During the past two decades, an accumulating body of information has led to the recognition that the predominant form of insulin-dependent diabetes mellitus (IDDM) is of immune etiology, that the disease can present at any age, and that individuals are not insulin-dependent early in the course of disease (1,2,3,4,5,6). Given this body of information, an expert committee of the American Diabetes Association has divided the “idiopathic” (e.g., not pancreatitis, mitochondrial DNA mutations) forms of diabetes resulting from β-cell loss and/or severe insulin secretory deficiency into type 1A and type 1B (1). Type 1A is the immune-mediated form and is best characterized by the presence of islet autoantibodies (see below) and insulitis (7,8), with selective destruction of islet β-cells (e.g., glucagon-producing cells are spared). In addition, type 1A diabetes is strongly associated with specific human leukocyte antigen (HLA) alleles (4,9,10) and almost always progresses to severe insulin deficiency (11). The term type 1B diabetes is reserved for forms of diabetes with severe insulin deficiency without evidence of β-cell autoimmunity (1). An interesting form of potential type 1B diabetes was reported in Japan (12). The patients had lymphocytic infiltration of the exocrine pancreas (with increased serum amylase levels) and an acute development of diabetes such that,
at the time of diabetes onset, levels of glycosylated hemoglobin (HbA_1c) were normal despite marked hyperglycemia. Japan has one of the lowest incidences of type 1A diabetes in the world, and thus type 1B forms of diabetes are likely to represent a larger proportion of their cases of childhood type 1 diabetes than that seen in other countries. In Europe and the United States, fewer than 10% of non-Hispanic white children presenting with diabetes do not have type 1A diabetes. In contrast, among African-American children and Hispanic-American children, almost one half do not have type 1A diabetes, with the majority believed to have early onset type 2 diabetes and relatively few having type 1B diabetes. In particular, a subset of African-American children can present with ketoacidosis but do not express islet autoantibodies, lack HLA alleles associated with type 1A diabetes, and often can be treated with oral hypoglycemic medications after resolution of their acute illness (13,14,15).

The present “etiologic” classification of diabetes is not completely satisfactory, since specific diagnostic markers are lacking for many forms of “idiopathic” diabetes (type 2 and type 1B), and some individuals with type 1A diabetes may even lack islet autoantibodies if they are tested only once at diagnosis. In addition, no combination of HLA alleles is completely diagnostic for type 1A diabetes. Only 20% to 50% of the patients with type 1A diabetes have the highest-risk HLA genotype (DR 3/4 DQ2/DQ8 heterozygous) compared with the 2.4% of individuals without diabetes who have this genotype (16). Approximately 1% of children with type 1A diabetes have highly “protective” HLA alleles (e.g., DQB1*0602) compared with 20% of the general public with these alleles. Given “biochemical” assays for islet autoantibodies with specificity set at greater than the 99th percentile, the terms autoantibody-positive and antibody-negative diabetes are perhaps more precise descriptors. Caveats for such designations include the loss of islet autoantibodies prior to the development of overt diabetes that occurs in a subset of children and the observation that individuals can have both type 1 and type 2 diabetes (17,18). Figure. 23.1 illustrates first-phase insulin secretion (1+3 minute insulin on intravenous glucose tolerance testing) for a markedly obese teenager who progressed to overt diabetes. At the time of diagnosis of diabetes, the fasting insulin level was approximately 25 μU/mL, and although the sum of insulin at 1+3 minutes (50 μU/mL) was above the first percentile (of 48 μU/mL), there was essentially no glucose-stimulated insulin secretion. This child with islet autoantibodies and progressive loss of first-phase insulin secretion has both type 1A diabetes and evidence of insulin resistance (marked by high fasting levels of insulin and obesity).

The category of diabetes that will expand with increased knowledge is that of “other specific forms of diabetes,” which will include the subset of “immune-mediated diabetes.” At present the best example of a defined form of type 1A diabetes is that in patients with diabetes as part of the autoimmune polyendocrine syndrome type 1 caused by a mutation of the AIRE (autoimmune regulator) gene on chromosome 21 (19) (see below).

Does the classification of diabetes matter? Most children presenting with diabetes have type 1A diabetes, and most adults have type 2 diabetes. We believe it does matter when providing prognostic information (20), information concerning likely associated disorders [e.g., autoimmune disorders for type 1A diabetes (21) and manifestations of insulin resistance for type 2 diabetes], for assessing genetic risk for relatives (22), and in providing some guidance concerning therapy [insulin versus oral medications (e.g., insulin secretagogues and insulin sensitizers)] (23). Patients with islet autoantibodies and who have diabetes are probably best treated with insulin even if they are not currently “insulin dependent (24).” Oral agents rapidly lose their efficacy in adults with type 1A diabetes.

In that type 1A diabetes is of immune etiology, it marks an inherited failure in the maintenance of self-tolerance. It is thus not surprising that individuals with diabetes and their relatives are at increased risk for a series of autoimmune disorders (25,26,27,28). The presence of type 1A diabetes is also a “marker” for the presence of specific HLA alleles that are associated with many immunologic disorders. The associated disorders are so prevalent among patients with type 1A diabetes, and some are so devastating when not diagnosed early, both a high index of suspicion and screening for asymptomatic disease are warranted. Four important disorders are Addison’s disease (28), celiac disease (29,30,31,32,33,34,35,36), thyroid autoimmunity (37,38,39,40), and pernicious anemia (41,42,43). In addition, two major autoimmune polyendocrine syndromes are recognized, termed autoimmune polyendocrine syndrome type-I (APS-I) and APS-II (44).

Type 1A diabetes can develop at any age. For example, Cilio and colleagues have described a child with fulminant autoimmunity and diabetes presenting at birth and we have followed the mother of a child with diabetes who developed type 1A diabetes at age 69 (67). Given this wide spectrum of age at diagnosis, long-term prospective studies are necessary to define the course of the disease. Such studies have benefited from the discovery of islet autoantibodies (68) and from the realization that type 1A diabetes is a chronic autoimmune disorder (69). We divide the development of type 1A diabetes into a series of stages beginning with genetic susceptibility (Fig. 23.3) and ending with complete or nearly complete β-cell destruction associated with a lack of C-peptide secretion. Studies of monozygotic twins illustrate many of the stages associated with type 1A diabetes. In that monozygotic twins are identical for all germ-line-encoded polymorphisms and mutations, if diabetes develops in one twin of a pair, the other twin is at high risk of developing diabetes (70,71). However, because diabetes does not develop in all such twins or activate autoimmunity (as evidenced by a lack of islet autoantibodies) (72), a subset of genetically susceptible individuals do not progress beyond stage I.

Factors that induce the expression of islet autoantibodies are currently poorly defined. The great majority of individuals expressing islet autoantibodies that react with multiple islet antigens progress to loss of first-phase insulin secretion on intravenous glucose tolerance testing and eventually to overt diabetes (73,74). Islet autoantibodies can appear during the first year of life but also can first develop in adults. Figure. 23.4 illustrates
the course of an identical twin whose islet autoantibodies were first detected at age 42 at the time of diagnosis of diabetes, even though his twin mate developed diabetes at age 12. A subset of individuals who express islet autoantibodies are found not to progress to diabetes with long-term follow-up. These individuals usually express a single islet autoantibody, such as antibodies that react only with the molecule GAD (75,76). Progressive loss of first-phase insulin secretion characteristically precedes the development of hyperglycemia (77,78,79).

The detection of progressive loss of first-phase insulin secretion in the presence of islet autoantibodies led to the hypothesis that type 1A diabetes is a “chronic” autoimmune disorder (69). In that data concerning the prediabetic pancreas are limited, chronic progressive islet destruction remains a hypothesis. An alternative hypothesis is that chronic loss of first-phase insulin secretion results from functional inhibition of insulin secretion by the immune system and that the actual destruction of pancreatic β-cells is acute and follows a long latency period during which islet autoantibodies are expressed (80,81). We believe this is unlikely, given the available histologic data and the observation that loss of β-cell mass correlates with loss of first-phase insulin secretion (82). In particular, the pancreases of identical twins of patients with type 1A diabetes, when biopsied (on the occasion of living related donor transplantation), appear normal (83). Pancreases from individuals who have died at the onset of diabetes often have lost most β-cells but still have a significant mass of islet β-cells remaining (84). Several years after the onset of diabetes, as reflected by loss of C-peptide secretion, this remaining β-cell mass is lost. It thus appears that the chronic destruction that precedes type 1A diabetes continues after the development of hyperglycemia.

The histology of the pancreas in individuals at the onset of diabetes shows a diversity of islet lesions. Within islets, β-cells are selectively destroyed (84). This specificity of β-cell destruction is very dramatic, and for islets containing no β-cells, there is no insulitis. Thus, the same section of the pancreas may contain normal islets, islets with β-cells and insulitis, and islets lacking all β-cells and without insulitis (pseudoatrophic islets). This spotty process is conceptually similar to vitiligo, with destruction of patches of melanocytes. This destruction of β-cells of individual islets probably underlies the chronic progression to type 1A diabetes.

A number of potential environmental causes of type 1 diabetes have been reported, but few have been established beyond doubt. However, there are examples of autoimmune diseases that not only are caused by environmental factors but also can be prevented or treated through avoidance of these factors (e.g., celiac disease). These diseases occur only through a strong interaction between environmental factors and specific alleles of mainly HLA genes, suggesting the futility of defining “genetic” versus “environmental” etiology.

Celiac disease, discussed earlier in this chapter, is induced by ingestion of wheat protein gliadin (146,147,148) in a person with DQ2 or DQ8 haplotypes. Removal of wheat from the diet results in the loss of transglutaminase autoantibodies and resolution of the intestinal lesions (149). There is some evidence that the delayed introduction of wheat into infant feeding in recent years has prevented a substantial number of symptomatic cases, although some of such prevented cases may manifest with milder symptoms later in life. Rheumatic fever, another autoimmune disease, is induced by streptococcal infection of a host with an HLA-DR4 genetic background. It has been nearly eradicated in many countries with the introduction of antibiotics and guidelines for diagnosis and treatment of streptococcal infections.

Diabetes in patients with congenital rubella syndrome is perhaps the only form of type 1A diabetes proven to be caused by a viral infection (150,151,152). Non-congenital rubella infection does not appear to be associated with diabetes risk. At present it is not clear whether congenital rubella is associated with endocrine autoimmunity caused by direct infection of target tissues, the triggering of autoimmunity (153), or the induction of changes in the immune system that lead to autoimmunity (154). Although only a small proportion of cases of type 1A diabetes have been found to be caused by congenital rubella infection, this is the only type of autoimmune diabetes that we currently can prevent (using live attenuated rubella vaccine, a component of the MMR vaccine).

Figure. 23.6 contrasts prevalence of type 1A diabetes for a series of countries with dramatic differences in its incidence and compares such diabetes prevalence to diabetes risk, taking into account genetic information. The incidence of type 1A diabetes varies geographically by more than 45-fold (e.g., in Japan the approximate incidence is 1 in 100,000 compared with Finland, where it is 45 in 100,000) (155,156,157,158,159). Nevertheless, even the highest-risk Scandinavian countries have a prevalence of type 1A diabetes less than 3%, while an identical twin of a patient with type 1A diabetes from Japan has a diabetes concordance of approximately 30% (88).

A sibling or offspring of a patient with type 1A diabetes with HLA DQ8/DQ2 has a diabetes risk of approximately 20% to 40% (17,160), and an individual with this genotype from the general U.S. population has a risk of approximately 6%. In addition, a dizygotic twin of a patient with type 1A diabetes has a risk of diabetes very similar to that of a sibling (72). This suggests that, if there are environmental factors triggering the development of type 1A diabetes, they account for a relatively small amount of the familial aggregation of the disease. This may explain the difficulty finding such environmental factors. One exception previously discussed is the rare congenital rubella syndrome that is strongly associated with the development of thyroiditis and type 1A diabetes (161,162,163) and recent reports from two studies that introduction of cereal before 3 months of age increases risk (160a,160b).

The most prominent proposed environmental triggers for type 1A diabetes are infections (particularly viruses), vaccination, and dietary factors (163). There is lack of clear consensus concerning the etiologic role of any of these factors. For both the NOD mouse and the BB rat, the development of diabetes is enhanced when animals are raised in a germ-free environment (164). This suggests that, for both of these animal models, infections are not necessary for the development of diabetes. In fact, when either animal becomes infected with relatively common viruses, the development of diabetes decreases. The BB rat has a severe T-cell lymphopenia inherited in an autosomal recessive manner (165,166,167,168,169). For strains of BB rats termed DR (diabetes resistant) that lack the T-cell lymphopenia locus, diabetes can be induced with a number of immunostimulatory maneuvers, including infection with the rat Kilham virus or with induction of the expression of interferon-α with injection of poly-IC (poly-inosinic-polycytidylic acid, a synthetic double-stranded RNA) (170). Of note, administration of poly-IC induces diabetes and insulitis or just insulitis in a broad range of rat strains with “HLA” class II U alleles (diabetes and insulitis strains: lew1.WR1, PVG.RT1^u, PVG.R8, WF, and WAG; only insulitis-LOU strain). In animal models, several forms of “vaccination” prevent diabetes (e.g., BCG vaccination for NOD mice), and dietary modification, usually with removal of complex proteins from the diet, decreases the development of diabetes (171,172,173). Thus, such manipulations are potential triggers of autoimmunity or may provide therapies (e.g., removal of triggering factors) of relevance to diabetes prevention.