The Melbourne Pre‐Diabetes Study: prediction of type 1 diabetes mellitus using antibody and metabolic testing

Abstract

Objectives: To determine the utility of various autoantibodies in predicting progression to clinical diabetes in first‐degree relatives of patients with type 1 diabetes mellitus. Participants: 3315 first‐degree relatives of patients with type 1 diabetes (1161 parents, 1206 siblings and 948 offspring) recruited through diabetes clinics, private endocrinologists, Diabetes Australia and the Juvenile Diabetes Foundation. Main outcome measures: Prevalence of islet cell antibodies (ICA) levels ≥20 JDFu, insulin autoantibodies (IAA) levels > 100nU/ml, and antibodies to glutamic acid decarboxylase (GADAb) and tyrosine phosphatase IA2 (IA2Ab); change in cell function over time; and development of clinical diabetes. Results: 2.6% of relatives had elevated ICA levels, 1.3% had elevated IAA levels and 0.3% had both. High ICA levels were significantly more frequent in siblings than in offspring or parents, and were more frequent in relatives younger than 20 years. GADAb were detected in 68% and IA2Ab in 57% of relatives with elevated ICA and/or IAA levels. Diabetes developed in 33 relatives (25 siblings, 2 offspring and 6 parents). Before diagnosis of clinical diabetes, high ICA levels were detected in 18 (58%), high IAA levels in 7 (23%), both in 5 (15%), and either in 19 (61%); GADAb were detected in 26 (84%), IA2Ab in 13 (42%), both in 11 (35%), and either in 28 (90%). First phase insulin release (FPIR) less than 50mU/L was very strongly associated with progression to diabetes. In relatives with FPIR initially greater than 50mU/L who eventually developed diabetes, there was a gradual and continuous reduction in FPIR over time before diagnosis. Conclusions: Type 1 diabetes can be diagnosed in the preclinical stage. The recently described antibodies to glutamic acid decarboxylase and tyrosine phosphatase IA2 appear superior to ICA as screening tools for the preclinical diagnosis of type 1 diabetes.

Genetic Determinants of Type 1 Diabetes: Immune Response Genes

“…The disease process may take months to years during which a number of immune related disease markers appear, indicating the presence of ongoing β-cell damage accompanied by a progressive decline of β-cell function [6][7][8]. This period is referred to as the 'preclinical phase' and can be identified by the presence of autoantibodies in the serum of 'at risk' individuals.…”

Measurement of islet cell antibodies in the Type 1 Diabetes Genetics Consortium: efforts to harmonize procedures among the laboratories

“…These laboratories have interacted for years (through DASP and other programs), using radiobinding assays with a generally similar format [8–10], but some differences as shown in Table 1. The following sections summarize the main similarities and differences.…”

Cellular and molecular pathogenesis of type 1A diabetes

“…Currently, multiple sequenced autoantigens have been discovered and autoantibodies are measured with recombinant autoantibody assays [1,2,53]. The standard assays measure autoantibodies reacting with insulin [54][55][56][57][58][59][60], glutamic acid decarboxylase (GAD) [61], ICA512/IA-2 [62,63], and I-A2 beta (phogrin) [64,65]. Despite the importance of autoantibodies for disease prediction, anti-islet autoantibodies do not by themselves cause b-cell destruction.…”