Emerging Concepts and Success Stories in Type 1 Diabetes Research: A Road Map for a Bright Future.

Type 1 diabetes treatment stands at a crucial and exciting crossroad since the 2022 U.S. Food and Drug Administration approval of teplizumab to delay disease development.

Gene expression profiles in placenta and their association with anesthesia, delivery mode and maternal diabetes.

Introduction: Fetal development is dependent on placenta and affected by multiple factors including maternal diabetes. Here we aimed to identify maternal diabetes-associated changes in placentas and analyzed placental gene expression to understand its modulation by maternal diabetes and birth mode.

Methods: Placental RNAseq transcriptome analyses were performed on maternally-derived decidua and fetal-derived villous tissue from pregnancies of mothers with type 1 diabetes (n = 14), gestational diabetes (n = 6) and without diabetes (n = 14).

The novel ribosome biogenesis inhibitor usnic acid blocks nucleolar pre-60S maturation.

The formation of new ribosomes is tightly coordinated with cell growth and proliferation. In eukaryotes, the correct assembly of all ribosomal proteins and RNAs follows an intricate scheme of maturation and rearrangement steps across three cellular compartments: the nucleolus, nucleoplasm, and cytoplasm. We demonstrate that usnic acid, a lichen secondary metabolite, inhibits the maturation of the large ribosomal subunit in yeast.

Clinical Outcomes in Pediatric Patients With Type 1 Diabetes With Early Versus Late Diagnosis: Analysis From the DPV Registry.

Objective: This study was conducted to evaluate the effects of early clinical diagnosis of type 1 diabetes by comparison of clinical parameters at diagnosis and during follow-up in patients with pediatric type 1 diabetes with early, intermediate, and late diagnosis.

Research Design And Methods: In a population-based analysis, data on 14,292 pediatric patients with type 1 diabetes diagnosed between 2015 and 2019 were retrieved from the Diabetes Prospective Documentation (DPV) registry in March 2023. Patients were divided into four groups: one with diabetic ketoacidosis (DKA) at diagnosis and three with early, intermediate, or late diagnosis based on age-dependent HbA1c terciles.

Small RNA-Seq and real time rt-qPCR reveal islet miRNA released under stress conditions.

Replacement of beta cells through transplantation is a potential therapeutic approach for individuals with pancreas removal or poorly controllable type 1 diabetes. However, stress and death of beta cells pose significant challenges. Circulating miRNA has emerged as potential biomarkers reflecting early beta cell stress and death, allowing for timely intervention.

Early Appearance of Thyroid Autoimmunity in Children Followed From Birth for Type 1 Diabetes Risk.

Context: Autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) define preclinical autoimmune thyroid disease (AITD), which can progress to either clinical hypothyroidism or hyperthyroidism.

Objective: We determined the age at seroconversion in children genetically at risk for type 1 diabetes.

Methods: TPOAb and TgAb seropositivity were determined in 5066 healthy children with human leukocyte antigen (HLA) DR3- or DR4-containing haplogenotypes from The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Autoantibodies to Truncated GAD(96-585) Antigen Stratify Risk of Early Insulin Requirement in Adult-Onset Diabetes.

We investigated whether characterization of full-length GAD (f-GADA) antibody (GADA) responses could identify early insulin requirement in adult-onset diabetes. In 179 f-GADA-positive participants diagnosed with type 2 diabetes, we assessed associations of truncated GADA (t-GADA) positivity, f-GADA IgG subclasses, and f-GADA affinity with early insulin requirement (<5 years), type 1 diabetes genetic risk score (T1D GRS), and C-peptide. t-GADA positivity was lower in f-GADA-positive without early insulin in comparison with f-GADA-positive type 2 diabetes requiring insulin within 5 years, and T1D (75% vs.

Infection episodes and islet autoantibodies in children at increased risk for type 1 diabetes before and during the COVID-19 pandemic.

Objectives: To determine the impact of the COVID-19 pandemic on the incidence rates of infection and islet autoimmunity in children at risk for type 1 diabetes.

Methods: 1050 children aged 4 to 7 months with an elevated genetic risk for type 1 diabetes were recruited from Germany, Poland, Sweden, Belgium and the UK. Reported infection episodes and islet autoantibody development were monitored until age 40 months from February 2018 to February 2023.

The Influence of Pubertal Development on Autoantibody Appearance and Progression to Type 1 Diabetes in the TEDDY Study.

Context: The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty.

Objective: We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes.

Methods: The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Improved Specificity of Glutamate Decarboxylase 65 Autoantibody Measurement Using Luciferase-Based Immunoprecipitation System Assays.

Autoantibodies to glutamate decarboxylase (GADA) are widely used in the prediction and classification of type 1 diabetes. GADA radiobinding assays (RBAs) using N-terminally truncated antigens offer improved specificity, but radioisotopes limit the high-throughput potential for population screening. Luciferase-based immunoprecipitation system (LIPS) assays are sensitive and specific alternatives to RBAs with the potential to improve risk stratification.

Vitamin D insufficiency in infants with increased risk of developing type 1 diabetes: a secondary analysis of the POInT Study.

Background: Vitamin D insufficiency (VDI) may be a factor in the development of type 1 diabetes (T1D). The aim of this study is to investigate the presence and persistence of VDI in a large cohort of infants with increased risk of developing T1D, in light of the differences in local supplementation guidelines.

Methods: In the POInT Study, a multicentre primary prevention study between February 2018 and March 2021 in Germany, Poland, Belgium, England and Sweden, including infants aged 4-7 months at high genetic risk of developing β-cell autoantibodies, vitamin D levels were analysed at each study visit from inclusion (4-7 months) until 3 years, with an interval of 2 months (first three visits) or 4-6 months (visits 4-8).

Proinflammatory pattern in the lower airways of non-asthmatic obese adolescents.

Background: Obesity is known to be a pro-inflammatory condition affecting multiple organs. Obesity as a systemic pro-inflammatory state, might be associated with bronchial inflammation in non-smoking adolescents with a BMI ≥ 30 kg/m without evidence of concomitant chronic diseases.

Materials And Methods: We studied non-asthmatic obese patients (n = 20; median age 15.

Clean air in Europe for all! Taking stock of the proposed revision to the ambient air quality directives: a joint ERS, HEI and ISEE workshop report.

Ambient air pollution is a major public health concern and comprehensive new legislation is currently being considered to improve air quality in Europe. The European Respiratory Society (ERS), Health Effects Institute (HEI), and International Society for Environmental Epidemiology (ISEE) organised a joint meeting on May 24, 2023 in Brussels, Belgium, to review and critically evaluate the latest evidence on the health effects of air pollution and discuss ongoing revisions of the European Ambient Air Quality Directives (AAQDs). A multi-disciplinary expert group of air pollution and health researchers, patient and medical societies, and policy representatives participated.

Characterisation and clinical outcomes in children and adolescents with diabetes according to newly defined subgroups: a cohort study from the DPV registry.

Background: Personalised therapy has emerged as a possibly more efficient approach taking disease heterogeneity into account. The aim of this study was to determine whether recently described subgroups of childhood diabetes have prognostic association with diabetes-specific complications and, therefore, might be a basis for personalised therapies.

Methods: We applied a previously developed subgroup classification to pediatric patients (diabetes onset <18 years) from the prospective Diabetes Patient Follow-up (DPV) registry with documented data between January 1, 2000 and March 31, 2022, from diabetes centers in Germany, Austria, Switzerland, and Luxembourg.

SARS-CoV-2 Infection and Development of Islet Autoimmunity in Early Childhood.

Importance: The incidence of diabetes in childhood has increased during the COVID-19 pandemic. Elucidating whether SARS-CoV-2 infection is associated with islet autoimmunity, which precedes type 1 diabetes onset, is relevant to disease etiology and future childhood diabetes trends.

Objective: To determine whether there is a temporal relationship between SARS-CoV-2 infection and the development of islet autoimmunity in early childhood.

The countdown to type 1 diabetes: when, how and why does the clock start?

'The clock to type 1 diabetes has started when islet antibodies are first detected', commented George Eisenbarth with regard to the pathogenesis of type 1 diabetes. This review focuses on 'starting the clock', i.e.

Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.

Objective: Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses.

Research Design And Methods: We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months.

Methylglyoxal products in pre-symptomatic type 1 diabetes.

Introduction: Progression to type 1 diabetes has emerged as a complex process with metabolic alterations proposed to be a significant driver of disease. Monitoring products of altered metabolism is a promising tool for determining the risk of type 1 diabetes progression and to supplement existing predictive biomarkers. Methylglyoxal (MG) is a reactive product produced from protein, lipid, and sugar metabolism, providing a more comprehensive measure of metabolic changes compared to hyperglycemia alone.

Single-copy locus proteomics of early- and late-firing DNA replication origins identifies a role of Ask1/DASH complex in replication timing control.

The chromatin environment at origins of replication is thought to influence DNA replication initiation in eukaryotic genomes. However, it remains unclear how and which chromatin features control the firing of early-efficient (EE) or late-inefficient (LI) origins. Here, we use site-specific recombination and single-locus chromatin isolation to purify EE and LI replication origins in Saccharomyces cerevisiae.

X-linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL.

Acute lymphoblastic leukemia (ALL) represents the most frequent malignancy in children, and relapse/refractory (r/r) disease is difficult to treat, both in children and adults. In search for novel treatment options against r/r ALL, we studied inhibitor of apoptosis proteins (IAP) and Smac mimetics (SM). SM-sensitized r/r ALL cells towards conventional chemotherapy, even upon resistance against SM alone.

A Dynamic rRNA Ribomethylome Drives Stemness in Acute Myeloid Leukemia.

Unlabelled: The development and regulation of malignant self-renewal remain unresolved issues. Here, we provide biochemical, genetic, and functional evidence that dynamics in ribosomal RNA (rRNA) 2'-O-methylation regulate leukemia stem cell (LSC) activity in vivo. A comprehensive analysis of the rRNA 2'-O-methylation landscape of 94 patients with acute myeloid leukemia (AML) revealed dynamic 2'-O-methylation specifically at exterior sites of ribosomes.

Elevations in blood glucose before and after the appearance of islet autoantibodies in children.

The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic β cells and promote β cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic β cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes.

Evolving polarisation of infiltrating and alveolar macrophages in the lung during metastatic progression of melanoma suggests CCR1 as a therapeutic target.

Metastatic tumour progression is facilitated by tumour associated macrophages (TAMs) that enforce pro-tumour mechanisms and suppress immunity. In pulmonary metastases, it is unclear whether TAMs comprise tissue resident or infiltrating, recruited macrophages; and the different expression patterns of these TAMs are not well established. Using the mouse melanoma B16F10 model of experimental pulmonary metastasis, we show that infiltrating macrophages (IM) change their gene expression from an early pro-inflammatory to a later tumour promoting profile as the lesions grow.