Katelijn Decochez

Screening for insulinoma antigen 2 and zinc transporter 8 autoantibodies: a cost‐effective and age‐independent strategy to identify rapid progressors to clinical onset among relatives of type 1 diabetic patients

In first‐degree relatives of type 1 diabetic patients, we investigated whether diabetes risk assessment solely based on insulinoma antigen 2 (IA‐2) and zinc transporter 8 (ZnT8) antibody status (IA‐2A, respectively, ZnT8A) is as effective as screening for three or four autoantibodies [antibodies against insulin (IAA), glutamate decarboxylase 65 kDa (GAD) glutamate decarboxylase autoantibodies (GADA) and IA‐2A with or without ZnT8A] in identifying children, adolescents and adults who progress rapidly to diabetes (within 5 years). Antibodies were determined by radiobinding assays during follow‐up of 6444 siblings and offspring aged 0–39 years at inclusion and recruited consecutively by the Belgian Diabetes Registry. We identified 394 persistently IAA+, GADA+, IA‐2A+ and/or ZnT8A+ relatives (6·1%). After a median follow‐up time of 52 months, 132 relatives developed type 1 diabetes. In each age category tested (0–9, 10–19 and 20–39 years) progression to diabetes was significantly quicker in the presence of IA‐2A and/or ZnT8A than in their joint absence (P < 0·001). Progression rate was age‐independent in IA‐2A+ and/or ZnT8A+ relatives but decreased with age if only GADA and/or IAA were present (P = 0·008). In the age group mainly considered for immune interventions until now (10–39 years), screening for IA‐2A and ZnT8A alone identified 78% of the rapid progressors (versus 75% if positive for ≥ 2 antibodies among IAA, GADA, IA‐2A and ZnT8A or versus 62% without testing for ZnT8A). Screening for IA‐2A and ZnT8A alone allows identification of the majority of rapidly progressing prediabetic siblings and offspring regardless of age and is more cost‐effective to select participants for intervention trials than conventional screening.

A Dual PPAR α/γ Agonist Increases Adiponectin and Improves Plasma Lipid Profiles in Healthy Subjects

AbstractBackground: The objective of these studies was to evaluate the pharmacokinetics and pharmacodynamics of MK-0767, a prototypical dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist, following administration of single and multiple oral doses in healthy male subjects. Methods: The first study was a double-blind, randomised, placebo-controlled, alternating two-panel, rising dose protocol in which single doses of l–80mg of MK-0767 were administered. The second study was a double-blind, randomised, placebo-controlled, staggered incremental dose, parallel-group protocol in which multiple doses of 0.3–25mg of MK-0767 were administered once daily for 14 days. In both studies at each dose level, six subjects received MK-0767 and two subjects received placebo. Results: Plasma area under the concentration-time curve and maximum plasma concentration increased with single and multiple doses of MK-0767 over the dose ranges studied. The apparent terminal half-life of MK-0767 averaged ≈36 hours following single and multiple doses. Steady-state plasma concentrations were achieved following ≈8 days of multiple doses. Compared with placebo, MK-0767 produced dose-dependent reductions in triglycerides (−26 ± 8% [p = 0.002] and −33 ± 13% [p = 0.008]) and free fatty acids (−50 ± 11% [p < 0.001] and −67 ± 23% [p = 0.008]) following single and multiple doses, respectively. Significant (p < 0.050) dose-dependent alterations in adiponectin (332 ± 36%), low-density lipoprotein cholesterol (−29 ± 5%), total cholesterol (−19 ± 3%), non-high-density lipoprotein cholesterol (−28 ± 4%), and fasting plasma glucose (−6 ± 2%; only in the 25mg group) were observed after multiple doses. Conclusions: The observed effects of MK-0767 on adiponectin, free fatty acids and lipids, even after single doses, demonstrate that this prototypical dual PPAR α/γ agonist has clinically meaningful activity in vivo.

Identification of prediabetes in first-degree relatives at intermediate risk of type I diabetes

Prevention trials of type I diabetes are limited by recruitment of individuals at high risk of the disease. We investigated whether demographic and biological characteristics can identify rapid progressors among first‐degree relatives of known patients at intermediate (< 10%) 5‐year risk. Diabetes‐associated antibodies, random proinsulin : C‐peptide (PI/C) ratio and HLA DQ genotype were determined (repeatedly) in 258 islet antibody‐positive IA‐2Antibody‐negative (Abpos/IA‐2Aneg) normoglycaemic first‐degree relatives. During follow‐up (median 81 months), 14 of 258 Abpos/IA‐2Aneg relatives developed type I diabetes; 13 (93%) of them had persistent antibodies conferring a 12% [95% confidence interval (CI): 5–19%] 5‐year risk of diabetes. In Abpos/IA‐2Aneg relatives with persistent antibodies (n = 126), the presence of ≥ 1 HLA DQ susceptibility haplotype in the absence of a protective haplotype (P = 0·033) and appearance on follow‐up of a high PI/C ratio (P = 0·007) or IA‐2A‐positivity (P = 0·009) were identified as independent predictors of diabetes. In persistently antibody‐positive relatives with HLA DQ risk a recurrently high PI/C ratio or development of IA‐2A identified a subgroup (n = 32) comprising 10 of 13 (77%) prediabetic relatives and conferred a 35% (95% CI: 18–53%) 5‐year risk. Under age 15 years, 5‐year progression (95% CI) was 57% (30–84%) and sensitivity 62%. In the absence of IA‐2A, the combination of antibody persistence, HLA DQ risk and elevated PI/C ratio or later development of IA‐2A and young age defines a subgroup of relatives with a high risk of type I diabetes (≥ 35% in 5 years). Together with initially IA‐2A‐positive relatives these individuals qualify for standardized beta cell function tests in view of prevention trials.

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. PARTICIPANTS Persistently autoAb(+) first-degree relatives of patients with T1D (n = 81; age 5-39 years). MAIN OUTCOME MEASURES We assessed 3-year predictive ability of OGTT- and clamp-derived markers using receiver operating characteristics (ROC) and Cox regression analysis. Area under the curve of clamp-derived first-phase C-peptide release (AUC(5-10 min); min 5-10) was determined in all relatives and second-phase release (AUC(120-150 min); min 120-150) in those aged 12-39 years (n = 62). RESULTS Overall, the predictive ability of AUC(5-10 min) was better than that of peak C-peptide, the best predictor among OGTT-derived parameters (ROC-AUC [95%CI]: 0.89 [0.80-0.98] vs 0.81 [0.70-0.93]). Fasting blood glucose (FBG) and AUC(5-10 min) provided the best combination of markers for prediction of diabetes within 3 years; (ROC-AUC [95%CI]: 0.92 [0.84-1.00]). In multivariate Cox regression analysis, AUC(5-10 min)) (P = .001) was the strongest independent predictor and interacted significantly with all tested OGTT-derived parameters. AUC(5-10 min) below percentile 10 of controls was associated with 50-70% progression to T1D regardless of age. Similar results were obtained for AUC(120-150 min). CONCLUSIONS Clamp-derived first-phase C-peptide release can be used as an efficient and simple screening strategy in persistently autoAb(+) offspring and siblings of T1D patients to predict impending diabetes.