Sarah Roels1, Olivier R Costa1,2, Sarah A Tersey3, Geert Stangé1, Dieter De Smet4, Eric V Balti1, Pieter Gillard5, Bart Keymeulen1,2, Zhidong Ling1,2, Daniel G Pipeleers1, Frans K Gorus1, Raghavendra G Mirmira3,6, Geert A Martens1,4. 1. Diabetes Research Center, Brussels Free University, Brussels, Belgium. 2. Department of Clinical Biology, University Hospital Brussels (UZ Brussel), Brussels, Belgium. 3. Department of Pediatrics, IU Center for Diabetes and Metabolic Disease, Indiana University School of Medicine, Indianapolis, Indiana. 4. Department of Laboratory Medicine, AZ Delta, Roeselare, Belgium. 5. Department of Endocrinology, University Hospitals Leuven - Katholieke Universiteit Leuven, Leuven, Belgium. 6. Departments of Biochemistry and Molecular Biology, Medicine, and Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana.
Abstract
Aim: Several biomarkers have been proposed to detect pancreatic β cell destruction in vivo but so far have not been compared for sensitivity and significance. Methods: We used islet transplantation as a model to compare plasma concentrations of miR-375, 65-kDa subunit of glutamate decarboxylase (GAD65), and unmethylated insulin DNA, measured at subpicomolar sensitivity, and study their discharge kinetics, power for outcome prediction, and detection of graft loss during follow-up. Results: At 60 minutes after transplantation, GAD65 and miR-375 consistently showed near-equimolar and correlated increases proportional to the number of implanted β cells. GAD65 and miR-375 showed comparable power to predict poor graft outcome at 2 months, with areas under the curve of 0.833 and 0.771, respectively (P = 0.53). Using receiver operating characteristic analysis, we defined likelihood ratios (LRs) for rationally selected result intervals. In GADA-negative recipients (n = 28), GAD65 <4.5 pmol/L (LR = 0.15) and >12.2 pmol/L (LR = ∞) predicted good and poor outcomes, respectively. miR-375 could be used in all recipients irrespective of GAD65 autoantibody status (n = 46), with levels <1.4 pmol/L (LR = 0.14) or >7.6 pmol/L (LR = 9.53) as dual thresholds. The posttransplant surge of unmethylated insulin DNA was inconsistent and unrelated to outcome. Combined measurement of these three biomarkers was also tested as liquid biopsy for β cell death during 2-month follow-up; incidental surges of GAD65, miR-375, and (un)methylated insulin DNA, alone or combined, were confidently detected but could not be related to outcome. Conclusions: GAD65 and miR-375 performed equally well in quantifying early graft destruction and predicting graft outcome, outperforming unmethylated insulin DNA.
Aim: Several biomarkers have been proposed to detect pancreatic β cell destruction in vivo but so far have not been compared for sensitivity and significance. Methods: We used islet transplantation as a model to compare plasma concentrations of miR-375, 65-kDa subunit of glutamate decarboxylase (GAD65), and unmethylated insulin DNA, measured at subpicomolar sensitivity, and study their discharge kinetics, power for outcome prediction, and detection of graft loss during follow-up. Results: At 60 minutes after transplantation, GAD65 and miR-375 consistently showed near-equimolar and correlated increases proportional to the number of implanted β cells. GAD65 and miR-375 showed comparable power to predict poor graft outcome at 2 months, with areas under the curve of 0.833 and 0.771, respectively (P = 0.53). Using receiver operating characteristic analysis, we defined likelihood ratios (LRs) for rationally selected result intervals. In GADA-negative recipients (n = 28), GAD65 <4.5 pmol/L (LR = 0.15) and >12.2 pmol/L (LR = ∞) predicted good and poor outcomes, respectively. miR-375 could be used in all recipients irrespective of GAD65 autoantibody status (n = 46), with levels <1.4 pmol/L (LR = 0.14) or >7.6 pmol/L (LR = 9.53) as dual thresholds. The posttransplant surge of unmethylated insulin DNA was inconsistent and unrelated to outcome. Combined measurement of these three biomarkers was also tested as liquid biopsy for β cell death during 2-month follow-up; incidental surges of GAD65, miR-375, and (un)methylated insulin DNA, alone or combined, were confidently detected but could not be related to outcome. Conclusions: GAD65 and miR-375 performed equally well in quantifying early graft destruction and predicting graft outcome, outperforming unmethylated insulin DNA.
Authors: Kevan C Herold; Sahar Usmani-Brown; Tara Ghazi; Jasmin Lebastchi; Craig A Beam; Melena D Bellin; Michel Ledizet; Jay M Sosenko; Jeffrey P Krischer; Jerry P Palmer Journal: J Clin Invest Date: 2015-02-02 Impact factor: 14.808
Authors: Matthew N Poy; Lena Eliasson; Jan Krutzfeldt; Satoru Kuwajima; Xiaosong Ma; Patrick E Macdonald; Sébastien Pfeffer; Thomas Tuschl; Nikolaus Rajewsky; Patrik Rorsman; Markus Stoffel Journal: Nature Date: 2004-11-11 Impact factor: 49.962
Authors: Pablo Landgraf; Mirabela Rusu; Robert Sheridan; Alain Sewer; Nicola Iovino; Alexei Aravin; Sébastien Pfeffer; Amanda Rice; Alice O Kamphorst; Markus Landthaler; Carolina Lin; Nicholas D Socci; Leandro Hermida; Valerio Fulci; Sabina Chiaretti; Robin Foà; Julia Schliwka; Uta Fuchs; Astrid Novosel; Roman-Ulrich Müller; Bernhard Schermer; Ute Bissels; Jason Inman; Quang Phan; Minchen Chien; David B Weir; Ruchi Choksi; Gabriella De Vita; Daniela Frezzetti; Hans-Ingo Trompeter; Veit Hornung; Grace Teng; Gunther Hartmann; Miklos Palkovits; Roberto Di Lauro; Peter Wernet; Giuseppe Macino; Charles E Rogler; James W Nagle; Jingyue Ju; F Nina Papavasiliou; Thomas Benzing; Peter Lichter; Wayne Tam; Michael J Brownstein; Andreas Bosio; Arndt Borkhardt; James J Russo; Chris Sander; Mihaela Zavolan; Thomas Tuschl Journal: Cell Date: 2007-06-29 Impact factor: 41.582
Authors: Lei Jiang; Benedicte Brackeva; Zhidong Ling; Gertjan Kramer; Johannes M Aerts; Frans Schuit; Bart Keymeulen; Daniel Pipeleers; Frans Gorus; Geert A Martens Journal: Diabetes Date: 2013-04-04 Impact factor: 9.461
Authors: Marisa M Fisher; Renecia A Watkins; Janice Blum; Carmella Evans-Molina; Naga Chalasani; Linda A DiMeglio; Kieren J Mather; Sarah A Tersey; Raghavendra G Mirmira Journal: Diabetes Date: 2015-07-27 Impact factor: 9.461
Authors: Oscar Alcazar; Luis F Hernandez; Ernesto S Nakayasu; Paul D Piehowski; Charles Ansong; Midhat H Abdulreda; Peter Buchwald Journal: J Proteomics Date: 2020-05-20 Impact factor: 4.044
Authors: Piotr J Bachul; Karolina Golab; Lindsay Basto; Steven Zangan; Jordan S Pyda; Angelica Perez-Gutierrez; Peter Borek; Ling-Jia Wang; Martin Tibudan; Dong-Kha Tran; Roi Anteby; Gabriela S Generette; Jędrzej Chrzanowski; Wojciech Fendler; Laurencia Perea; Kumar Jayant; Aaron Lucander; Celeste Thomas; Louis Philipson; J Michael Millis; John Fung; Piotr Witkowski Journal: Cell Transplant Date: 2021 Jan-Dec Impact factor: 4.064
Authors: Marilyn Arosemena; Farah A Meah; Kieren J Mather; Sarah A Tersey; Raghavendra G Mirmira Journal: Int J Mol Sci Date: 2021-02-21 Impact factor: 5.923