Adult-Onset Type 1 Diabetes: Current Understanding and Challenges

Abstract

Recent epidemiological data have shown that more than half of all new cases of type 1 diabetes occur in adults. Key genetic, immune, and metabolic differences exist between adult-and childhood-onset type 1 diabetes, many of which are not well understood. A substantial risk of misclassification of diabetes type can result. Notably, some adults with type 1 diabetes may not require insulin at diagnosis, their clinical disease can masquerade as type 2 diabetes, and the consequent misclassification may result in inappropriate treatment. In response to this important issue, JDRF convened a workshop of international experts in November 2019. Here, we summarize the current understanding and unanswered questions in the field based on those discussions, highlighting epidemiology and immunogenetic and metabolic characteristics of adult-onset type 1 diabetes as well as disease-associated comorbidities and psychosocial challenges. In adultonset, as compared with childhood-onset, type 1 diabetes, HLA-associated risk is lower, with more protective genotypes and lower genetic risk scores; multiple diabetes-associated autoantibodies are decreased, though GADA remains dominant. Before diagnosis, those with autoantibodies progress more slowly, and at diagnosis, serum C-peptide is higher in adults than children, with ketoacidosis being less frequent. Tools to distinguish types of diabetes are discussed, including body phenotype, clinical course, family history, autoantibodies, comorbidities, and C-peptide. By providing this perspective, we aim to improve the management of adults presenting with type 1 diabetes.Clinically, it has been relatively easy to distinguish the acute, potentially lethal, childhood-onset diabetes from the less aggressive condition that affects adults. However, experience has taught us that not all children with diabetes are insulin dependent and not all adults are non-insulin dependent. Immune, genetic, and metabolic analysis of these two, apparently distinct, forms of diabetes revealed inconsistencies, such that insulin-dependent and immune-mediated diabetes was redefined as type 1 diabetes, while most other forms were relabeled as type 2 diabetes. Recent data suggest a further shift in our thinking, with the recognition that more than half of all new cases of type 1 diabetes occur in adults. However, many adults may not require insulin at diagnosis of type 1 diabetes and have a more gradual onset of hyperglycemia, often leading to misclassification and inappropriate care. Indeed, misdiagnosis occurs in nearly 40% of adults with new type 1 diabetes, with the risk of error increasing with age (1,2). To consider this important issue, JDRF convened a workshop of international experts in November 2019 in New York, NY. In this Perspective, based on that workshop, we outline the evidence for

The Incidence of Adult-Onset Type 1 Diabetes: A Systematic Review From 32 Countries and Regions

“…Though autoantibody testing among all people with adult-onset diabetes may aid identification of T1D, it is important to remember that in a setting of high prior odds of T2D, and known background population autoantibody positivity, this could also lead to overestimation of T1D in adults. Therefore, combining clinical features that increase odds of T1D, prior to autoantibody measurement, or a combined diagnostic model including clinical features such as low BMI may in the future be the most accurate way to identify and classify individuals with adult-onset T1D ( 37 – 39 ). Indeed, in a 2021 joint consensus statement (published after our Systematic Review was conducted) ( 40 ), the American Diabetes Association and the European Association for the Study of Diabetes recommend the use of islet antibodies, in conjunction with clinical features and a C-peptide test (particularly after >3 years’ diabetes duration [ 41 ]), to distinguish T1D from T2D in adults with suspected T1D.…”

Adult-onset type 1 diabetes: A changing perspective

“…Diabetes represents a disease state, irrespective of the presence of clinical symptoms, determined by raised glucose or HbA1c levels. Diabetes has surged in prevalence in recent years, whether type 1 diabetes (T1D approximately 5-10% of all diabetes [1]) or type 2 diabetes (T2D), reaching epidemic, even pandemic, levels globally [1]. By implication, non-genetic factors have a close resemblance in these two major types of the disease providing a potential explanation in the shared increase in cases.…”

Diagnosing Type 1 diabetes in adults: Guidance from the UK T1D Immunotherapy consortium

“…Patients with positive beta-cell autoantibodies in this context are likely to have autoimmune T1D. 5 Whilst negative beta-cell autoantibodies do not exclude T1D (sensitivity with the three autoantibodies is approximately 90%), they should prompt consideration of T2D in older adults, and of MODY in those diagnosed in the age ≤35. The probability of MODY based on clinical features can be assessed using the MODY calculator (https://www.diabe tesge nes.org/exete r-diabetes app/ModyCalculator).…”

“…Measurement of autoantibodies to beta‐cell antigens (GADA, IA2A and ZnT8A) is valuable at diagnosis 4 (or no later than 3 years after diagnosis when measurement of C‐peptide level is more appropriate—see below) in adults who are likely to have T1D on clinical criteria or have rapid glycaemic progression following diagnosis of T2D. Patients with positive beta‐cell autoantibodies in this context are likely to have autoimmune T1D 5 . Whilst negative beta‐cell autoantibodies do not exclude T1D (sensitivity with the three autoantibodies is approximately 90%), they should prompt consideration of T2D in older adults, and of MODY in those diagnosed in the age ≤35.…”