Search Results (53)

Type 1 diabetes (T1D) is an autoimmune disease characterized by β-cell destruction as a common trait, in which variability in age at onset, progression rate, and clinical presentation shape heterogeneous phenotypes. Disentangling this heterogeneity is pivotal for a better understanding of clinical risk, evolution and a precision medicine approach to the disease. In this context, circulating islet autoantibodies, including the last discovered Zinc Transporter 8 autoantibodies (ZnT8A), represent crucial tools. This narrative review provides an overview of the current knowledge on ZnT8A in autoimmune diabetes from its structural and pathogenetic basis to its clinical relevance and therapeutic perspectives. A literature search was conducted in PubMed, Scopus, Google Scholar, and ResearchGate up to March 2026, that included preclinical, pediatric, adult, and assay-comparison studies. While the identification of ZnT8-targeted antigenic determinants is still ongoing, we discuss the pathogenic role of a newly identified specific class of antibodies directed against extracellular ZnT8 epitopes (ZnT8ecA). According to this finding, ZnT8ecA could facilitate the identification of an early phase of islet injury process, holding promise to provide a framework for new therapeutic strategies based on masking or modulating surface-exposed ZnT8 epitopes and interfering with the early stages of the disease. Moving from the role of ZnT8A in various clinical settings, we also focus on recent advancements in detection technologies, whose implementation accounts for invaluable contributions to diagnosis, disease risk, and, contextually, to a better understanding of autoimmune diabetes. Finally, we provide future perspectives, in T1D and T1-related diseases, for the potential clinical application of ZnT8A in early diagnosis, risk stratification and profiling, as well as in the development of targeted therapies as part of precision medicine. Full article

This review aims to present an updated, comprehensive analysis of data on the diversity and challenges of current approaches to the screening and monitoring of subjects at risk of T1D, as the earliest interventions during the course of the disease. Previously, screening for T1D was justified only for research purposes. A major turning point occurred when teplizumab, an immunomodulatory drug that delays the onset of overt T1D, was approved. Nowadays, there is a growing number of screening initiatives, and this trend is spreading fast across the world. In this context, novel recommendations emphasize the need for the wider identification of subjects at risk of T1D, suggesting that screening should not include only first-degree relatives of persons with T1D. Furthermore, current experts’ opinions have shifted the detection of T1D risk in the direction of ultimate goal-screening in the general population. Also, subjects at risk should be monitored, undergo metabolic testing, be informed about their risk, and be educated about the disease. Currently, there is a diversity in approaches to the screening and monitoring of subjects at risk of T1D, predominantly in the pediatric population. Several knowledge gaps persist in this area of investigation, especially in recommendations and potential benefits for the adult population. However, the scientific community is focusing on developing and adapting screening and monitoring strategies to suit particular countries, aiming to make them more universal while refining the definition of individual risk for T1D. Nevertheless, the screening and monitoring of subjects at risk should be the earliest interventions focused on delaying T1D. Full article

Objective: Current knowledge surrounding the diagnosis and mechanisms that result in immune checkpoint inhibitor-associated diabetes (ICI-DM) remain to be fully defined. We present clinical vignettes of patients that have presented to our hospital to illustrate the heterogenous clinical profiles that patients with ICI-DM can experience. We also provide an update on ICI-DM, focusing on current and future perspectives and emerging therapies. Methods: We performed a retrospective review of the electronic records of five ICI-DM patients who presented to St. Vincent’s Hospital Melbourne between 2020 and 2024, with patients identified from the hospital endocrinology and oncology databases. We also performed a literature review via a PubMed search using the keywords “checkpoint inhibitors” and “diabetes” between the years 2015 and 2025 to allow us to collate a descriptive review on ICI-DM. Results: Our cases show some heterogeneity in presentation, with biochemical evidence of diabetic ketoacidosis (DKA) in 4/5 patients, presentation 18–253 days (median 47 days) from ICI commencement, HbA1c 59–78 mmol/mol (median 66 mmol/mol), and c-peptide 0.06–0.77 pmol/mL (median 0.09 pmol/mL). Islet autoantibodies were present in 4/5 cases and high-risk HLA alleles identified in 1/2 tested patients. The findings from our descriptive review support a similar heterogeneity in ICI-DM presentations. Inconsistent diagnostic criteria for ICI-DM were noted with low c-peptide being the most common biochemical presentation. Pancreatic volume is emerging as a useful predictive marker of ICI-DM development. We found no reports of the reversal of ICI-DM with immunosuppression in humans, although recent preclinical studies suggest that this approach is feasible. Conclusions: Diagnostic criteria should include new-onset hyperglycaemia with low paired c-peptide, and may be supported with T1DM-associated autoantibodies and evidence of pancreatic atrophy on imaging. Further research is needed in the realm of predicting ICI-DM and considering the role of immunosuppression as a treatment modality. Full article

Background: Celiac disease (CD) is frequently associated with autoimmune disorders such as Hashimoto’s thyroiditis and type 1 diabetes. Endocrine-specific autoantibodies may emerge during the course of CD, but their true prevalence and clinical relevance in children remain unclear. This study evaluated endocrine autoantibodies and inflammatory profiles in pediatric CD to inform a more tailored diagnostic approach. Methods: In this retrospective cross-sectional study, 240 consecutive children referred to a tertiary center for suspected CD and/or autoimmune endocrine disorders were included. CD was diagnosed according to ESPGHAN criteria. Laboratory evaluation comprised blood counts, metabolic parameters, thyroid function tests, thyroid autoantibodies (anti-TPO, anti-Tg), and type 1 diabetes-related autoantibodies (GAD, IA-2, ZnT8). A subgroup of children with CD (n = 28) underwent exploratory multiplex cytokine analysis. Results: Children with CD were slightly older and more often female than controls. Platelet counts were modestly lower in CD, while other hematologic parameters were similar. Thyroid autoimmunity prevalence did not differ significantly (anti-TPO: 2.7% in CD vs. 5.4% in controls; p = 0.348), and antibody titers and TSH levels were comparable. Anti-TPO positivity was associated with older age (p = 0.038), independent of CD status. Islet autoantibodies were similarly distributed between groups. Cytokine levels were not associated with tTG-IgA status; however, girls with CD showed higher IL-2, IL-4, and IL-10 levels than boys (all p < 0.05), with a trend toward higher IL-1α. Conclusions: In this pediatric cohort enriched for immune and endocrine concerns, CD was not linked to increased thyroid or pancreatic autoimmunity. Distinct sex-related differences in inflammatory profiles were observed, suggesting distinct immune patterns in girls with CD. These findings support a clinically driven rather than routine approach to endocrine autoantibody screening and warrant further studies on cytokine-based immune stratification. Full article

Background: Screening for presymptomatic type 1 diabetes (T1D) reduces the risk of diabetic ketoacidosis (DKA) and allows for early intervention with disease-modifying therapies. Despite the rising incidence of T1D in Bulgaria, screening initiatives remain limited. This pilot study aims to evaluate the feasibility of selective T1D screening in high-risk children and identify potential clinical associations with islet autoimmunity. Methods: The study targeted a recruitment of 250 children aged 0–18 years (200 with a relative with T1D and 50 without). Screening for islet autoantibodies (AABs), including glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated-2 (IA-2A), zinc transporter-8 (ZnT8A), and islet cell cytoplasmic autoantibodies (ICAs), was performed via chemiluminescence immunoassay (CLIA). Participants testing positive for one or more AABs were scheduled for longitudinal immunological and metabolic follow-up to evaluate the persistence of autoimmunity and disease progression. Results: Between October 2024 and February 2026, the pilot study recruited 210 participants (84% of the 250 target), including 160 children with a relative (target 200) and 50 without a family history of T1D (target 50). Within the high-risk group, seven children (4.4%) tested positive for a single autoantibody (3 GADA, 2 ZnT8A, 1 IA-2A, and 1 IAA), while no autoantibodies were detected in the group without a relative. No cases of multiple autoantibody positivity or stage 3 T1D were identified in either group. Furthermore, no statistically significant associations were observed between autoantibody positivity and secondary factors, including breastfeeding, allergic status, a high-glycemic diet, frequent illness, and personal history of autoimmune disease. Conclusions: The findings validate the feasibility of selective T1D screening in Bulgaria, driven by high public interest and successful recruitment across both high-risk and general population cohorts. While this exploratory study found no significant clinical correlations, it establishes a vital roadmap for larger, longitudinal research. Ultimately, this pilot framework provides a scalable model for implementing standardized early detection to reduce the burden of T1D on the national healthcare system. Full article

Type 1 diabetes (T1D) is an immune-mediated disease characterized by progressive autoimmune destruction of pancreatic β cells. Although traditionally viewed as primarily T-cell-driven, B cells play essential roles in disease pathogenesis. In addition to producing islet autoantibodies, B cells contribute to immune activation through antigen presentation and cytokine secretion, thereby shaping autoreactive T-cell responses. The earliest clinical predictor of T1D is the appearance of islet autoantibodies in the blood, reflecting a breach in B-cell tolerance well before symptomatic disease onset. In individuals at high genetic risk, type I interferon (IFN) signatures are detectable in peripheral blood prior to seroconversion, suggesting that type I IFNs may act as upstream regulators of B-cell tolerance. Peripheral tolerance is enforced through layered checkpoints including transitional selection, maintenance of anergy, germinal center regulation, and regulatory B-cell differentiation. Studies in systemic autoimmunity demonstrate that type I IFN signaling lowers B-cell activation thresholds, enhances BCR and TLR responsiveness, promotes survival of autoreactive transitional clones via BAFF induction, destabilizes anergy, and skews differentiation toward inflammatory phenotypes such as T-bet+ age-associated B cells. Consistent with this model, single-cell transcriptomic and BCR repertoire analyses in T1D reveal clonal expansion and proinflammatory signatures in islet-reactive B cells during the preclinical stage. Together, these findings implicate the IFN–B-cell axis as a potential target for early disease modification. Full article

The ADA 2026 Standards of Care in Diabetes introduces pivotal updates that refine diagnostic and therapeutic workflows. Expanding upon the 2025 guidelines, the 2026 edition broadens continuous-glucose-monitoring (CGM) eligibility to include all individuals on insulin or non-insulin therapies where CGM aids management. Significant new guidance addresses hyperglycemia management in oncology, identifying metformin as the preferred first-line intervention for drug-induced glycemic excursions. Additionally, type 1-diabetes (T1D) risk stratification is refined; a confirmed single IA-2 autoantibody now warrants monitoring levels similar to the Stage 2 disease. Furthermore, prerequisites for automated-insulin-delivery (AID) initiation have been removed to streamline technology access. For laboratory professionals, these revisions emphasize the critical role of advanced glycemic metrics and precise autoantibody profiling in complex clinical contexts. Full article

Autoantibodies targeting islet antigen 2 (IA2) are critical diagnostic and prognostic markers for type 1 diabetes (T1D). Standard clinical assays do not differentiate between IgG and IgM isotypes, yet these antibodies have distinct roles in the T1D autoimmunity. We therefore adapted electrochemiluminescence (ECL) assays to separately detect IgG and IgM antibodies against the IA2 intracellular domain (AA601-979). Assay specificity was confirmed by indirect immunofluorescence, which showed autoantibody binding to IA2-overexpressing cells. Plasma samples were analyzed from two independent cohorts: organ donors of the Human Pancreas Analysis Program (HPAP, n = 69) and children from a Janssen–Breakthrough T1D-funded study (n = 65). Diabetics had significantly higher levels of IA2 IgG (p < 0.001) but not IgM (p > 0.05) compared with controls. Notably, IgM and IgG IA2 antibody levels were not correlated. However, IgM modulates IgG detection: IgM depletion increased detected IgG levels to IA2 in some donors, and sera from donors with high IA2-specific IgM levels reduced monoclonal IgG anti-IA2 antibody binding to IA2. Purified IgM from healthy individuals also suppressed monoclonal IgG binding. These findings support distinct, non-redundant roles for IA2-specific IgG and IgM in T1D serology. Isotype-specific autoantibody analysis may improve risk stratification and monitoring of T1D individuals receiving immunomodulatory therapies. Full article

Type 1 diabetes (T1D) is a common chronic autoimmune disease in childhood, often presenting abruptly and frequently complicated by diabetic ketoacidosis at diagnosis. T1D develops through well-defined presymptomatic stages characterized by islet autoimmunity and progressive dysglycemia, offering a window for early identification. This narrative review summarizes current evidence on screening for T1D in children and adolescents, focusing on target populations, screening strategies, and methodological approaches for autoantibody detection. Data from major international programs involving familial, high-risk, and general population screening are discussed, highlighting their impact on reducing diabetic ketoacidosis at onset, improving metabolic outcomes, and facilitating structured follow-up and family education. Advances in assay technologies, including electrochemiluminescence, multiplex platforms, and novel ultrasensitive methods, have enhanced the feasibility and accuracy of large-scale screening. The review also examines the public health implications, cost-effectiveness, and ethical considerations of implementing population-based screening, particularly in light of emerging disease-modifying therapies such as teplizumab. Overall, available evidence supports screening as a meaningful strategy to shift T1D diagnosis from an acute emergency to a predictable clinical trajectory, with potential benefits extending from individual patient outcomes to healthcare system sustainability. Full article

Background/Objectives: To evaluate pancreatic size and echogenicity using ultrasonography in newly diagnosed pediatric Type 1 Diabetes Mellitus patients within five days of diagnosis, and compare early childhood (<7 years) and adolescent (≥13 years) endotypes with clinical and laboratory findings. Methods: This prospective, cross-sectional, case–control study included 69 pediatric patients with newly diagnosed type 1 diabetes mellitus, aged 1–18 years, and 78 age- and sex-matched healthy controls. Patients with chronic conditions (e.g., pancreatitis or cystic fibrosis), other forms of diabetes, or medications affecting glucose metabolism were excluded. Ultrasonography was performed within five days of diagnosis, after metabolic stabilization, to assess pancreatic dimensions and echogenicity. Laboratory analyses included measurements of C-peptide, HbA1c, and autoantibodies (anti-GAD, islet cell antibody, and insulin antibody). Results: Pancreatic dimensions were significantly smaller in type 1 diabetes mellitus patients (p < 0.001), with greater reductions in adolescents (head: 21%, body: 26.7%) vs. young children (head: 14.4%, body: 15.5%). Isoechoic pancreases were more common in young patients (80% vs. 40.9%; p = 0.033). C-peptide and HgbA1c were higher in adolescents (p < 0.05), with no echogenicity–autoantibody association. Conclusions: This first early-post-diagnosis ultrasonography study reveals age-specific pancreatic atrophy and echogenicity changes in children, more severe in adolescents, reflecting type 1 diabetes mellitus endotypes. Ultrasonography offers a practical noninvasive tool for early detection and endotype stratification, informing personalized diabetes care. Full article

Continuous glucose monitoring (CGM)-based interventions have been predominantly conducted in people with established diabetes. Recently, there has been an increasing interest in using CGM for clinical and research purposes in people without diabetes. In this review, we describe the current evidence regarding the use of CGM in people at high risk of diabetes. To date, there is no strong evidence to support the global implementation of CGM in individuals who are at risk of developing diabetes. However, there are promising results highlighting the benefits of CGM in specific populations such as people living with obesity, prediabetes, gestational diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, other endocrinopathies, and genetic syndromes. Also, CGM has shown promising potential in people with positive islet autoantibodies and pre-symptomatic type 1 diabetes, those treated with medications that induce hyperglycaemia or diabetes, and individuals receiving solid organ transplantation who are at risk of post-transplant diabetes mellitus. However, larger studies are needed to confirm these preliminary results. CGM-derived data are not currently validated for the diagnosis of diabetes. There is no CGM-derived definition of normoglycaemia in people without diabetes. Looking to the future, CGM metrics, in tandem with physical activity, dietary intake, and clinical parameters, and eventually bioinformatics, may inform personalised risk scores for precision prevention of individuals at risk. We conclude that further research is needed to clarify the indications, drawbacks, and feasibility of CGM use in people at high risk of diabetes to identify those groups who could benefit most from this technology. Full article

Type 1 Diabetes Mellitus (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells, predominantly manifesting in childhood or adolescence. The lack of clearly interpretable biological markers in the early stages, combined with the insidious onset of the disease, poses significant challenges to early diagnosis and the implementation of preventive strategies. The applicability of classic T1D biomarkers for understanding the mechanisms of the autoimmune process, preclinical diagnostics and treatment efficiency is limited. Despite advances in next-generation sequencing (NGS) technologies, which have enabled large-scale genome-wide association studies (GWASs) and the identification of polygenic risk scores (PRSs) associated with T1D predisposition, as well as progress in bioinformatics approaches for assessing dysregulated gene expression, no universally accepted risk assessment model or definitive predictive biomarker has been established. Until now, the use of new promising biomarkers for T1D diagnostics is limited by insufficient evidence base. However, they have great potential for the development of diagnostic methods on their basis, which has been shown in single or serial large-scale studies. This critical review covers both well-known biomarkers widely used in clinical practice, such as HLA-haplotype, non-HLA SNPs, islet antigen autoantibodies, C-peptide, and the promising ones, such as cytokines, cfDNA, microRNA, T1D-specific immune cells, islet-TCR, and T1D-specific vibrational bands. Additionally, we highlight new approaches that have been gaining popularity and have already demonstrated their potential: GWAS, single-cell transcriptomics, identification of antigen-specific T cells using scRNA-seq, and FTIR spectroscopy. Although some of the biomarkers, in our opinion, are still limited to a research context or are far from being implemented in clinical diagnostics of T1D, they have the greatest potential of being applied in clinical practice. When integrated with the monitoring of the classical autoimmune diabetes markers, they would increase the sensitivity and specificity during diagnostics of early and preclinical stages of the disease. This critical review aims to evaluate the current landscape of classical and emerging biomarkers in autoimmune diabetes, with a focus on those enabling early detection—prior to extensive destruction of pancreatic islets. Another goal of the review is to focus the attention of the scientific community on the gaps in early T1D diagnostics, and to help in the selection of markers, targets, and methods for scientific studies on creating novel diagnostic panels. Full article

Background/Objectives: Differentiating Type 1 from Type 2 diabetes mellitus (T1DM vs. T2DM) remains clinically challenging, especially in early-onset cases with overlapping features. This study assessed the diagnostic utility of diabetes-related autoantibodies in an Omani cohort and evaluated their predictive performance using machine learning. Methods: Clinical and laboratory data from 448 patients (aged ≥ 2 years) in Al Batinah North, Oman, were retrospectively analyzed. We assessed autoantibody positivity (anti-GAD, anti-islet, anti-TPO, anti-tissue), age, sex, and HbA1c. Receiver operating characteristic (ROC) curves and a neural network model were used to evaluate diagnostic accuracy. Results: Anti-GAD and anti-islet antibodies were significantly more prevalent in T1DM (69.0% and 64.1%) than T2DM (7.4% and 3.8%; p < 0.0001). HbA1c was elevated in both subtypes but lacked discriminatory specificity. Nearly half (48.5%) of T1DM patients showed multiple antibody positivity, especially in younger age groups. Anti-TPO and anti-tissue antibodies were more frequently detected in T1DM, suggesting broader autoimmunity. ROC analysis showed strong predictive value for anti-islet (AUC = 0.835) and anti-GAD (AUC = 0.827). Neural network modeling identified anti-GAD, anti-islet, and age as the most informative predictors, achieving over 92% classification accuracy. Importantly, antibody positivity in a subset of insulin-treated T2DM patients suggested potential latent autoimmune diabetes (LADA) misclassification. Conclusions: This is the first study in Oman to combine autoantibody screening with AI-based modeling to refine diabetes classification. Our findings highlight the value of immunological profiling in early diagnosis, uncover possible misclassification, and support AI integration to guide individualized management. Full article

Over the past century, the understanding of type 1 diabetes mellitus (T1DM) has evolved significantly, transitioning from a fatal metabolic disorder to a well-characterized autoimmune disease. This review explores the historical developments and scientific milestones that have reshaped the perception of T1DM, highlighting key discoveries and shifts in medical paradigms. Methods: A comprehensive narrative review was conducted, examining literature spanning from ancient medical texts to contemporary research up to 2024. Emphasis was placed on pivotal moments such as the discovery of insulin in 1921, the recognition of autoimmune mechanisms in the 1970s, and recent advancements in immunotherapy. Results: The reclassification of T1DM as an autoimmune disease was supported from multiple lines of evidences including the presence of islet cell autoantibodies, the identification of lymphocytic infiltration in pancreatic islets, and the associations of the disease with certain HLA class II alleles. The development of animal models and large-scale cohort studies facilitated the establishment of disease staging and risk prediction models. Notably, the approval of immunotherapies like teplizumab underscores the translational impact of these scientific insights. Conclusions: The historical trajectory of T1DM exemplifies the dynamic nature of medical knowledge and the interplay between clinical observations and scientific research. Recognizing these developments enhances our comprehension of disease mechanisms and informs current approaches to diagnosis and treatment. Full article

Type 1 diabetes is classified into three clinical subtypes: fulminant type 1 diabetes, acute-onset type 1 diabetes, and slowly progressive type 1 diabetes, also known as latent autoimmune diabetes in adults. Among these, the fulminant and slowly progressive forms may develop in association with pregnancy and are herein collectively referred to as “pregnancy-associated type 1 diabetes”. Fulminant type 1 diabetes can manifest suddenly during pregnancy, often accompanied by ketoacidosis, posing a significant risk to both the mother and the fetus. Early diagnosis and treatment are, therefore, critical. In pregnant women with no prior history of diabetes who present with marked hyperglycemia (≥288 mg/dL) but relatively low HbA1c levels (<8.7%), fulminant type 1 diabetes should be suspected, and insulin therapy should be initiated immediately. Conversely, women diagnosed with gestational diabetes who test positive for anti-islet autoantibodies are at high risk of developing slowly progressive type 1 diabetes postpartum. For these patients, regular monitoring of blood glucose levels, HbA1c, and endogenous insulin secretion is essential for early detection and management. Full article