Deficiency of immunoregulatory indoleamine 2,3-dioxygenase 1 in juvenile diabetes

A defect in indoleamine 2,3-dioxygenase 1 (IDO1), which is responsible for immunoregulatory tryptophan catabolism, impairs development of immune tolerance to autoantigens in NOD mice, a model for human autoimmune type 1 diabetes (T1D). Whether IDO1 function is also defective in T1D is still unknown. We investigated IDO1 function in sera and peripheral blood mononuclear cells (PBMCs) from children with T1D and matched controls. These children were further included in a discovery study to identify SNPs in IDO1 that might modify the risk of T1D. T1D in children was characterized by a remarkable defect in IDO1 function. A common haplotype, associated with dysfunctional IDO1, increased the risk of developing T1D in the discovery and also confirmation studies. In T1D patients sharing such a common IDO1 haplotype, incubation of PBMCs in vitro with tocilizumab (TCZ) - an IL-6 receptor blocker - would, however, rescue IDO1 activity. In an experimental setting with diabetic NOD mice, TCZ was found to restore normoglycemia via IDO1-dependent mechanisms. Thus, functional SNPs of IDO1 are associated with defective tryptophan catabolism in human T1D, and maneuvers aimed at restoring IDO1 function would be therapeutically effective in at least a subgroup of T1D pediatric patients.The authors wish to thank patients and subjects who participated in this study, as well as nurses and staff of the Pediatric Clinic of S. Maria della Misericordia Hospital (Perugia), Juvenile Diabetes Center-Anna Meyer Children's Hospital (Florence), Unit of Endocrinology and Diabetes-'Bambino Gesu' Children's Hospital (Rome), Hopital Necker-Enfants Malades (Paris), and Diabetes and Metabolism Service-University Hospital Centre of Coimbra (Coimbra). The authors wish also to thank Roberto Gerli for the gift of TCZ, Giovanni Ricci for histologies, and Francisco Carrilho and Eduarda Coutinho for providing and processing, respectively, DNA samples from the Portuguese cohorts. This work was supported by the European Research Council (338954-DIDO to UG) and, in part, by Associazione per l'Aiuto ai Giovani con Diabete Italia e dell'Umbria (to UG) and the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013 to AC) and the Fundacao para a Ciencia e Tecnologia (contracts IF/00735/2014 to AC, and SFRH/BPD/96176/2013 to CC).info:eu-repo/semantics/publishedVersio

Growth Trajectory in Children with Type 1 Diabetes Mellitus: The Impact of Insulin Treatment and Metabolic Control

Background: Linear growth was reported to be negatively affected by type 1 diabetes mellitus (T1DM), in relation to disease duration and poor metabolic control. It is unclear whether a subtle growth failure still persists despite the optimization of therapy. Our aim was to analyse pubertal growth, adult height, and metabolic profile in a cohort of children with T1DM undergoing intensive insulin treatment by multiple daily injections or continuous subcutaneous insulin infusion (CSII). Methods: One-hundred and four children (51 males) with prepubertal onset of T1DM were prospectively followed up to final height attainment. Results: Age at puberty onset was 11.7 ± 1.1 years in males and 10.9 ± 1.3 in females. Age at adult height attainment was 16.4 ± 1.6 years in males and 14.1 ± 1.8 years in females. Pubertal height gain was 24.4 ± 4.9 cm in males and 19.0 ± 3.8 cm in females. HbA1c, HDL cholesterol, and triglyceride levels increased during puberty. HDL cholesterol levels were higher in patients treated with CSII. Height standard deviation score (SDS) at diagnosis (0.52 ± 1.04) was higher than target height SDS (0.01 ± 1.07), but declined afterwards, and both height SDS at puberty onset (0.22 ± 1.1) and adult height SDS (-0.1 ± 1.02) were not significantly different from target height SDS. BMI SDS showed a positive trend from diagnosis to puberty onset and stabilized later (-0.04 ± 1.4 at T1DM onset, 0.55 ± 2.1 at puberty onset, and 0.53 ± 2.1 at adult height attainment). Conclusions: Although subtle abnormalities of growth still persist, the modern advancements of insulin therapy are able to normalize puberty and final height of children with T1DM