Version May 2024
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). (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].
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 "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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