 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 [125], 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 [115,126].

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 [127]. 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 [128].

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 "Type 1 diabetes mellitus: Prevention and disease-modifying therapy".)

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 "Type 1 diabetes mellitus: Prevention and disease-modifying therapy".)

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 [129,130] or a high-risk HLA genotype [129]), first exposure to cereal before age three months [129,130] or after seven months [129] was associated with an increased risk of developing islet cell autoantibodies [129,130] 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 [131]. The increased risk was associated with gluten-containing cereals in one study [130], but with either gluten- or rice-containing cereals in the other [129]. Early introduction of gluten (<3 months of age) increases the risk of celiac disease [132].

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 [133,134]. 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 [102]. 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) [135]. A clinical trial of omega-3 fatty acid supplementation in infants with high genetic risk of type 1 diabetes is underway. (See "Type 1 diabetes mellitus: Prevention and disease-modifying therapy".)

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 [136]. 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.

Treatment with checkpoint inhibitor immunotherapy — Immune checkpoint inhibitors (ICIs) are monoclonal antibodies (mAbs) that block the immune regulatory "checkpoint" receptors, the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), or its ligand PD-L1. ICIs produce durable responses in many patients. Despite important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects termed immune-related adverse events (irAEs). (See "Overview of toxicities associated with immune checkpoint inhibitors".)

Autoimmune endocrine diseases and rheumatic diseases occur in approximately 50 percent of patients treated with antibodies to CTLA-4 and/or PD-1/PD-L1 [137-139]. These irAEs can be serious or even life-threatening, such as autoimmune type 1 diabetes presenting in diabetic ketoacidosis (DKA), primary adrenal insufficiency caused by autoimmune adrenalitis, or myocarditis [140]. In one report, one-half of the patients with ICI-related diabetes presented in DKA (50.2 percent) [140].

There seems to be a predominance of HLA-DR4 genotypes in ICI-induced type 1 diabetes, which is present in 76 percent of patients, whereas other HLA alleles associated with high risk of spontaneous type 1 diabetes (eg, HLA-DR3, -DQ2, and -DQ8) are not overrepresented. Approximately 40 percent of the patients have exhibited islet autoantibodies, a prevalence lower than that of islet autoantibodies found in spontaneous type 1 diabetes [141]. The pathologic mechanisms underlying the autoimmune adverse events (ie, type 1 diabetes) caused by immune checkpoint blockade and classical autoimmune diseases are presently unknown.

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 [142,143]. Impaired glucose tolerance frequently precedes the onset of overt diabetes [144]. 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 [145,146] is used, along with immunologic measurements, to identify subjects at high risk for type 1 diabetes. (See "Type 1 diabetes mellitus: Disease prediction and screening".)

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 [147]. 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) [148].

●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 [149].

●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 [150]. 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 [151]. 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 [152]. 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.

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 education: Type 1 diabetes (The Basics)")

●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 "Type 1 diabetes mellitus: Disease prediction and screening".)

●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.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Massimo Pietropaolo, MD (deceased), who contributed to earlier versions of this topic review.

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  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.
  117. Pietropaolo M, Hotez P, Giannoukakis N. Incidence of an Insulin-Requiring Hyperglycemic Syndrome in SARS-CoV-2-Infected Young Individuals: Is It Type 1 Diabetes? Diabetes 2022; 71:2656.
  118. Rewers M, Bonifacio E, Ewald D, et al. SARS-CoV-2 Infections and Presymptomatic Type 1 Diabetes Autoimmunity in Children and Adolescents From Colorado, USA, and Bavaria, Germany. JAMA 2022; 328:1252.
  119. Dyrberg T, Schwimmbeck PL, Oldstone MB. Inhibition of diabetes in BB rats by virus infection. J Clin Invest 1988; 81:928.
  120. Oldstone MB. Prevention of type I diabetes in nonobese diabetic mice by virus infection. Science 1988; 239:500.
  121. Like AA, Guberski DL, Butler L. Influence of environmental viral agents on frequency and tempo of diabetes mellitus in BB/Wor rats. Diabetes 1991; 40:259.
  122. Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Childhood vaccination and type 1 diabetes. N Engl J Med 2004; 350:1398.
  123. Yoon JW. The role of viruses and environmental factors in the induction of diabetes. Curr Top Microbiol Immunol 1990; 164:95.
  124. Virtanen SM, Saukkonen T, Savilahti E, et al. Diet, cow's milk protein antibodies and the risk of IDDM in Finnish children. Childhood Diabetes in Finland Study Group. Diabetologia 1994; 37:381.
  125. Norris JM, Beaty B, Klingensmith G, et al. Lack of association between early exposure to cow's milk protein and beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young (DAISY). JAMA 1996; 276:609.
  126. 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.
  127. 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.
  128. Elliott RB, Harris DP, Hill JP, et al. Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption. Diabetologia 1999; 42:292.
  129. Norris JM, Barriga K, Klingensmith G, et al. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA 2003; 290:1713.
  130. Ziegler AG, Schmid S, Huber D, et al. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA 2003; 290:1721.
  131. 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.
  132. 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.
  133. Krishna Mohan I, Das UN. Prevention of chemically induced diabetes mellitus in experimental animals by polyunsaturated fatty acids. Nutrition 2001; 17:126.
  134. 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.
  135. 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.
  136. 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.
  137. Dougan M, Pietropaolo M. Time to dissect the autoimmune etiology of cancer antibody immunotherapy. J Clin Invest 2020; 130:51.
  138. Akturk HK, Michels AW. Immune Checkpoint Inhibitor-Induced Type 1 Diabetes: An Underestimated Risk. Mayo Clin Proc 2020; 95:614.
  139. 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.
  140. Wright JJ, Salem JE, Johnson DB, et al. Increased Reporting of Immune Checkpoint Inhibitor-Associated Diabetes. Diabetes Care 2018; 41:e150.
  141. Stamatouli AM, Quandt Z, Perdigoto AL, et al. Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors. Diabetes 2018; 67:1471.
  142. McCulloch DK, Palmer JP, Benson EA. Beta cell function in the preclinical period of insulin-dependent diabetes. Diabetes Metab Rev 1987; 3:27.
  143. Thai AC, Eisenbarth GS. Natural history of IDDM. Diabetes Reviews 1993; 1:1.
  144. 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.
  145. Bingley PJ, Colman P, Eisenbarth GS, et al. Standardization of IVGTT to predict IDDM. Diabetes Care 1992; 15:1313.
  146. 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.
  147. 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.
  148. 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.
  149. 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.
  150. Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 2007; 117:2553.
  151. 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.
  152. 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 24.0

References

1 : The pathogenesis of insulin-dependent diabetes mellitus.

2 : The appropriate use of B-cell function testing in the preclinical period of type 1 diabetes.

3 : Interleukin-1-receptor antagonist in type 2 diabetes mellitus.

4 : A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region.

5 : Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.

6 : Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.

7 : A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.

8 : Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes.

9 : A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3.

10 : Genetics of type 1A diabetes.

11 : Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci.

12 : Shared and distinct genetic variants in type 1 diabetes and celiac disease.

13 : Extreme genetic risk for type 1A diabetes.

14 : Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study.

15 : Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland.

16 : A genome-wide search for human type 1 diabetes susceptibility genes.

17 : Insulin-dependent diabetes mellitus.

18 : A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus.

19 : High genetic risk for IDDM in the Pacific Northwest. First report from the Washington State Diabetes Prediction Study.

20 : Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY).

21 : HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection.

22 : HLA-DPB1*0402 protects against type 1A diabetes autoimmunity in the highest risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY population.

23 : HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM.

24 : A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus.

25 : Remapping the insulin gene/IDDM2 locus in type 1 diabetes.

26 : A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.

27 : Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus.

28 : Genetics of type 1 diabetes.

29 : A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.

30 : Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.

31 : CTLA-4 gene polymorphisms and susceptibility to type 1 diabetes mellitus: a HuGE Review and meta-analysis.

32 : Mouse models of insulin dependent diabetes: low-dose streptozocin-induced diabetes and nonobese diabetic (NOD) mice.

33 : Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2.

34 : Clinical review 103: T helper type 1 and 2 cytokines mediate the onset and progression of type I (insulin-dependent) diabetes.

35 : Therapeutic vaccination using CD4+CD25+ antigen-specific regulatory T cells.

36 : IPEX and FOXP3: clinical and research perspectives.

37 : Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.

38 : Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes. The Childhood Diabetes In Finland Study Group.

39 : A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group.

40 : The differentiation of the immune system towards anti-islet autoimmunity. Clinical prospects.

41 : Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.

42 : Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP.

43 : Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase.

44 : Protein tyrosine phosphatase-like proteins: link with IDDM.

45 : Value of antibodies to islet protein tyrosine phosphatase-like molecule in predicting type 1 diabetes.

46 : The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.

47 : On the appearance of islet associated autoimmunity in offspring of diabetic mothers: a prospective study from birth.

48 : Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes.

49 : Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library.

50 : A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin.

51 : Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse.

52 : 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.

53 : International Workshop on Lessons from Animal Models for Human Type 1 Diabetes: analyzing target autoantigens of humoral immunity in nonobese diabetic mice.

54 : Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase.

55 : Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5.

56 : The relationship between humoral and cellular immunity to IA-2 in IDDM.

57 : Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies.

58 : Kinetics of the post-onset decline in zinc transporter 8 autoantibodies in type 1 diabetic human subjects.

59 : Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive.

60 : Humoral autoimmunity in type 1 diabetes: prediction, significance, and detection of distinct disease subtypes.

61 : Development of type 1 diabetes despite severe hereditary B-cell deficiency.

62 : Development of insulitis and diabetes in B cell-deficient NOD mice.

63 : Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice.

64 : Translational mini-review series on type 1 diabetes: Systematic analysis of T cell epitopes in autoimmune diabetes.

65 : Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4.

66 : Plasmacytoid dendritic cells are proportionally expanded at diagnosis of type 1 diabetes and enhance islet autoantigen presentation to T-cells through immune complex capture.

67 : Studies on autoimmunity for initiation of beta-cell destruction. X. Delayed expression of a membrane-bound islet cell-specific 38 kDa autoantigen that precedes insulitis and diabetes in the diabetes-prone BB rat.

68 : T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in thymus.

69 : 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.

70 : Deletional tolerance mediated by extrathymic Aire-expressing cells.

71 : Thymic microenvironments for T-cell repertoire formation.

72 : Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity.

73 : Lessons on immune tolerance from the monogenic disease APS1.

74 : Isolation and characterization of proinsulin-producing medullary thymic epithelial cell clones.

75 : Thymus-specific deletion of insulin induces autoimmune diabetes.

76 : Insulin alleles and autoimmune regulator (AIRE) gene expression both influence insulin expression in the thymus.

77 : Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus.

78 : Divergence between genetic determinants of IGF2 transcription levels in leukocytes and of IDDM2-encoded susceptibility to type 1 diabetes.

79 : Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes.

80 : Islet cell autoantigen 69 kD (ICA69). Molecular cloning and characterization of a novel diabetes-associated autoantigen.

81 : Gene expression of islet cell antigen p69 in human, mouse, and rat.

82 : Deviation of islet autoreactivity to cryptic epitopes protects NOD mice from diabetes.

83 : Reduced thymic expression of islet antigen contributes to loss of self-tolerance.

84 : 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.

85 : 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.

86 : Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration.

87 : Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution.

88 : Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells.

89 : Reversal of type 1 diabetes in mice.

90 : Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes.

91 : Clinical features of children with screening-identified evidence of celiac disease.

92 : Comparative analysis of organ-specific autoantibodies and celiac disease--associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects.

93 : Screening patients with insulin-dependent diabetes mellitus for adrenal insufficiency.

94 : Screening patients with insulin-dependent diabetes mellitus for adrenal insufficiency.

95 : Increasing incidence of type 1 diabetes in 0- to 17-year-old Colorado youth.

96 : The rise of childhood type 1 diabetes in the 20th century.

97 : The effect of infections on susceptibility to autoimmune and allergic diseases.

98 : 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)

99 : Perinatal risk factors for childhood type 1 diabetes in Europe. The EURODIAB Substudy 2 Study Group.

100 : Birth weight and childhood onset type 1 diabetes: population based cohort study.

101 : Birthweight and risk of type 1 diabetes in children and young adults: a population-based register study.

102 : 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.

103 : Diabetes mellitus due to viruses--some recent developments.

104 : Isolation of a virus from the pancreas of a child with diabetic ketoacidosis.

105 : A search for evidence of viral infection in pancreases of newly diagnosed patients with IDDM.

106 : Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients.

107 : Coxsackie-B-virus-specific IgM responses in children with insulin-dependent (juvenile-onset; type I) diabetes mellitus.

108 : 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.

109 : Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus.

110 : Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes.

111 : Rubella infection and diabetes mellitus.

112 : The role of viruses in human diabetes.

113 : TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats.

114 : Interferon-alpha as a mediator of polyinosinic:polycytidylic acid-induced type 1 diabetes.

115 : No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study.

116 : Coxsackie B virus-induced autoimmunity to GAD does not lead to type 1 diabetes.

117 : Incidence of an Insulin-Requiring Hyperglycemic Syndrome in SARS-CoV-2-Infected Young Individuals: Is It Type 1 Diabetes?

118 : SARS-CoV-2 Infections and Presymptomatic Type 1 Diabetes Autoimmunity in Children and Adolescents From Colorado, USA, and Bavaria, Germany.

119 : Inhibition of diabetes in BB rats by virus infection.

120 : Prevention of type I diabetes in nonobese diabetic mice by virus infection.

121 : Influence of environmental viral agents on frequency and tempo of diabetes mellitus in BB/Wor rats.

122 : Childhood vaccination and type 1 diabetes.

123 : The role of viruses and environmental factors in the induction of diabetes.

124 : Diet, cow's milk protein antibodies and the risk of IDDM in Finnish children. Childhood Diabetes in Finland Study Group.

125 : Lack of association between early exposure to cow's milk protein and beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young (DAISY)

126 : Lack of association between duration of breast-feeding or introduction of cow's milk and development of islet autoimmunity.

127 : Cell-mediated immune response to beta casein in recent-onset insulin-dependent diabetes: implications for disease pathogenesis.

128 : Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption.

129 : Timing of initial cereal exposure in infancy and risk of islet autoimmunity.

130 : Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies.

131 : Infant exposures and development of type 1 diabetes mellitus: The Diabetes Autoimmunity Study in the Young (DAISY).

132 : Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease.

133 : Prevention of chemically induced diabetes mellitus in experimental animals by polyunsaturated fatty acids.

134 : Impact of dietary fat on Th1/Th2 cytokine gene expression in the pancreas and gut of diabetes-prone BB rats.

135 : Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes.

136 : Incidence of childhood diabetes mellitus in Yorkshire, northern England, is associated with nitrate in drinking water: an ecological analysis.

137 : Time to dissect the autoimmune etiology of cancer antibody immunotherapy.

138 : Immune Checkpoint Inhibitor-Induced Type 1 Diabetes: An Underestimated Risk.

139 : Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.

140 : Increased Reporting of Immune Checkpoint Inhibitor-Associated Diabetes.

141 : Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors.

142 : Beta cell function in the preclinical period of insulin-dependent diabetes.

143 : Natural history of IDDM

144 : 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.

145 : Standardization of IVGTT to predict IDDM.

146 : 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.

147 : Correlations of in vivo beta-cell function tests with beta-cell mass and pancreatic insulin content in streptozocin-administered baboons.

148 : Reversal of beta-cell suppression in vitro in pancreatic islets isolated from nonobese diabetic mice during the phase preceding insulin-dependent diabetes mellitus.

149 : Human pancreatic islet function at the onset of type 1 (insulin-dependent) diabetes mellitus.

150 : Recovery from diabetes in mice by beta cell regeneration.

151 : Beta cell expression of IGF-I leads to recovery from type 1 diabetes.

152 : beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass.