Combined Analysis of GAD65, miR-375, and Unmethylated Insulin DNA Following Islet Transplantation in Patients With T1D

Sarah Roels, Olivier R. Costa, Sarah A. Tersey, Geert Stangé, Dieter De Smet, Eric V. Balti, Pieter Gillard, Bart Keymeulen, Zhidong Ling, Daniel G. Pipeleers, Frans K. Gorus, Raghu Mirmira, Geert A. Martens

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)451-460
Number of pages10
JournalThe Journal of clinical endocrinology and metabolism
Volume104
Issue number2
DOIs
StatePublished - Feb 1 2019

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Islets of Langerhans Transplantation
Grafts
Insulin
Transplants
DNA
Biomarkers
Biopsy
Cell death
ROC Curve
Autoantibodies
Area Under Curve
Cell Death
Cell Count
Transplantation
Plasmas
Kinetics
Liquids

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Combined Analysis of GAD65, miR-375, and Unmethylated Insulin DNA Following Islet Transplantation in Patients With T1D. / Roels, Sarah; Costa, Olivier R.; Tersey, Sarah A.; Stangé, Geert; De Smet, Dieter; Balti, Eric V.; Gillard, Pieter; Keymeulen, Bart; Ling, Zhidong; Pipeleers, Daniel G.; Gorus, Frans K.; Mirmira, Raghu; Martens, Geert A.

In: The Journal of clinical endocrinology and metabolism, Vol. 104, No. 2, 01.02.2019, p. 451-460.

Research output: Contribution to journalArticle

Roels, S, Costa, OR, Tersey, SA, Stangé, G, De Smet, D, Balti, EV, Gillard, P, Keymeulen, B, Ling, Z, Pipeleers, DG, Gorus, FK, Mirmira, R & Martens, GA 2019, 'Combined Analysis of GAD65, miR-375, and Unmethylated Insulin DNA Following Islet Transplantation in Patients With T1D', The Journal of clinical endocrinology and metabolism, vol. 104, no. 2, pp. 451-460. https://doi.org/10.1210/jc.2017-02520
Roels, Sarah ; Costa, Olivier R. ; Tersey, Sarah A. ; Stangé, Geert ; De Smet, Dieter ; Balti, Eric V. ; Gillard, Pieter ; Keymeulen, Bart ; Ling, Zhidong ; Pipeleers, Daniel G. ; Gorus, Frans K. ; Mirmira, Raghu ; Martens, Geert A. / Combined Analysis of GAD65, miR-375, and Unmethylated Insulin DNA Following Islet Transplantation in Patients With T1D. In: The Journal of clinical endocrinology and metabolism. 2019 ; Vol. 104, No. 2. pp. 451-460.
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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.",
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T1 - Combined Analysis of GAD65, miR-375, and Unmethylated Insulin DNA Following Islet Transplantation in Patients With T1D

AU - Roels, Sarah

AU - Costa, Olivier R.

AU - Tersey, Sarah A.

AU - Stangé, Geert

AU - De Smet, Dieter

AU - Balti, Eric V.

AU - Gillard, Pieter

AU - Keymeulen, Bart

AU - Ling, Zhidong

AU - Pipeleers, Daniel G.

AU - Gorus, Frans K.

AU - Mirmira, Raghu

AU - Martens, Geert A.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

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