Baseline plasma proinsulin response to glucose for predicting therapeutic response to otelixizumab in recent-onset type 1 diabetes.

Aims: In recent-onset type 1 diabetes, clamp-derived C-peptide predicts good response to anti-CD3. Elevated proinsulin and proinsulin/C-peptide ratio (PI/CP) suggest increased metabolic/inflammatory beta cell burden. We reanalyzed trial data to compare the ability of baseline acutely glucose-stimulated proinsulin, C-peptide and PI/CP to predict functional outcome.

CTLA4, SH2B3, and CLEC16A diversely affect the progression of early islet autoimmunity in relatives of Type 1 diabetes patients.

The HLA region is the major genetic risk determinant of Type 1 diabetes. How non-HLA loci contribute to the genetic risk is incompletely understood, but there are indications that at least some impact progression of asymptomatic autoimmunity. We examined whether SNPs in 7 susceptibility loci (INS, SH2B3, PTPN2, PTPN22, CTLA4, CLEC16A, and IL2RA) could improve prediction of the progression from single to multiple autoantibody positivity, and from there on to diagnosis.

Age-period-cohort modelling of type 1 diabetes incidence rates among children included in the EURODIAB 25-year follow-up study.

Aims: Specific patterns in incidence may reveal environmental explanations for type 1 diabetes incidence. We aimed to study type 1 diabetes incidence in European childhood populations to assess whether an increase could be attributed to either period or cohort effects.

Methods: Nineteen EURODIAB centres provided single year incidence data for ages 0-14 in the 25-year period 1989-2013.

Genetic variation at ERBB3/IKZF4 and sexual dimorphism in epitope spreading in single autoantibody-positive relatives.

Aims/hypothesis: We examined whether the non-HLA susceptibility locus ERBB3/IKZF4 influences progression of type 1 diabetes stage specifically according to sex.

Methods: SNPs of ERBB3 (rs2292239 T/G) and IKZF4 (rs1701704 G/T) were screened by allelic discrimination quantitative PCR assay in first-degree relatives of type 1 diabetes patients who had developed at least one circulating autoantibody. The effect of ERBB3/IKZF4 genotypes and sex, on the progression of single autoantibody positivity to multiple autoantibody positivity and from multiple autoantibody positivity to diabetes, was studied by Kaplan-Meier analysis and multivariate Cox regression.

The MicroRNA Landscape of Acute Beta Cell Destruction in Type 1 Diabetic Recipients of Intraportal Islet Grafts.

Ongoing beta cell death in type 1 diabetes (T1D) can be detected using biomarkers selectively discharged by dying beta cells into plasma. microRNA-375 (miR-375) ranks among the top biomarkers based on studies in animal models and human islet transplantation. Our objective was to identify additional microRNAs that are co-released with miR-375 proportionate to the amount of beta cell destruction.

Insulitis in the pancreas of non-diabetic organ donors under age 25 years with multiple circulating autoantibodies against islet cell antigens.

Autoantibodies against islet cell antigens are routinely used to identify subjects at increased risk of symptomatic type 1 diabetes, but their relation to the intra-islet pathogenetic process that leads to positivity for these markers is poorly understood. We screened 556 non-diabetic organ donors (3 months to 24 years) for five different autoantibodies and found positivity in 27 subjects, 25 single- and two double autoantibody-positive donors. Histopathological screening of pancreatic tissue samples showed lesion characteristic for recent-onset type 1 diabetes in the two organ donors with a high-risk profile, due to their positivity for multiple autoantibodies and HLA-inferred risk.

A randomised, single-blind, placebo-controlled, dose-finding safety and tolerability study of the anti-CD3 monoclonal antibody otelixizumab in new-onset type 1 diabetes.

Aims/hypothesis: Numerous clinical studies have investigated the anti-CD3ɛ monoclonal antibody otelixizumab in individuals with type 1 diabetes, but limited progress has been made in identifying the optimal clinical dose with acceptable tolerability and safety. The aim of this study was to evaluate the association between dose-response, safety and tolerability, beta cell function preservation and the immunological effects of otelixizumab in new-onset type 1 diabetes.

Methods: In this randomised, single-blind, placebo-controlled, 24 month study, conducted in five centres in Belgium via the Belgian Diabetes Registry, participants (16-27 years old, <32 days from diagnosis of type 1 diabetes) were scheduled to receive placebo or otelixizumab in one of four dose cohorts (cumulative i.

A composite immune signature parallels disease progression across T1D subjects.

At diagnosis, most people with type 1 diabetes (T1D) produce measurable levels of endogenous insulin, but the rate at which insulin secretion declines is heterogeneous. To explain this heterogeneity, we sought to identify a composite signature predictive of insulin secretion, using a collaborative assay evaluation and analysis pipeline that incorporated multiple cellular and serum measures reflecting β cell health and immune system activity. The ability to predict decline in insulin secretion would be useful for patient stratification for clinical trial enrollment or therapeutic selection.

Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review.

Objective: To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs).

Design And Methods: We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy.

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.

SLC30A8 polymorphism and BMI complement HLA-A*24 as risk factors for poor graft function in islet allograft recipients.

Aims/hypothesis: HLA-A*24 carriership hampers achievement of insulin independence in islet allograft recipients. However, less than half of those who fail to achieve insulin independence carry the allele. We investigated whether genetic polymorphism at the recipients' zinc transporter 8-encoding SLC30A8 gene (rs13266634) could complement their HLA-A*24 status in predicting functional graft outcome.

Accelerated Progression to Type 1 Diabetes in the Presence of and Is Restricted to Multiple Islet Autoantibody-Positive Individuals With Distinct and Autoantibody Risk Profiles.

Objective: We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes.

Research Design And Methods: A registry-based group of siblings/offspring (aged 0-39 years) was monitored from single- to multiple-autoantibody positivity ( = 267) and from multiple-autoantibody positivity to clinical onset ( = 252) according to , , , and status. Genetic markers were determined by PCR sequence-specific oligotyping.

An analytical comparison of three immunoassay platforms for subpicomolar detection of protein biomarker GAD65.

A disproportional increase of circulating GAD65 within hours from an intraportal islet allotransplantation has been validated as biomarker of beta cell loss and poor functional outcome. More sensitive assays are, however, needed to allow detection of episodes of subtle beta cell loss during late-stage graft rejection or in the peri-onset period of type 1 diabetes. We applied the same sandwich monoclonal antibody couple reactive towards the C- and N-terminus of GAD65 on three advanced immunoassay platforms-the Cytometric Bead Array (CBA, Becton, Dickinson and Company), ElectroChemiLuminescence ImmunoAssay (ECLIA, Meso Scale Discovery) and digital ELISA technology (Single Molecule Array-SIMOA, Quanterix.

A novel LIPS assay for insulin autoantibodies.

Aims: Insulin autoantibodies (IAA) are often the first marker of autoimmunity detected in children in the preclinical phase of type 1 diabetes (T1D). Currently, the vast majority of laboratories adopt the radiobinding micro-assay (RBA) for measuring IAA. Our aim was to replace RBA with a novel non-radioactive IAA Luciferase Immuno Precipitation System (LIPS) assay with improved performance.

Twenty-Year Progression Rate to Clinical Onset According to Autoantibody Profile, Age, and Genotype in a Registry-Based Group of Children and Adults With a First-Degree Relative With Type 1 Diabetes.

Objective: We investigated whether islet autoantibody profile, genotype, and age influenced a 20-year progression to diabetes from first autoantibody positivity (autoAb) in first-degree relatives of patients with type 1 diabetes.

Research Design And Methods: Persistently islet autoAb siblings and offspring ( = 462) under 40 years of age were followed by the Belgian Diabetes Registry. AutoAbs against insulin (IAA), GAD (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A) were determined by radiobinding assay.

Correction: Prediction of Impending Type 1 Diabetes through Automated Dual-Label Measurement of Proinsulin:C-Peptide Ratio.

[This corrects the article DOI: 10.1371/journal.pone.

Prediction of Impending Type 1 Diabetes through Automated Dual-Label Measurement of Proinsulin:C-Peptide Ratio.

Background: The hyperglycemic clamp test, the gold standard of beta cell function, predicts impending type 1 diabetes in islet autoantibody-positive individuals, but the latter may benefit from less invasive function tests such as the proinsulin:C-peptide ratio (PI:C). The present study aims to optimize precision of PI:C measurements by automating a dual-label trefoil-type time-resolved fluorescence immunoassay (TT-TRFIA), and to compare its diagnostic performance for predicting type 1 diabetes with that of clamp-derived C-peptide release.

Methods: Between-day imprecision (n = 20) and split-sample analysis (n = 95) were used to compare TT-TRFIA (AutoDelfia, Perkin-Elmer) with separate methods for proinsulin (in-house TRFIA) and C-peptide (Elecsys, Roche).

Evaluation of the Sebia Capillarys 3 Tera and the Bio-Rad D-100 Systems for the Measurement of Hemoglobin A1c.

Objectives: We evaluated the Bio-Rad (Irvine, CA) D-100 and the Sebia (Lisses, France) Capillarys 3 Tera for the measurement of hemoglobin A1c (HbA1c) in venous blood samples.

Methods: Whole-blood samples and control material were analyzed with the D-100 and Capillarys 3 Tera and compared with our routine method, HLC-723G7 (Tosoh, Tokyo, Japan). An evaluation protocol to test precision, trueness, linearity, carryover, and selectivity was set up according to Clinical and Laboratory Standards Institute guidelines.

HLA-A*24 Carrier Status and Autoantibody Surges Posttransplantation Associate With Poor Functional Outcome in Recipients of an Islet Allograft.

Objective: We investigated whether changes in islet autoantibody profile and presence of HLA risk markers, reported to predict rapid β-cell loss in pre-type 1 diabetes, associate with poor functional outcome in islet allograft recipients.

Research Design And Methods: Forty-one patients received ≥2.3 million β-cells/kg body wt in one to two intraportal implantations.

Development of an Enhanced Sensitivity Bead-Based Immunoassay for Real-Time In Vivo Detection of Pancreatic β-Cell Death.

There is a clinical need for plasma tests to detect and quantify the in vivo destruction of pancreatic β-cells in type 1 diabetes. We previously developed a time-resolved fluorescence immunoassay (TRFIA) to glutamate decarboxylase 65 kDa (GAD65) (GAD65-TRFIA) that was able to detect the synchronous necrotic destruction of transplanted β-cells in the hours after their infusion in the liver. This GAD65-TRFIA, however, lacked sensitivity to detect continued β-cell rejection beyond this acute phase.

Relationship between glycaemic variability and hyperglycaemic clamp-derived functional variables in (impending) type 1 diabetes.

Aims/hypothesis: We examined whether measures of glycaemic variability (GV), assessed by continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG), can complement or replace measures of beta cell function and insulin action in detecting the progression of preclinical disease to type 1 diabetes.

Methods: Twenty-two autoantibody-positive (autoAb(+)) first-degree relatives (FDRs) of patients with type 1 diabetes who were themselves at high 5-year risk (50%) for type 1 diabetes underwent CGM, a hyperglycaemic clamp test and OGTT, and were followed for up to 31 months. Clamp variables were used to estimate beta cell function (first-phase [AUC5-10 min] and second-phase [AUC120-150 min] C-peptide release) combined with insulin resistance (glucose disposal rate; M 120-150 min).

Plasma GAD65, a Marker for Early β-Cell Loss After Intraportal Islet Cell Transplantation in Diabetic Patients.

Context And Objective: Intraportal islet transplantation can restore insulin production in type 1 diabetes patients, but its effect is subject to several interfering processes. To assess the influence of β-cell loss before and during engraftment, we searched for a real-time marker of β-cell destruction. Previous studies showed that 65-kDa isoform of glutamate decarboxylase (GAD65) is discharged by chemically damaged rat β-cells.

Potential of UCHL1 as biomarker for destruction of pancreatic beta cells.

Unlabelled: There is a clinical need for plasma tests for real-time detection of beta cell destruction, as surrogate endpoint in islet transplantation and immunoprevention trials in type 1 diabetes. This study reports on the use of label-free LC-MS/MS proteomics for bottom-up selection of candidate biomarkers. Ubiquitin COOH-terminal hydrolase 1 (UCHL1) was identified as abundant protein in rat and human beta cells, showing promising beta cell-selectivity, and was selected for further validation in standardized toxicity models.

Preexisting insulin autoantibodies predict efficacy of otelixizumab in preserving residual β-cell function in recent-onset type 1 diabetes.

Objective: Immune intervention trials in recent-onset type 1 diabetes would benefit from biomarkers associated with good therapeutic response. In the previously reported randomized placebo-controlled anti-CD3 study (otelixizumab; GlaxoSmithKline), we tested the hypothesis that specific diabetes autoantibodies might serve this purpose.

Research Design And Methods: In the included patients (n = 40 otelixizumab, n = 40 placebo), β-cell function was assessed as area under the curve (AUC) C-peptide release during a hyperglycemic glucose clamp at baseline (median duration of insulin treatment: 6 days) and every 6 months until 18 months after randomization.

Hyperglycemic clamp and oral glucose tolerance test for 3-year prediction of clinical onset in persistently autoantibody-positive offspring and siblings of type 1 diabetic patients.

Context And Objective: In preparation of future prevention trials, we aimed to identify predictors of 3-year diabetes onset among oral glucose tolerance test (OGTT)- and hyperglycemic clamp-derived metabolic markers in persistently islet autoantibody positive (autoAb(+)) offspring and siblings of patients with type 1 diabetes (T1D).

Design: The design is a registry-based study.

Setting: Functional tests were performed in a hospital setting.