Browsing by Author "Ylescupidez, Alyssa"

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    Circulating Unmethylated Insulin DNA As a Biomarker of Human Beta Cell Death: A Multi-laboratory Assay Comparison
    (Endocrine Society, 2020-03-01) Speake, Cate; Ylescupidez, Alyssa; Neiman, Daniel; Shemer, Ruth; Glaser, Benjamin; Tersey, Sarah A.; Usmani-Brown, Sahar; Clark, Pamela; Wilhelm, Joshua J.; Bellin, Melena D.; Herold, Kevan C.; Mirmira, Raghavendra G.; Dor, Yuval; Evans-Molina, Carmella; Pediatrics, School of Medicine
    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.
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    High residual C-peptide likely contributes to glycemic control in type 1 diabetes
    (American Society for Clinical Investigation, 2020-01-02) Rickels, Michael R.; Evans-Molina, Carmella; Bahnson, Henry T.; Ylescupidez, Alyssa; Nadeau, Kristen J.; Hao, Wei; Clements, Mark A.; Sherr, Jennifer L.; Pratley, Richard E.; Hannon, Tamara S.; Shah, Viral N.; Miller, Kellee M.; Greenbaum, Carla J.; Medicine, School of Medicine
    BACKGROUND Residual C-peptide is detected in many people for years following the diagnosis of type 1 diabetes; however, the physiologic significance of low levels of detectable C-peptide is not known. METHODS We studied 63 adults with type 1 diabetes classified by peak mixed-meal tolerance test (MMTT) C-peptide as negative (<0.007 pmol/mL; n = 15), low (0.017–0.200; n = 16), intermediate (>0.200–0.400; n = 15), or high (>0.400; n = 17). We compared the groups’ glycemia from continuous glucose monitoring (CGM), β cell secretory responses from a glucose-potentiated arginine (GPA) test, insulin sensitivity from a hyperinsulinemic-euglycemic (EU) clamp, and glucose counterregulatory responses from a subsequent hypoglycemic (HYPO) clamp. RESULTS Low and intermediate MMTT C-peptide groups did not exhibit β cell secretory responses to hyperglycemia, whereas the high C-peptide group showed increases in both C-peptide and proinsulin (P ≤ 0.01). All groups with detectable MMTT C-peptide demonstrated acute C-peptide and proinsulin responses to arginine that were positively correlated with peak MMTT C-peptide (P < 0.0001 for both analytes). During the EU-HYPO clamp, C-peptide levels were proportionately suppressed in the low, intermediate, and high C-peptide compared with the negative group (P ≤ 0.0001), whereas glucagon increased from EU to HYPO only in the high C-peptide group compared with negative (P = 0.01). CGM demonstrated lower mean glucose and more time in range for the high C-peptide group. CONCLUSION These results indicate that in adults with type 1 diabetes, β cell responsiveness to hyperglycemia and α cell responsiveness to hypoglycemia are observed only at high levels of residual C-peptide that likely contribute to glycemic control. FUNDING Funding for this work was provided by the Leona M. and Harry B. Helmsley Charitable Trust, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases.