INTRODUCTION — Type 1 diabetes mellitus is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors [1]. The increase in understanding of the pathogenesis of type 1 diabetes mellitus has made it possible to consider intervention to delay the autoimmune disease process in an attempt to delay or even prevent the onset of hyperglycemia (figure 1). Although no successful strategy for the prevention of type 1 diabetes has yet been identified, subjects who are at high risk for type 1 diabetes can be identified using a combination of immune, genetic, and metabolic markers.
This topic will review the use of genetic, immunologic, and metabolic markers to predict type 1 diabetes. The definition, epidemiology, pathogenesis, and prevention of type 1 diabetes are discussed in detail elsewhere. (See "Classification of diabetes mellitus and genetic diabetic syndromes" and "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents" and "Pathogenesis of type 1 diabetes mellitus" and "Prevention of type 1 diabetes mellitus".)
OVERVIEW OF TYPE 1 DIABETES — Type 1 diabetes mellitus is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors [1]. It is usually caused by an immune-mediated destruction of the insulin-producing beta cells in the islets of Langerhans [2]. Immune-mediated type 1 diabetes is called type 1A to distinguish it from some rarer cases in which an autoimmune etiology cannot be determined (type 1B); the latter are said to be idiopathic [3]. The term type 1 diabetes used here refers to type 1A, or autoimmune diabetes. (See "Classification of diabetes mellitus and genetic diabetic syndromes".)
●Genetic – Type 1 diabetes occurs in genetically susceptible subjects. It is a polygenic disease with a small number of genes having large effects, (ie, human leukocyte antigen [HLA]) and a large number of genes having small effects. Risk of type 1 diabetes progression is conferred by specific HLA DR/DQ alleles (eg, DRB1*03-DQB1*0201 [DR3] or DRB1*04-DQB1*0302 [DR4]). In addition, HLA alleles such as DQB1*0602 are associated with dominant protection from disease in multiple populations [4]. (See 'Genetic markers' below.)
●Immunologic – Similar to the majority of autoimmune diseases, type 1 diabetes usually has a relapsing, remitting disease course with autoantibody and T cellular responses to islet autoantigens that precede the clinical onset of the disease process. The immunologic diagnosis of autoimmune diseases relies primarily on the detection of autoantibodies directed to islet autoantigens in the serum of type 1 diabetic patients. Although their pathogenic significance remains uncertain, they have the practical advantage of serving as surrogate biomarkers for predicting the clinical onset of type 1 diabetes. (See 'Immunologic markers' below.)
●Natural history – Type 1 diabetes is probably triggered by one or more environmental agents and usually progresses over many months or years, during most of which the individual is asymptomatic and euglycemic. Individuals with multiple islet autoantibodies with normoglycemia are considered to be at stage 1 type 1 diabetes, those with multiple islet autoantibodies and dysglycemia are at stage 2 type 1 diabetes, and those who developed the clinical symptoms of type 1 diabetes are stage 3 (figure 2) [5,6]. A large percentage of the functioning beta cells are lost before hyperglycemia appears.
The rate of progression of the immune injury is highly variable, even among high-risk subjects who have one or more of the relevant serum autoantibodies. In some people, as an example, progression is so slow that diabetes does not occur for many years or perhaps ever [7-10]. These subjects presumably regain tolerance in some way, eg, regulatory T cells (Tregs) become more numerous or helper T cells become less numerous or active. One report described a 10-year follow-up in 18 nondiabetic twins of type 1 diabetes probands; the eight twins who developed diabetes had persistently high numbers of CD8 HLA DR+ T cells, whereas the 10 twins who remained euglycemic did not [11].
Similarly, nonobese diabetic (NOD) mice that do not develop diabetes have Tregs that suppress autoimmune destruction of the islets [12]. In addition, suppression of insulitis and protection from the development of diabetes can be achieved by injecting insulin-reactive CD4 T cell clones from mice that do not develop diabetes into mice that would otherwise have developed diabetes [13].
This variability in progression of injury causes a major therapeutic dilemma with respect to intervention during the preclinical period. Early therapy is likely to preserve more beta cells but may also result in some patients being treated unnecessarily. There is also concern that treatment of a subject in whom the disease is not progressing might increase the risk of type 1 diabetes by disrupting the balance between helper and suppressor activity, a sequence that has been demonstrated in BioBreeding (BB) rats and NOD mice [14,15]. However, delaying therapy runs the risk that fewer beta cells will be left to preserve.
ANIMAL MODELS OF TYPE 1 DIABETES — The availability of two animal models of type 1 diabetes has made it possible to evaluate plausible therapeutic strategies before starting human trials. Nonobese diabetic (NOD) mice and BioBreeding (BB) rats are inbred strains that spontaneously develop autoimmune insulitis and diabetes with striking similarities to type 1 diabetes in humans [14-17]. The cumulative incidence of type 1 diabetes in these animals is high, and the onset of insulitis as well as hyperglycemia can be readily detected. Several interventions have been tested in these animals, often at a very early stage in the autoimmune disease process before the onset of insulitis. Examples include subcutaneous and oral insulin, nicotinamide, and the beta cell antigen glutamic acid decarboxylase (GAD). Of note, many interventions have been effective in the murine models when applied before the development of hyperglycemia; however, very few interventions have reversed established diabetes.
Strategies for prevention or reversal of diabetes in animal models and in humans are discussed in detail elsewhere. (See "Prevention of type 1 diabetes mellitus".)
USE OF MARKERS TO PREDICT TYPE 1 DIABETES
Genetic markers — Many immune-mediated disorders, including certain endocrine syndromes, are genetically associated with specific human leukocyte antigen (HLA) molecules, and several hypotheses have been suggested to explain HLA disease associations [1,4]. Some HLA-associated diseases have been linked with polymorphisms of the genes encoding the class II molecule. One typical example is type 1 diabetes. Genetic markers may be helpful in assessing the risk of type 1 diabetes in relatives of a patient with type 1 diabetes. The risk is markedly increased in these relatives, averaging at approximately 6 percent in offspring and 5 percent in siblings (versus 0.4 percent in subjects with no family history) [2]. The risk in siblings is importantly influenced by the degree of genetic similarity, falling from 33 percent in identical twins [2] to 12.9 to 4.5 to 1.8 percent, respectively, if the siblings share two, one, or no haplotypes [18].
The major susceptibility genes for type 1 diabetes are in the HLA region on chromosome 6p [18]. Over 90 percent of patients with type 1 diabetes carry DR4, DQB*0302, and/or DR3, DQB*0201. Thus, if the proband is heterozygous for DR3 and DR4 (the highest risk combination), the incidence of type 1 diabetes in a sibling who shares these two haplotypes rises to 19 percent. On the other hand, the absence of the above alleles makes type 1 diabetes very unlikely, especially if the subject carries a protective allele such as DQB*0301, *0602 [19], DRB*0403, or *0406 [20]. (See "Human leukocyte antigens (HLA): A roadmap".)
The combined effect of susceptibility or protective alleles and the presence or absence of a first-degree relative with type 1 diabetes is shown in the table (table 1). Use of genetic markers plus the family history make it possible to estimate the risk of type 1 diabetes as being as low as 1 in 5000 (no susceptibility alleles or family history) to as high as one in four (two susceptibility alleles and a positive family history). However, the prevalence of the HLA susceptibility genes is relatively high in White individuals. As a result, the predictive value of HLA typing is much lower in population screening than it is among families in which one or more members have type 1 diabetes [21].
In one study, the risk for islet autoimmunity drastically increased in DR3/4-DQ2/DQ8 siblings who shared both HLA haplotypes identical by descent with their diabetic proband sibling (63 and 85 percent by ages 7 and 15, respectively) as compared with siblings who did not share both HLA haplotypes with their diabetic proband sibling [22]. These data suggest that HLA genotyping at birth may identify individuals at very high risk of developing type 1 diabetes before the occurrence of clear signs of islet autoimmunity and type 1 diabetes onset. Rapid automated assays make it possible to do large-scale population screening for HLA easily, even in newborns [23,24].
In general, the additional measurement of 2 HLA-DQ high-risk haplotypes does not increase the predictive value of combined autoantibody assays. However, in relatives who are seronegative for conventional islet autoantibodies, the presence of two HLA-DQ high-risk haplotypes is associated with an increased risk of progression to type 1 diabetes [25]. This observation suggests that unidentified autoimmune phenomena may be present in seronegative relatives who carry the 2 HLA-DQ high-risk haplotypes.
Immunologic markers
Autoantibodies — Several clinically useful serum autoantibodies can be detected during the preclinical phase of type 1 diabetes, including islet cell antibodies (ICA), insulin autoantibodies (IAA), antibodies to glutamic acid decarboxylase (GAD), antibodies to tyrosine phosphatase-like proteins such as insulinoma-associated protein (IA-2, ICA512) [26], and antibodies to the zinc transporter 8 (ZnT8) [27]. 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.
The measurement of autoantibodies is a prerequisite in screening for individuals at risk of developing type 1 diabetes. The presence of two or more of these autoantibodies is being used as entry criteria for type 1 diabetes prevention trials such as those supported by the TrialNet network [28].
Children with the earliest evidence of autoimmunity are at greatest risk for and progress more quickly to the development of type 1 diabetes. Periodic testing for islet autoantibodies appears to help assess the risk of diabetes in children of parents with type 1 diabetes.
●Risk of type 1 diabetes – In several prospective family studies (including the large combined data set of the Islet Cell Antibody Registry Users Study [ICARUS]) in which unaffected first-degree relatives of patients with type 1 diabetes were followed, the presence of ICA was associated with an increased risk of diabetes, particularly if the ICA titer was high, ICA were persistently detected, or ICA were present in combination with IAA or GAD antibodies [29,30].
Additional findings have been reported with regard to IA-2. In one study of first-degree relatives of type 1 diabetic probands, those with IA-2 autoantibodies in the upper three quartiles were at higher risk than relatives with an IA-2 autoantibody titer in the lowest quartile [31]. An autoantibody response directed to a new IA-2 variant [32] and the extracellular domain of IA-2 was associated with very high risk of type 1 diabetes progression, suggesting the presence of new antigenic determinants within the extracellular domain of IA-2 [33]. This has considerable implications not only for stratifying high type 1 diabetes risk, but also to facilitate the search for pathogenic epitopes to enable the design of peptide-based immunotherapies, which may prevent the progression to overt type 1 diabetes at its preclinical stages.
Unlike nonobese diabetic (NOD) mice, humans exhibit any combination of ICA, IAA, GAD, and IA-2 antibodies [10,34,35]. The risk of type 1 diabetes is relatively low with IAA alone but is higher with the presence of multiple autoantibodies against islet antigens (insulin, GAD, IA-2 and ICA) [25,30,36-38]. Antibodies to GAD are predictive of progression to hyperglycemia even in the absence of ICA or IAA [29]. As with IAA, however, the risk is higher in subjects who are ICA positive [29].
●Time to progression – The titer of IAA has been used to predict the time to onset of type 1 diabetes, particularly in children younger than five years of age [39]. In a prospective cohort study of 1353 offspring of parents with type 1 diabetes, antibodies detected in the first six months were derived by placental transfer from the mother. Autoantibodies began to appear by nine months and frequently persisted. IAA were almost always the first to appear, with other antibodies (ICA, GAD, or IA-2) appearing later. By age five years, nine (1.8 percent) children had developed type 1 diabetes, and all had one or more autoantibodies beforehand. Fifty percent of children who had two or more antibodies present by two years had diabetes by age five years [40]. In a follow-up report of a slightly larger cohort (1610 offspring), the following results were seen [41]:
•By age five years, the frequencies of islet autoantibodies, multiple autoantibodies, and type 1 diabetes were 5.9, 3.5, and 1.5 percent, respectively.
•The risk of diabetes was highest in those with multiple autoantibodies (40 percent within five years versus 3 percent in those with single autoantibodies).
•Progression to multiple islet autoantibodies was fastest in children who developed their first autoantibody by age two years.
•The risk of progression to diabetes was inversely related to the age of positivity for multiple islet autoantibodies (50 percent of children who had multiple positivity before age nine months developed diabetes within two years, compared with 7 percent in those who had multiple autoantibodies at age five years).
In another study of 81 Swedish children who later developed type 1 diabetes, 14 (17 percent) had at least one autoantibody present at birth (either GAD, IAA, or ICA512), as compared with 12 of 320 (4 percent) control children [42]. Four percent had more than one autoantibody present, compared with none of the control children. This study suggests that the autoimmune process may start in utero, but that this is rare.
An autoantibody risk score (ABRS) has been developed from a proportional hazards model that combined autoantibody levels from each autoantibody along with their designations of positivity and negativity [43]. The ABRS score appears to improve prediction of the clinical onset of type 1 diabetes in first-degree relatives of type 1 diabetic patients.
●Late-onset type 1 diabetes – In addition to identifying children at risk for type 1 diabetes, the presence of ICA and GAD antibodies can also identify late-onset type 1 diabetes in adults thought to have type 2 diabetes. In a study of 97 Swedish diabetic patients who were initially thought to have type 2 or unclassifiable diabetes, 70 became insulin dependent after six years of follow-up. Among these 70 patients, 60 percent were positive for either ICA or GAD at diagnosis, compared with only 2 percent of the 27 patients who remained responsive to oral therapy [44]. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Latent autoimmune diabetes in adults (LADA)'.)
Screening low-risk populations — Type 1 diabetes mellitus can also be predicted in children without familial diabetes. In a study of 4505 healthy schoolchildren, measurement of autoantibodies (GAD, IAA, and IA2/ICA512) prospectively identified all children who developed diabetes within eight years [45]. However, the prediction of rare diseases such as type 1 diabetes is a difficult undertaking (estimated prevalence = 1.2 to 1.5/1000 in the United States) [46]. We would anticipate that a large proportion of individuals with positive screening test results, including multiple autoantibodies to islet antigens, will inevitably be found not to have the disease upon further diagnostic testing [47]. As an example, in a study in healthy French schoolchildren who were screened with islet antibody markers, the number of children with positive ICA was 40 times greater than the number of cases in the cohort expected to develop type 1 diabetes [48].
Metabolic markers — Although glucose tolerance remains normal until close to the onset of hyperglycemia [49], the acute insulin response to several secretagogues (glucose, arginine, glucagon, and isoproterenol) decreases progressively during the preclinical period [50]. The most useful and widely performed test is the acute (or "first phase") insulin response to glucose (FPIR) during an intravenous glucose tolerance test (IVGTT); in this test, the rise in serum insulin above baseline is measured during the first 10 minutes after an intravenous glucose challenge; the response correlates with the functioning beta cell mass (figure 3). The IVGTT has been standardized to allow easier comparison between centers [51,52]. In first-degree relatives of patients with type 1 diabetes, for example, an FPIR below the first percentile of normal is a strong predictor of type 1 diabetes [30].
In the Diabetes Prevention Trial of Type 1 Diabetes (DPT-1), subjects at high risk for developing diabetes were followed with serial IVGTTs and oral glucose tolerance tests (OGTTs), and in a subsequent study, the metabolic factors associated with progression to diabetes were evaluated [53].
Abnormalities of FPIR and two-hour glucose during OGTT had similar sensitivities for diabetes prediction within six months of diagnosis (76 percent for OGTT [95% CI 60-83 percent] and 73 percent for FPIR [95% CI 60-83 percent]). Sensitivity was better when both tests were performed, and the vast majority of these individuals (97 percent) had abnormal IVGTTs and/or OGTTs before the development of the overt diabetes. In contrast, fasting blood glucose levels were a poor predictor of diabetes.
A simpler test that may prove useful is to measure the fasting serum concentration of proinsulin, the precursor of insulin. In normal subjects, proinsulin accounts for approximately 15 percent of serum immunoreactive insulin [54]. This proportion rises as beta cell function declines. One report, as an example, found that serum proinsulin concentrations were three to four times higher among ICA-positive relatives of type 1 diabetes patients as compared with ICA-negative relatives [55]. However, prospective studies are needed to determine whether elevated serum proinsulin values will help in predicting the development of type 1 diabetes.
The use of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) may improve risk classification accuracy for type 1 diabetes by identifying high-risk normoglycemic and low-risk dysglycemic individuals [56].
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 AND RECOMMENDATIONS — Although the prevention of type 1 diabetes is still at the stage of research trials, the trials are often mentioned in the lay press. As a result, many patients with type 1 diabetes (or their parents) ask their doctors about screening of other family members (particularly children) and what could be done if the family member has a high risk for the development of type 1 diabetes.
In a research setting, the following approach may be used:
●Test individuals at risk for type 1 diabetes progression for glutamic acid decarboxylase 65 (GAD65) and insulinoma-associated protein 2 (IA-2) autoantibodies.
●If they are present and confirmed in a subsequent sample, tests for insulin, zinc transporter 8 (ZnT8), and islet cell antibodies (ICA) can be done and the first phase insulin response to glucose (FPIR) determined.
The occurrence of multiple antibodies against islet autoantigens serves as a surrogate marker of disease in primary or secondary intervention strategies aimed at halting the disease process.
Genetic typing for susceptibility or protective human leukocyte antigen (HLA) alleles can also be performed. In the aggregate, this information can be used to ascertain if a high-risk subject is eligible to be entered into an ongoing prevention trial.
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier versions of this topic review.
The UpToDate editorial staff also acknowledges Massimo Pietropaolo, MD (deceased), who contributed to earlier versions of this topic.
