In type 1 diabetes (T1D), autoimmune-mediated
destruction of pancreatic b-cells results in
diabetes. Although islet autoantibodies (AB) identify individuals progressing
to T1D, additional biomarkers are needed to elucidate disease
immunopathogenesis. In a cross-sectional design, we quantified peripheral blood
(PB) NF-kB DNA binding, pro-inflammatory cytokine and
stress gene expression, and serum analytes in AB+ and AB-
first degree relative (FDR) and healthy control children. Using feature
selection, stress and inflammatory biomarkers, including RELB DNA binding and
serum soluble LAG3 significantly predicted AB- FDR from healthy
controls. Clinical, inflammatory and gastro-intestinal hormone biomarkers,
including IL-20 and peptide YY significantly predicted FDR with multiple AB. By
clustering biomarkers correlated with significantly predictive variables, FDR segregated
into 2 phenotypic groups dominated by serum ACTH. These biomarker sets suggest
that groups of subjects at risk of T1D differ in their physiological response
to stress, innate and adaptive immunity, insulin resistance, blood glucose and
appetite regulation.