The number and titre of islet autoantibodies (AB+) in FDR predict who are at risk of progressing to T1D. Additional biomarkers are needed to elucidate immune-pathogenesis, stratify risk, to identify screening tools and therapeutic targets in at risk subjects before and after the development of auto-antibodies. In a cross-sectional design, we quantified peripheral blood (PB) NF-kB DNA binding, pro-inflammatory cytokine and stress gene expression, and 133 serum analytes in AB-, single AB+ and multiple AB+ FDR, and healthy control children (HC). Feature selection was used to identify biomarkers that predicted AB- FDR status from HC children, and the presence of multiple AB among AB+ FDR. Markers of stress and inflammatory, including RELB DNA binding, TNF mRNA expression, and serum soluble LAG3 significantly predicted AB- FDR from HC. Multiple AB+ FDR were predicted on the basis of clinical features (BMI percentile, 2h OGTT glucose levels, HbA1c and insulin resistance), as well as serum levels of the gastro-intestinal hormone peptide YY, and the chemokines IL-20 and XCL1. By clustering biomarkers correlated with significantly predictive variables, FDR segregated into 2 phenotypic groups dominated by ACTH levels. In summary the data sets suggest that subjects at risk of T1D differ in their physiological response to stress, innate and adaptive immunity, insulin resistance, blood glucose and appetite regulation.