Etiology of Autoimmune Islet Disease: Timing Is Everything

Abstract

Life is about timing. —Carl Lewis The understanding of autoimmune type 1 diabetes is increasing, and examining etiology separate from pathogenesis has become crucial. The components to explain type 1 diabetes development have been known for some time. The strong association with HLA has been researched for nearly 50 years. Genome-wide association studies added another 60+ non-HLA genetic factors with minor contribution to risk. Insulitis has long been known to be present close to clinical diagnosis. T and B cells recognizing β-cell autoantigens are detectable prior to diagnosis and in newly diagnosed patients. Islet autoantibody tests against four major autoantigens have been standardized and used as biomarkers of islet autoimmunity. However, to clarify the etiology would require attention to time. Etiology may be defined as the cause of a disease (i.e., type 1 diabetes) or abnormal condition (i.e., islet autoimmunity). Timing is everything, as neither the prodrome of islet autoimmunity nor the clinical onset of type 1 diabetes tells us much about the etiology. Rather, the islet autoantibody that appears first and persists would mark the diagnosis of an autoimmune islet disease (AID). Events after the diagnosis of AID would represent the pathogenesis. Several islet autoantibodies without (stage 1) or with impaired glucose tolerance (stage 2) or with symptoms (stage 3) would define the pathogenesis culminating in clinical type 1 diabetes. Etiology would be about the timing of events that take place before the first-appearing islet autoantibody.

The relationship between islet autoantibody status and the genetic risk of type 1 diabetes in adult-onset type 1 diabetes

“…The reasons for this observed reduction are not known but it could be due to the presence of other unmeasured autoantibodies or a new discrete form of diabetes or the inadvertent misclassification of non-autoimmune diabetes. Genetic predisposition to type 1 diabetes has been shown to influence the presence of autoantibodies [ 10 – 14 ]. Therefore, detailed immunogenetic studies may help us to better understand the reasons for the lower prevalence of autoantibody positivity in adult-onset type 1 diabetes studies and improve our understanding of the pathophysiology and clinical utility of autoantibodies in adult-onset type 1 diabetes.…”

Possible heterogeneity of initial pancreatic islet beta‐cell autoimmunity heralding type 1 diabetes

“…Future directions may include analysis of the molecular structure of the HLA heterodimer which determines which peptides are able to form the trimolecular complex that is the ligand for the T cell receptor. The longitudinal studies of TEDDY, DIPP, and similar investigations underscore that “timing is everything” [90]. The risk for a first‐appearing autoantibody may be related to the number of variable amino acid residues in the groove of the HLA Class II heterodimer, be it DQ [91, 92] or DR [93, 94].…”

HbA1c as a time predictive biomarker for an additional islet autoantibody and type 1 diabetes in seroconverted TEDDY children

“…The disease pathway to type 1 diabetes is heterogenous and associated with many factors including HLA genotype, age, age at the first appearing islet autoantibody, type of first appearing autoantibody, gender, and BMI giving rise to different endotypes. 2 , 19 Considering this, the TEDDY cohort was analyzed in two subcohorts with IAA or GADA as the first appearing autoantibody. The present analysis showed, however, that lower levels of HbA1c in GADA single positive TEDDY children was associated with the risk to develop IA‐2A as the second autoantibody.…”