TY - JOUR
T1 - Circulating Unmethylated Insulin DNA As a Biomarker of Human Beta Cell Death
T2 - A Multi-laboratory Assay Comparison
AU - Speake, Cate
AU - Ylescupidez, Alyssa
AU - Neiman, Daniel
AU - Shemer, Ruth
AU - Glaser, Benjamin
AU - Tersey, Sarah A.
AU - Usmani-Brown, Sahar
AU - Clark, Pamela
AU - Wilhelm, Joshua J.
AU - Bellin, Melena D.
AU - Herold, Kevan C.
AU - Mirmira, Raghavendra G.
AU - Dor, Yuval
AU - Evans-Molina, Carmella
N1 - Publisher Copyright:
© 2020 Endocrine Society 2020.
PY - 2020/1/8
Y1 - 2020/1/8
N2 - Context: 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.
AB - Context: 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.
KW - Beta cell
KW - cell-free DNA
KW - islet transplantation
KW - type 1 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85079348786&partnerID=8YFLogxK
U2 - 10.1210/clinem/dgaa008
DO - 10.1210/clinem/dgaa008
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C2 - 31913467
AN - SCOPUS:85079348786
SN - 0021-972X
VL - 105
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 3
M1 - dgaa008
ER -