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

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 12.2 pmol/L (LR = z) predicted good and poor outcomes, respectively. miR-375 could be used in all recipients irrespective of GAD65 autoantibody status (n = 46), with levels 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.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice

Disclosures: VC, MES, DS, and MJM are employees of HiberCell, Inc. SAT, RGM, and HiberCell have filed a provisional patent on compounds to inhibit PERK in type 1 diabetes. SAT and RGM received an investigator-initiated award from HiberCell, Inc. for use of PERK inhibitors in this study. KAS is a consultant for and has received research support from HiberCell, Inc. SAO is a co-founder, equity holder, and consultant for OptiKIRA, LLC.SCOPUS: ar.jinfo:eu-repo/semantics/publishe