The challenges of identifying and studying type 1 diabetes in adults

Abstract

Diagnosing type 1 diabetes in adults is difficult since type 2 diabetes is the predominant diabetes type, particularly with an older age of onset (approximately >30 years). Misclassification of type 1 diabetes in adults is therefore common and will impact both individual patient management and the reported features of clinically classified cohorts. In this article, we discuss the challenges associated with correctly identifying adult-onset type 1 diabetes and the implications of these challenges for clinical practice and research. We discuss how many of the reported differences in the characteristics of autoimmune/type 1 diabetes with increasing age of diagnosis are likely explained by the inadvertent study of mixed populations with and without autoimmune aetiology diabetes. We show that when type 1 diabetes is defined by high-specificity methods, clinical presentation, islet-autoantibody positivity, genetic predisposition and progression of C-peptide loss remain broadly similar and severe at all ages and are unaffected by onset age within adults. Recent clinical guidance recommends routine islet-autoantibody testing when type 1 diabetes is clinically suspected or in the context of rapid progression to insulin therapy after a diagnosis of type 2 diabetes. In this moderate or high prior-probability setting, a positive islet-autoantibody test will usually confirm autoimmune aetiology (type 1 diabetes). We argue that islet-autoantibody testing of those with apparent type 2 diabetes should not be routinely undertaken as, in this low prior-prevalence setting, the positive predictive value of a single-positive islet antibody for autoimmune aetiology diabetes will be modest. When studying diabetes, extremely high-specificity approaches are needed to identify autoimmune diabetes in adults, with the optimal approach depending on the research question. We believe that until these recommendations are widely adopted by researchers, the true phenotype of late-onset type 1 diabetes will remain largely misunderstood.

Keywords: Age; C-peptide; Genotype; Islet autoantibodies; Phenotype; Prior probability; Review; Type 1 diabetes adult-onset.

Fig. 1

The incidence of genetically defined type 1 and type 2 diabetes in the first six decades of life. Recreated from original data from UK Biobank [1]. This figure is available as part of a downloadable slideset

Fig. 2

The prevalence of GADA positivity for an assay and threshold with 97.5% specificity (positive defined as >10 units/ml) for: (1) a control population without diabetes (HbA_1c <48 mmol/mol [<6.5%]) (data from [66]); (2) individuals with HNF1A and HNF4A MODY (T. J. McDonald, University of Exeter, UK, unpublished data associated with [67]); (3) individuals aged ≥18 years, with recently diagnosed diabetes that was initially treated as type 2 diabetes (without initial insulin for >2 weeks) (A. G. Jones, University of Exeter, UK, unpublished data from the StartRight Study [31, 37]); and (4) individuals with long-duration type 2 diabetes, aged ≥35 years at diagnosis, with a clinical diagnosis of type 2 diabetes, absence of insulin requirement within 6 months of diagnosis and with median diabetes duration of 11 years (data from [6]). This figure is available as part of a downloadable slideset

Fig. 3

The impact of misclassification of clinician-classified type 1 diabetes on the observed clinical features of type 1 diabetes. Rates of misclassification taken from [28]. This figure is available as part of a downloadable slideset

Fig. 4

The pattern of islet autoantibodies at diagnosis in (a) clinician-diagnosed type 1 diabetes in children (<18 years old), young adults (18–31 years old) and older adults (>31 years old) and (b) after genetic adjustment for non-autoimmune diabetes. Data from [13, 32]. This figure is available as part of a downloadable slideset