Natural history and staging type 1 diabetes
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 205-206
2025-11-11
63
The description of the natural history of autoimmune type 1 diabetes has changed in a major way during recent years. The aetiology and pathogenesis are better understood, especially as the aetiology can be better defined in terms of genetic and environmental aetiology and that the cause and origin of autoimmune type 1 diabetes are beginning to be understood. First, HLA genetic risk for type 1 diabetes allowed screening to identify neonates at increased genetic risk. Second, islet autoantibodies detected in standard radiobinding assays were validated and found to be reliable biomarker end- points of islet autoimmunity. The four commonly used islet autoantibody markers (Table 1) are detectable not only in radiobinding assays but also in double- sided enzyme- linked immunosorbent assay (ELISA), chemiluminescence, and autoantibody detection by agglutination polymerase chain reaction (ADAP). Third, general population screening at birth has been proven to be both feasible and well tolerated by parents and children.
Table1. Biomarkers of islet autoimmunity predict clinical onset of type 1 diabetes.
Follow- up studies from birth in more than 26 000 individuals in nine different studies have made it possible to stage the pathogenesis of type 1 diabetes (Figure 1). The Environmental Determinants of Diabetes in the Young (TEDDY) study is by far the largest and represents a major effort by the National Institutes of Health (NIH) that brought DIPP, DAISY, DiPiS, BABYDIAB, PANDA, and DEW- IT (Table 2) together to increase the power of the investigation. Because type 1 diabetes is detected in most individuals with type 1 diabetes after a relatively short period of symptoms, the natural history of the disease has been poorly defined until recently. With the current ability to define individuals at increased risk for type 1 diabetes based on high- risk HLA and islet autoantibodies, the understanding of the pre- diabetes period is improving.
Fig1. Staging of the natural history of autoimmune type 1 diabetes. The aetiological stage is thought to be associated with enterovirus infection in people at increased genetic risk for type 1 diabetes. A series of unknown events, such as prolonged shedding of virus, may trigger islet autoimmunity by yet unknown mechanisms. A first islet autoantibody against islet antigen or glutamic acid decarboxylase, dependent on genetic risk, appears and represents the biomarker for islet autoimmunity. Following the appearance of a second autoantibody, the person is classified in stage 1, which is defined by the presence of two or more islet autoantibodies, normoglycaemia, and no symptoms. In stage 2 the person has multiple autoantibodies and has developed dysglycaemia or impaired glucose tolerance without symptoms. Stage 3 is also characterized by multiple autoantibodies. Individuals may lose autoantibodies prior to stage 3. Diabetes is diagnosed according to the American Diabetes Association and World Health Organization criteria and the person may have symptoms and will also require insulin. Sources: Adapted from Insel et al. 2015 and Lloyd et al. 2022.
Table2. Observational birth cohorts in autoimmune type 1 diabetes.
The prospective studies from birth of children with increased risk for type 1 diabetes in TEDDY and the other studies listed in Table 2 have revealed that GADA, IAA, IA- 2A, or ZnT8A may develop several years before the clinical diagnosis. The sequence of events preceding the diagnosis of overt type 1 diabetes would include the following:
1. Genetic predisposition.
2. Overt immunological abnormality, reflected in a first- appearing islet autoantibody but with normal glucose levels and no symptoms.
3. Development of a second or third islet autoantibody, still with normal blood glucose and no symptoms (type 1 diabetes stage 1).
4. Development of β- cell dysfunction and dysglycaemia, but no symptoms (type 1 diabetes stage 2).
5. Development of overt hyperglycaemia with detectable C- peptide (type 1 diabetes stage 3).
6. The final stage of insulin dependency, with loss of detectable C- peptide (Figure 1).
The fact that type 1 diabetes develops in people of all ages must be considered when studying the natural history in children and adults. Early histological studies of pancreatic tissue of people who died shortly after the clinical onset of diabetes revealed that the pancreatic islets were altered by fibrosis, hyalinosis, atrophy, and infiltration of inflammatory cells. The inflammatory lesion of the islets of Langerhans was described as insulitis, and quantitative studies of the pancreatic islets showed a specific loss of insulin- positive cells in association with the clinical onset of type 1 diabetes. It was therefore suggested that the pathogenesis of type 1 diabetes involved autoimmune reactions directed towards the endocrine pancreas.
This notion was supported by leucocyte migration inhibition to pancreatic islet antigens. Numerous studies have confirmed the presence of insulitis, however, despite the assumption that type 1 diabetes is a T- cell mediated disease, reproducible and standardised tests of blood T- cell reactivity against islet autoantigens or other specific autoantigens are yet to be fully established.
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