First-emerging islet autoantibody and glucose metabolism: search for type 1 diabetes subtypes

Abstract

Objective: Subtypes in type 1 diabetes pathogenesis have been implicated based on the first-appearing autoantibody (primary autoantibody). We set out to describe the glucose metabolism in preclinical diabetes in relation to the primary autoantibody in children with HLA-conferred disease susceptibility.

Design and methods: Dysglycemic markers are defined as a 10% increase in HbA1c in a 3-12 months interval or HbA1c ≥5.9% (41 mmol/mol) in two consecutive samples, impaired fasting glucose or impaired glucose tolerance, or a random plasma glucose value ≥7.8 mmol/L. A primary autoantibody could be detected in 295 children who later developed at least 1 additional biochemical autoantibody. These children were divided into three groups: insulin autoantibody (IAA) multiple (n = 143), GAD antibody (GADA) multiple (n = 126) and islet antigen 2 antibody (IA-2A) multiple (n = 26). Another 229 children seroconverted to positivity only for a single biochemical autoantibody and were grouped as IAA only (n = 87), GADA only (n = 114) and IA-2A only (n = 28).

Results: No consistent differences were observed in selected autoantibody groups during the preclinical period. At diagnosis, children with IAA only showed the highest HbA1c (P < 0.001 between groups) and the highest random plasma glucose (P = 0.005 between groups). Children with IA-2A only progressed to type 1 diabetes as frequently as those with IA-2A multiple (46% vs 54%, P = 0.297) whereas those with IAA only or GADA only progressed less often than children with IAA multiple or GADA multiple (22% vs 62% (P < 0.001) and 7% vs 43% (P < 0.001)), respectively.

Conclusions: The phenotype of preclinical diabetes defined by the primary autoantibody is not associated with any discernible differences in glucose metabolism before the clinical disease manifestation.

Keywords: dysglycemia; glucose metabolism; islet autoantibodies; preclinical type 1 diabetes; type 1 diabetes.

Figure 1

Flow-chart showing children with detectable first-appearing islet autoantibodies from the Type 1 Diabetes Prediction and Prevention (DIPP) study. The children presenting with ≥2 biochemical autoantibodies during the whole follow-up and those with only one biochemical autoantibody have been analyzed separately. Data collected by August 31, 2014, was included in this analysis.

Figure 2

Adjusted mean HbA1c during the follow-up in children with different primary autoantibodies who progressed to type 1 diabetes (A) or remained disease-free (B). Children developing at least one additional autoantibody and children who remained positive for a single autoantibody only have been combined. The last point is the diagnosis of type 1 diabetes (A) or the last visit (B) (IAA, squares; GADA, dots; IA-2A, triangles). Whiskers show 95% CIs of the adjusted mean.

Figure 3

Adjusted mean plasma glucose in OGTT (fasting and 2-h plasma glucose) during the follow-up in children with different primary autoantibodies who progressed to type 1 diabetes (A) or remained disease-free (B). Children developing at least one additional autoantibody and children who remained positive for a single autoantibody only have been combined. The last point is the diagnosis of type 1 diabetes (A) or the last visit (B) (IAA, squares; GADA, dots; IA-2A, triangles). Whiskers show 95% CIs of the adjusted mean.

Figure 4

Adjusted mean random plasma glucose during the follow-up in children with different primary autoantibodies who progressed to type 1 diabetes (A) or remained disease-free (B). Children developing at least one additional autoantibody, and children who remained positive for a single autoantibody only have been combined. The last point is the diagnosis of type 1 diabetes (A) or the last visit (B) (IAA, squares; GADA, dots; IA-2A, triangles). Whiskers show 95% CIs of the adjusted mean.