Type 1 diabetes represents a major public health burden. While the availability of improved insulin pumps and continuous glucose monitors has eased some of the daily practical and psychological burden of T1D, technology has not dramatically improved glucose control, with studies conducted by the T1DExchange ~5 years apart showing no improvement in HbA1c over the lifespan. There has also been only limited improvement in the shortened lifespan observed in those with T1D, and the incidence of T1D has increased over the last twenty or more years. Initiated and perpetuated by a complex interplay of genetic risk factors, environmental triggers and dysregulated immune responses, the natural history of T1D unfolds in a series of events that progress at variable rates towards onset of clinical disease. Yet the precise correlates and determinants of T1D pathogenesis remain incompletely defined. The identification and validation of novel biomarkers is critical to promote better stratification of T1D risk and progression, can illuminate pathways of disease pathogenesis and heterogeneity, and likely will inform the development of interventional strategies to delay or prevent disease.
To precipitate the identification of robust and improved biomarkers, the TrialNet consortium designed the key question 1 (KQ1) PBMC study, a nested case/control study of 178 multiple Aab+ at-risk individuals that over a period of three years either did (“cases”) or did not (“controls”) progress to clinical disease. This earlier study aimed to correlate the evolution of transcriptomic and phenotypic immune cell profiles with incipient T1D onset. KQ1 analyses incorporating detailed clinical metadata are currently ongoing, and we now seek to complement these efforts with a broad interrogation of soluble serum factors from the very same KQ1 donor cohort. Here, the “KQ1 serum study” aims to 1., to identify and validate serum biomarkers for T1D risk, development and/or progression; 2., to establish a comprehensive data resource for reference and orientation, hypothesis generation and improved interventional study design; and 3., to execute broadly integrated data analyses in particular with emerging transcriptional and phenotypic immune cell data from the KQ1 cohort. To this end, we have identified and prioritized suitable targets and analytical approaches, robust technology platforms, and investigator teams with track records to perform high-throughput analyses. Since the scope of our proposal is delimited by the amount of available KQ1 serum samples, we developed a highly collaborative Research Plan that deploys both discovery- and hypothesis-driven investigative strategies. Our proposed interrogations include expansive measurements of serum proteins, antibody responses against commensal bacteria, PBMC responder transcriptomics, and exocrine pancreatic factors. Integrative analytics will be leveraged to define novel serum signatures for T1D risk stratification, improve prediction of disease progression rates, and elucidate aspects of T1D pathogenesis that may accelerate the development of tailored diagnostic, prophylactic and therapeutic modalities. Altogether, the KQ1 serum study has unique potential to build a robust framework for future integration of serum biomarkers in the improved management of T1D.