Latent Autoimmune Diabetes of Adults (LADA) Is Likely to Represent a Mixed Population of Autoimmune (Type 1) and Nonautoimmune (Type 2) Diabetes

Abstract

Latent autoimmune diabetes of adults (LADA) is typically defined as a new diabetes diagnosis after 35 years of age, presenting with clinical features of type 2 diabetes, in whom a type 1 diabetes-associated islet autoantibody is detected. Identifying autoimmune diabetes is important since the prognosis and optimal therapy differ. However, the existing LADA definition identifies a group with clinical and genetic features intermediate between typical type 1 and type 2 diabetes. It is unclear whether this is due to 1) true autoimmune diabetes with a milder phenotype at older onset ages that initially appears similar to type 2 diabetes but later requires insulin, 2) a disease syndrome where the pathophysiologies of type 1 and type 2 diabetes are both present in each patient, or 3) a heterogeneous group resulting from difficulties in classification. Herein, we suggest that difficulties in classification are a major component resulting from defining LADA using a diagnostic test-islet autoantibody measurement-with imperfect specificity applied in low-prevalence populations. This yields a heterogeneous group of true positives (autoimmune type 1 diabetes) and false positives (nonautoimmune type 2 diabetes). For clinicians, this means that islet autoantibody testing should not be undertaken in patients who do not have clinical features suggestive of autoimmune diabetes: in an adult without clinical features of type 1 diabetes, it is likely that a single positive antibody will represent a false-positive result. This is in contrast to patients with features suggestive of type 1 diabetes, where false-positive results will be rare. For researchers, this means that current definitions of LADA are not appropriate for the study of autoimmune diabetes in later life. Approaches that increase test specificity, or prior likelihood of autoimmune diabetes, are needed to avoid inclusion of participants who have nonautoimmune (type 2) diabetes. Improved classification will allow improved assignment of prognosis and therapy as well as an improved cohort in which to analyze and better understand the detailed pathophysiological components acting at onset and during disease progression in late-onset autoimmune diabetes.

Figure 1

Proportion of GADA-positive individuals who have autoimmune etiology diabetes in a 95% and 5% prevalence population. Expected results from testing 100 participants, using median GADA assay performance from the 2010 Diabetes Autoantibody Standardization Program (assay specificity 94%, sensitivity 86%).

Figure 2

The effect of prior prevalence and assay performance on GADA PPV. Calculated as described in the text for GADA assays with the following characteristics: 94% specificity, 86% sensitivity (Diabetes Autoantibody Standardization Program 2010 median performance); 97.5% specificity, 74% sensitivity; and 99% specificity, 69% sensitivity (Diabetes Autoantibody Standardization Program 2018 median performance).

Figure 3

Excess prevalence of GADA in participants with clinically diagnosed diabetes in comparison with a control population without diabetes. GADA assessed using the RSR Limited (Cardiff, U.K.) bridging ELISA by the Blood Sciences Department of Royal Devon and Exeter Hospital, Exeter, U.K. A value >10 units was considered positive. *No known diabetes, HbA_1c <48 mmol/mol, n = 1,500 (45). #Aged >18 years at diagnosis, clinical diagnosis of type 2 diabetes, median duration 3 months (A.G.J., StartRight Study Group, unpublished observation). ⁁Age ≥35 years at diagnosis, clinical diagnosis of type 2 diabetes, absence of insulin requirement within 6 months of diagnosis (45).