Type 1 diabetes (T1D) is a progressive, autoimmune disease resulting from CD4+ and CD8+ T cell-mediated destruction of pancreatic β cells; inflammatory infiltrate of pancreatic islets, or insulitis; genetic susceptibility associated with the human leukocyte antigen (HLA) region; and the development of autoantibodies reactive against β-cell antigens.1
Activated B-cells interact with CD4+ and CD8+ T-cells, and antigen presentation by B cells and dendritic cells drives the activation of cytotoxic, β-cell-specific T cells, also leading to the development of islet autoantibodies (IAs) by B cells.2 The IAs that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2, and zinc transporter 8 are associated with secretory granules in β cells. They serve as biomarkers of T1D-associated autoimmunity that are found months to years before symptom onset and can be used to identify and study individuals who are at risk of developing the disease.2 Figure 1 depicts the pathogenesis of T1D.
Other potential contributors to the disease include perinatal factors such as a lack of passive transfer of immune protection or embryonic insult, immunization timing, the use of cow’s milk formula, gut biome changes, and other environmental factors, including enteroviruses.1
Genetic susceptibility is confirmed in twin and immediate-family studies, with a 30% to 70% concordance of diagnosis in identical twins. There is a 6% to 7% increased risk of co-occurrence among siblings of an individual with T1D, as well as 1% to 9% risk in children with a parent who has T1D (Table 1).3–6
Genetic susceptibility is mediated by polygenic features in HLA class II genes, which account for 40% to 50% of familial risk. The most frequent or high-risk alleles (present in up to 90% of patients with T1D) are HLA-DR3-Q2 and DR4-Q8.7 In addition, the presence of HLA‑DR and HLA‑DQ genotypes (HLA-DR-DQ) convey an increased risk of developing two or more autoantibodies and T1D.2
Individuals with T1D are also more likely to have other autoimmune disorders as well as monogenic polyglandular autoimmune syndromes.8
However, 90% of people diagnosed with T1D have no family history of the disease.10 This highlights the need for population-based screening.
An estimated 1.7 million adults in the United States and approximately 304,000 children and adolescents (<20 years old), had T1D in 2021. It is the most common form of diabetes in childhood and adolescence, but it can occur at any age. The incidence is increasing across age groups, including in adults, as shown in figures below, with an estimated 5 million people in the US diagnosed with T1D by 2050, including nearly 600,00 children and adolescents.11 Figure 2 depicts trends in the incidence of T1D in children and adolescents between 2002 and 2018; Figure 3 highlights the incidence by age and sex between 2001 and 2015.
One study found a 1.9% annual percentage change in incidence from 2002 through 2015.13 Although the incidence of T1D is still high in non-Hispanic Whites, it is increasing at a faster rate in other racial and ethnic groups. Non-Hispanic Asian or Pacific Islander children and adolescents had the largest significant increases, followed by Hispanic and non-Hispanic Black children and adolescents.11
It is estimated that up to 40% of adults older than age 30 with T1D may have been misdiagnosed with type 2 diabetes (T2D) or monogenic diabetes, with increased risk for error associated with increasing age.14 Key challenges to a timely, accurate diagnosis in adults include the assumption that T1D is a disease of childhood and adolescents and that adults with diabetes have T2D. Yet up to 70% of all cases of T1D are adult-onset.15 This results in delayed diagnosis, worse symptoms, and delayed treatment.16–18
A survey of 3030 adults with T1D and parents of children with T1D found that 1 in 4 were misdiagnosed, resulting in an 18% increased risk for diabetic ketoacidosis (DKA) compared with those individuals with a correct diagnosis.17
Despite technological advances in the management of T1D, including continuous glucose monitoring and insulin pumps, hypoglycemia, hyperglycemia, and DKA are still common occurrences. They all have a significant impact on patient quality of life as well as long-term outcomes, including an increased risk of macro- and microvascular complications.19 Indeed, DKA is one of the most common causes of death in children with T1D, given the resulting cerebral edema.20
Adults may also present with DKA at diagnosis and after, although the frequency is unknown. However, the primary risk factor for adults is not undiagnosed T1D; the main risk factors are nonadherence with insulin use and infections.16
A review of 31 studies found that uncontrolled T1D—both immediate hypoglycemic episodes and longer-term hyperglycemia complications—adversely affects the physical, emotional, practical, and social domains of a patient’s life (Table 2). The quality of life for patients’ family members is also negatively impacted.21
