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J Clin Endocrinol Metab. 2020 Mar 1;105(3). pii: dgaa008. doi: 10.1210/clinem/dgaa008.

Circulating Unmethylated Insulin DNA As a Biomarker of Human Beta Cell Death: A Multi-laboratory Assay Comparison.

Author information

1
Diabetes Clinical Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, US.
2
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
3
Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
4
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, US.
5
Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, US.
6
L2 Diagnostics, New Haven, CT, US.
7
Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT, US.
8
Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, US.
9
Departments of Pediatrics and Surgery, University of Minnesota, Minneapolis, MN, US.
10
The Richard L. Roudebush VA Medical Center, Indianapolis, IN, US.

Abstract

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.

KEYWORDS:

Beta cell; cell-free DNA; islet transplantation; type 1 diabetes

PMID:
31913467
PMCID:
PMC7015459
[Available on 2021-01-08]
DOI:
10.1210/clinem/dgaa008

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