Speake, CateYlescupidez, AlyssaNeiman, DanielShemer, RuthGlaser, BenjaminTersey, Sarah A.Usmani-Brown, SaharClark, PamelaWilhelm, Joshua J.Bellin, Melena D.Herold, Kevan C.Mirmira, Raghavendra G.Dor, YuvalEvans-Molina, Carmella2022-05-092022-05-092020-03-01Speake C, Ylescupidez A, Neiman D, et al. Circulating Unmethylated Insulin DNA As a Biomarker of Human Beta Cell Death: A Multi-laboratory Assay Comparison. J Clin Endocrinol Metab. 2020;105(3):781-791. doi:10.1210/clinem/dgaa008https://hdl.handle.net/1805/28868Context: There is an unmet need for biomarkers of pancreatic beta-cell death to improve early diagnosis of type 1 diabetes, enroll subjects into clinical trials, and assess treatment response. To address this need, several groups developed assays measuring insulin deoxyribonucleic acid (DNA) with unmethylated CpG sites in cell-free DNA. Unmethylated insulin DNA should be derived predominantly from beta-cells and indicate ongoing beta-cell death. Objective: To assess the performance of three unmethylated insulin DNA assays. Design and participants: Plasma or serum samples from 13 subjects undergoing total pancreatectomy and islet autotransplantation were coded and provided to investigators to measure unmethylated insulin DNA. Samples included a negative control taken post-pancreatectomy but pretransplant, and a positive control taken immediately following islet infusion. We assessed technical reproducibility, linearity, and persistence of detection of unmethylated insulin DNA for each assay. Results: All assays discriminated between the negative sample and samples taken directly from the islet transplant bag; 2 of 3 discriminated negative samples from those taken immediately after islet infusion. When high levels of unmethylated insulin DNA were present, technical reproducibility was generally good for all assays. Conclusions: The measurement of beta cell cell-free DNA, including insulin, is a promising approach, warranting further testing and development in those with or at-risk for type 1 diabetes, as well as in other settings where understanding the frequency or kinetics of beta cell death could be useful.en-USAttribution-NonCommercial 4.0 InternationalBeta cellCell-free DNAIslet transplantationType 1 diabetesArticle