Objectives: In type 1 diabetes mellitus, autoimmune destruction of pancreatic beta cells results in insulin deficiency, leading to hyperglycaemia. Serum islet autoantibodies, which mark the underlying autoimmune process, usually develop years before clinical diabetes onset. Although there is a large window of opportunity for secondary prevention efforts, not all children developing islet antibodies will develop hyperglycemia. There is no test to stratify those at greatest risk. We used longitudinal gene expression data from two cohort studies to investigate the genes and pathways involved in the progression from antibody positivity to the clinical onset of diabetes, then developed a model to risk-stratify antibody-positive children.
Methods: We integrated longitudinal peripheral blood gene expression profiles collected in 31 high-risk islet autoantibody-positive children in the BABYDIET and DIPP cohorts, of whom 18 progressed to diabetes, and identified differentially expressed (DE) genes that predicted diabetes progression.
Results: Comparing DE genes from 3 existing datasets, we identified immune response, olfactory receptors, beta cell stress and apoptosis, and the pancreatic lipidome pathways as pathogenetic pathways particularly relevant to the post-seroconversion period before diabetes onset (stage 2), which may be modifiable with drug intervention. Seven genes predicted diabetes progression (AUC > 0.76), of which the most robust predictive in peripheral blood mononuclear cells were LIPC and NPEPPS.
Conclusion: Peripheral blood gene expression predicts progression to type-1 diabetes mellitus in autoantibody positive children through potentially modifiable pathways. A prediction tool developed from DE genes could enhance potential to apply secondary prevention strategies to children at highest risk of progression.