T1D Onset Research Articles

Instigator of Type 1 Diabetes Mellitus (T1D): Connecting Human Leukocyte Antigen (HLA) with Infant Gut Microbiome

Type 1 Diabetes Mellitus (T1D) is driven by the interplay between genetics and other factors, though the exact relationship between gut microbiome and T1D onset remains unclear. This study aims to investigate the connections between Human Leukocyte Antigen (HLA) genetics, gut microbiome, and their relationships to T1D seroconversion. Data from the Diabimmune website provided stool samples (n=1443) from children aged 16 to 36 months from Finland, Russia, and Estonia, categorized by HLA risk factors and seroconversion status. Statistical analyses using the Wilcoxon rank-sum test measure were conducted. High-risk HLA individuals generally had a lower relative abundance of beneficial bacteria such as Lachnospira. Predicted metabolic pathways PWY.5676 and PWY.7220/7222 had an increased abundance in low-risk HLA infants in multiple age groups. Prevotella was more abundant in seroconverted samples, while Ruminococcus, Hungatella, and Sutterella were more abundant in non-seroconverted samples. Shared pathways between different age groups such as GLYOXYLATE.BYPASS showed higher abundance in non-seroconverted samples, each with similar median abundance across different age groups. The findings suggest that gut microbiome dysbiosis, characterized by a lower abundance of beneficial SCFA-producing bacteria and the prevalence of pathways supporting bacterial persistence and immune stimulation, contributes to T1D onset. Future research should focus on advanced genomic and metabolomic analyses, functional assays, co-culture experiments, and developing predictive models using machine learning to assess autoimmune disease risk based on bacterial strains and HLA haplotypes

NOD alleles at Idd1 and Idd2 loci drive exocrine pancreatic inflammation.

Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes and have enabled the identification of several loci associated with diabetes susceptibility, termed insulin-dependent diabetes (Idd). The generation of congenic mice has allowed the characterization of the impact of several loci on disease susceptibility. For instance, NOD.B6-Idd1 and B6.NOD-Idd1 congenic mice were instrumental in demonstrating that susceptibility alleles at the MHC locus (known as Idd1) are necessary but not sufficient for autoimmune diabetes progression. We previously showed that diabetes resistance alleles at the Idd2 locus provide significant protection from autoimmune diabetes onset, second to Idd1. In search of the minimal genetic factors required for T1D onset, we generated B6.Idd1.Idd2 double-congenic mice. Although the combination of Idd1 and Idd2 is not sufficient to induce diabetes onset, we observed immune infiltration in the exocrine pancreas of B6.Idd2 mice, as well as an increase in neutrophils and pancreatic tissue fibrosis. In addition, we observed phenotypic differences in T-cell subsets from B6.Idd1.Idd2 mice relative to single-congenic mice, suggesting epistatic interaction between Idd1 and Idd2 in modulating T-cell function. Altogether, these data show that Idd1 and Idd2 susceptibility alleles are not sufficient for autoimmune diabetes but contribute to inflammation and immune infiltration in the pancreas.

Controlling autoimmune diabetes onset by targeting Protease-Activated Receptor 2

BackgroundType 1 diabetes (T1D) is a challenging autoimmune disease, characterized by an immune system assault on insulin-producing β-cells. As insulin facilitates glucose absorption into cells and tissues, β-cell deficiency leads to elevated blood glucose levels on one hand and target-tissues starvation on the other. Despite efforts to halt β-cell destruction and stimulate recovery, success has been limited. Our recent investigations identified Protease-Activated Receptor 2 (Par2) as a promising target in the battle against autoimmunity. We discovered that Par2 activation’s effects depend on its initial activation site: exacerbating the disease within the immune system but fostering regeneration in affected tissue. MethodsWe utilized tissue-specific Par2 knockout mice strains with targeted Par2 mutations in β-cells, lymphocytes, and the eye retina (as a control) in the NOD autoimmune diabetes model, examining T1D onset and β-cell survival. ResultsWe discovered that Par2 expression within the immune system accelerates autoimmune processes, while its presence in β-cells offers protection against β-cell destruction and T1D onset. This suggests a dual-strategy treatment for T1D: inhibiting Par2 in the immune system while activating it in β-cells, offering a promising strategy for T1D. ConclusionsThis study highlights Par2's potential as a drug target for autoimmune diseases, particularly T1D. Our results pave the way for precision medicine approaches in treating autoimmune conditions through targeted Par2 modulation.

Whole Exome Sequencing in Children With Type 1 Diabetes Before Age 6 Years Reveals Insights Into Disease Heterogeneity.

Aims: This study is aimed at comparing whole exome sequencing (WES) data with the clinical presentation in children with type 1 diabetes onset ≤ 5 years of age (EOT1D). Methods: WES was performed in 99 unrelated children with EOT1D with subsequent analysis to identify potentially deleterious rare variants in MODY genes. High-resolution HLA class II haplotyping, SNP genotyping, and T1D-genetic risk score (T1D-GRS) were also evaluated. Results: Eight of the ninety-nine EOT1D participants carried a potentially deleterious rare variant in a MODY gene. Rare variants affected five genes: GCK (n = 1), HNF1B (n = 2), HNF4A (n = 1), PDX1 (n = 2), and RFX6 (n = 2). At diagnosis, these children had a mean age of 3.0 years, a mean HbA1c of 10.5%, a detectable C-peptide in 5/8, and a positive islet autoantibody in 6/7. Children with MODY variants tend to exhibit a lower number of pancreatic autoantibodies and a lower fasting C-peptide compared to EOT1D without MODY rare variants. They also carried at least one high-risk DR3-DQ2 or DR4-DQ8 haplotype and exhibited a T1D-GRS similar to the other individuals in the EOT1D cohort, but higher than healthy controls. Conclusions: WES found potentially deleterious rare variants in MODY genes in 8.1% of EOT1D, occurring in the context of a T1D genetic background. Such genetic variants may contribute to disease precipitation by a β-cell dysfunction mechanism. This supports the concept of different endotypes of T1D, and WES at T1D onset may be a prerequisite for the implementation of precision therapies in children with autoimmune diabetes.

Gut Microbiota Is Associated with Onset and Severity of Type 1 Diabetes in Nonobese Diabetic Mice Treated with Anti-PD-1.

Our bodies are home to individual-specific microbial ecosystems that have recently been found to be modified by cancer immunotherapies. The interaction between the gut microbiome and islet autoimmunity leading to type I diabetes (T1D) is well described and highlights the microbiome contribution during the onset and T1D development in animals and humans. As cancer immunotherapies induce gut microbiome perturbations and immune-mediated adverse events in susceptible patients, we hypothesized that NOD mice can be used as a predictive tool to investigate the effects of anti-PD-1 treatment on the onset and severity of T1D, and how microbiota influences immunopathology. In this longitudinal study, we showed that anti-PD-1 accelerated T1D onset, increased glutamic acid decarboxylase-reactive T cell frequency in spleen, and precipitated destruction of β cells, triggering high glucose levels and pancreatic islet reduction. Anti-PD-1 treatment also resulted in temporal microbiota changes and lower diversity characteristic of T1D. Finally, we identified known insulin-resistance regulating bacteria that were negatively correlated with glucose levels, indicating that anti-PD-1 treatment impacts the early gut microbiota composition. Moreover, an increase of mucin-degrading Akkermansia muciniphila points to alterations of barrier function and immune system activation. These results highlight the ability of microbiota to readily respond to therapy-triggered pathophysiological changes as rescuers (Bacteroides acidifaciens and Parabacteroides goldsteinii) or potential exacerbators (A. muciniphila). Microbiome-modulating interventions may thus be promising mitigation strategies for immunotherapies with high risk of immune-mediated adverse events.

Pediatric Type 1 Diabetes: Is Age at Onset a Determining Factor in Advanced Hybrid Closed-Loop Insulin Therapy?

The integration of continuous glucose monitoring systems with insulin infusion pumps has shown improved glycemic control, with improvements in hyperglycemia, hypoglycemia, Hb1Ac, and greater autonomy in daily life. These have been most studied in adults and there are currently not many articles published in the pediatric population that establish their correlation with age of debut. Prospective, single-study. A total of 28 patients (mean age 12 ± 2.43 years, 57% male, duration of diabetes 7.84 ± 2.46 years) were included and divided into two groups according to age at T1D onset (≤4 years and >4 years). Follow-up for 3 months, with glucometric variables extracted at different cut-off points after the start of the closed-loop (baseline, 1 month, 3 months). Significant improvement was evidenced at 1 month and 3 months after closed-loop system implantation, with better glycemic control in the older age group at baseline at TIR (74.06% ± 6.37% vs. 80.33% ± 7.49% at 1 month, p < 0.003; 71.87% ± 6.58% vs. 78.75% ± 5.94% at 3 months, p < 0.009), TAR1 (18.25% ± 4.54% vs. 14.33% ± 5.74% at 1 month, p < 0.006; 19.87% ± 5.15% vs. 14.67% ± 4. 36% at 3 months, p < 0.009) and TAR2 (4.75% ± 2.67% vs. 2.75% ± 1.96% at 1 month, p = 0.0307; 5.40% ± 2.85% vs. 3% ± 2.45% at 3 months, p < 0.027). the use of automated systems such as the MiniMedTM780G system brings glucometric results closer to those recommended by consensus, especially in age at T1D onset >4 years. However, the management in pediatrics continues to be a challenge even after the implementation of these systems, especially in terms of hyperglycemia and glycemic variability.

Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review

BackgroundType 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification.MethodsTo understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ge50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.ResultsWe identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings.ConclusionsWhile the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.

1447-P: Young Children with T1D on Three Continents—An Especially Vulnerable Group in Need of Specialized Health Care

We aimed to identify differences in care and outcomes of very young children with T1D onset from 3 multicenter registries from three continents: T1DX-QI (US), DPV (Germany/Austria/Switzerland/Luxembourg), and ADDN (Australia/New Zealand). These results are an update of 2,011 children of this age-group treated in 2011/2012 in European/US centers (Diabetologia 57:1578-585, 2014). For treatment years 2019-2021, there were 8,004 children with T1D &amp;lt;6 years of age in the 3 registries. The most recent treatment year per child was analyzed. To ensure data protection, analyses were pre-defined and conducted separately by each group. Age at onset, median diabetes duration and gender ratio, as well as anthropometry, and insulin requirement were very similar between the three registries (Table). In DPV, the vast majority of children in this age-group used insulin pumps and glucose sensors, followed by ADDN and T1DX-QI. HbA1c was lowest in DPV, followed by ADDN. Severe hypoglycemia and DKA were rare. Celiac disease was reported most often in Europe, while thyroid disease was more prevalent in the US. Both T1DX-QI and DPV improved metabolic control in this age-group compared to an analysis 10 years ago. However, the majority of children still do not reach currently recommended A1C levels. This young group of subjects needs extensive resources in terms of education, insulin dose adjustment, and family support. Disclosure S.R.Tittel: None. M.E.Craig: None. O.Ebekozien: Advisory Panel; Medtronic, Research Support; Eli Lilly and Company, Dexcom, Inc. E.Fröhlich-reiterer: None. J.L.Sandy: None. S.Rompicherla: None. B.Karges: None. S.James: None. N.Noor: None. A.Zimmermann: None. D.M.Maahs: Advisory Panel; Medtronic, LifeScan Diabetes Institute, MannKind Corporation, Consultant; Abbott, Research Support; Dexcom, Inc. R.W.Holl: None.

217-LB: Heterogeneity of Single Cells Obtained from Peripheral Blood Mononuclear Cells Collected from Youth with Recent-Onset Type 1 Diabetes

Whole blood bulk RNA sequencing has been used to guide T1D clinical trial design and assess response to disease modifying interventions, whereas it is with limited information about cell specific gene expression changes. Here, we aimed to apply computational strategies to deconvolute cell type composition using cell specific gene expression references. Single-cell RNA sequencing (scRNA-seq) was conducted to profile 108,795 peripheral blood mononuclear cells obtained from 5 youth within 48 hrs of Stage 3 T1D onset (avg age 11.4; 3M;2F) and 5 age- and sex-matched controls and identified 31 distinct cell clusters. In T1D, the proportion of CD4+ T central memory (TCM) cells was increased (P = 0.018), while plasmacytoid dendritic cells (pDC), platelets, and hematopoietic stem and progenitor cells (HSPC) proportions were reduced (P = 0.021, 0.012 and 0.017 respectively) compared to controls. The most robust transcriptomic changes were observed in CD14+ and CD16+ monocyte populations and CD1C+ conventional type-2 dendritic (cDC2) cells. Using this scRNA-seq reference dataset, we ran computational algorithms CIBERSORTx and our in-house reference-free method ICTD to deconvolute cell proportions using public clinical trial data testing the anti-CD20 monoclonal antibody rituximab (n=37) vs. placebo (n=17). Strong correlation was observed between the methods for cell proportion estimates (P &amp;lt; 2.2*10-16). It showed that B cell subsets were reduced by rituximab. At baseline, non-responders had a higher proportion of CD8+ T cells (P = 0.04), and responders had higher proportions of neutrophils (P =0.04). These data suggest that deconvolution approaches can be utilized for secondary analysis of existing clinical trial bulk RNA-seq data, to link cell specific immune signatures associated with drug responder status. Disclosure W. Wu: None. C. Parks-schenck: None. T. Guo: None. C. Zhang: None. R. G. Mirmira: None. C. Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. Funding dkNET; Indiana University Center for Diabetes and Metabolic Diseases; National Institutes of Health (U01DK127786)

1279-P: The INNODIA Natural History Study of Children, Adolescents, and Adults Newly Diagnosed with Type 1 Diabetes

Using the INNODIA consortium European infrastructure, we aimed to discover novel biomarkers of T1D progression. Here we report clinical and biochemical characteristics of people with new-onset T1D during the first year from diagnosis. Children and adults (age 1-45 yrs) were recruited within 6 weeks from T1D onset in 11 European countries. Baseline clinical characteristics, C-peptide (fasted and mixed meal tolerance test), HbA1c, autoantibodies, and their overtime changes were assessed across 3 age groups: &amp;lt;10, 10-17, ≥18yrs. The study population included 655 individuals (280: &amp;lt;10 yrs; 274: 10-17 yrs; 101: ≥18 yrs): 57% male; age: 12.1±8.4 yrs; 96% were positive for ≥1 autoantibodies. Autoantibody frequency was IAA 77%, GAD 73%, IA-2A 69%, ZnT8A 66%. Diabetic ketoacidosis prevalence was 35%, with the highest rate in the 10-17 yrs group (44%). At baseline, median [IQR] fasting and area-under-the curve (AUC) C-peptide were 242[140-384] and 753[469-1109]pmol/L, with levels increasing with age (p&amp;lt;0.001; Fig). Over time C-peptide remained lower in participants &amp;lt;10yrs but rates of decline were similar between age groups. HbA1c significantly decreased during the first 3 months (p&amp;lt;0.001). In this large cohort with new-onset T1D, we identified age-related differences in clinical and biochemical parameters. Of note, C-peptide was lower in younger children but there was no age effect on its rate of decline. Disclosure M.Marcovecchio: None. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. Innodia consortium: n/a. C.Delfin: Employee; Novo Nordisk A/S. M.Hulsmans: None. L.Overbergh: None. S.S.Pazmino: None. D.E.Picton: None. N.Steenackers: None. B.Van der schueren: None. A.E.J.Hendriks: Advisory Panel; Alira Health. Funding Innovative Medicines Initiative 2 Joint Undertaking (115797, 945268)

1143-P: Elevated Serum IgA and the Gut Microbiome in Pediatric Type 1 Diabetes (T1D)

Elevated serum IgA occurs in ~20% of children with new onset T1D, although its potential role in T1D pathogenesis is not understood. Gut dysbiosis is present at onset of T1D and is strongly associated with its pathogenesis. Mucosal IgA is well known to influence the microbiome and vice versa. In animal models, serum IgA responds to microbiome changes, thereby inducing a protective response to gut invasion by pathogens. However, the relationship between gut microbiome and serum IgA in humans with T1D is unknown. Thus, we aimed to assess if elevated serum IgA is associated with gut dysbiosis at T1D onset. We enrolled 47 children between 7/2021 and 9/2022: New onset T1D with elevated serum IgA (T1D-Hi-IgA, n=14), new onset T1D with normal serum IgA (T1D-Nl-IgA, n=18) and controls (siblings of new onset T1D, n=15). Exclusions: &amp;lt;2 yrs age; antibiotics; probiotics; inflammatory bowel disease; celiac disease; or acute illness &amp;lt;10 days of stool collection. Demographic and clinical variables, diet questionnaires and stool were collected. Stool microbiome was determined via 16Sv4 rDNA sequencing. Differences in alpha and beta diversity along with taxa abundance were assessed. We found that the relative abundance of members of families Oscillospiraceae and Lachnospiraceae, both of which contain butyrate producers, were significantly associated with elevated IgA irrespective of T1D status (p&amp;lt;0.05); higher in T1D-Hi-IgA vs T1D-Nl-IgA (p&amp;lt;0.05); yet similar in T1D-Hi-IgA vs controls. Measures of alpha diversity, including richness and evenness, were also increased in T1D-Hi-IgA vs T1D-Nl-IgA, though these differences did not reach significance (richness: p=0.074; evenness: p=0.135). Similar results were observed for beta diversity. In sum, in children with new onset T1D, elevated serum IgA is associated with beneficial microbial taxa such as butyrate producers, with a trend towards increased diversity, similar to healthy siblings. Further studies are needed to understand its involvement in T1D pathogenesis. Disclosure A.Thakkar: None. M.J.Redondo: None. J.Hajjar: None. J.Petrosino: None. K.L.Hoffman: Consultant; Cooper Surgical. J.Cormier: None. M.Ahmed: None. X.C.Huang: None.

Validation of Register-Based Diabetes Classifiers in Danish Data.

To validate two register-based algorithms classifying type 1 (T1D) and type 2 diabetes (T2D) in a general population using Danish register data. After linking data on prescription drug usage, hospital diagnoses, laboratory results and diabetes-specific healthcare services from nationwide healthcare registers, diabetes type was defined for all individuals in Central Denmark Region age 18-74 years on 31 December 2018 according to two distinct register-based classifiers: 1) a novel register-based diabetes classifier incorporating diagnostic hemoglobin-A1C measurements, the Open-Source Diabetes Classifier (OSDC), and 2) an existing Danish diabetes classifier, the Register for Selected Chronic Diseases (RSCD). These classifications were validated against self-reported data from the Health in Central Denmark survey - overall and stratified by age at onset of diabetes. The source-code of both classifiers was made available in the open-source R package osdc. A total of 2633 (9.0%) of 29,391 respondents reported having any type of diabetes, divided across 410 (1.4%) self-reported cases of T1D and 2223 (7.6%) cases of T2D. Among all self-reported diabetes cases, 2421 (91.9%) were classified as diabetes cases by both classifiers. In T1D, sensitivity of OSDC-classification was 0.773 [95% CI 0.730-0.813] (RSCD: 0.700 [0.653-0.744]) and positive predictive value (PPV) 0.943 [0.913-0.966] (RSCD: 0.944 [0.912-0.967]). In T2D, sensitivity of OSDC-classification was 0.944 [0.933-0.953] (RSCD: 0.905 [0.892-0.917]) and PPV 0.875 [0.861-0.888] (RSCD: 0.898 [0.884-0.910]). In age at onset-stratified analyses of both classifiers, sensitivity and PPV were low in individuals with T1D onset after age 40 and T2D onset before age 40. Both register-based classifiers identified valid populations of T1D and T2D in a general population, but sensitivity was substantially higher in OSDC compared to RSCD. Register-classified diabetes type in cases with atypical age at onset of diabetes should be interpreted with caution. The validated, open-source classifiers provide robust and transparent tools for researchers.

Is β-Cell Dysfunction Present in Adult Autoantibody Negative Relatives of Individuals with Type 1 Diabetes Mellitus?

Background/Objective: Individuals with a family history of type 1 diabetes mellitus (T1D) are at increased genetic risk for T1D. Previous studies identified the presence of β-cell dysfunction before clinical onset and diagnosis of T1D. However, it is unclear if β-cell dysfunction predates islet autoimmunity in individuals at high genetic risk. Our objective was to test β-cell function in islet antibody negative adults who have a first-degree relative with T1D. We hypothesized that individuals at genetic risk for T1D would exhibit β-cell dysfunction even without detectable islet autoimmunity.Methods: We used ordinary one-way and Brown-Forsythe ANOVA to compare the repeated mixed meal tolerance test (MMTT) and hyperglycemic clamp glucose-stimulated β-cell response and function measures between three groups of individuals: normoglycemic adults without T1D family history age, sex, and BMI-matched islet antibody negative first-degree relatives of individuals with T1D, and islet antibody positive first-degree relatives of individuals with T1D.Results: Neither the MMTT first-phase insulin secretion measures (c-peptide0-15 minutes, c-peptide0-30 minutes, insulin0-15 minutes, insulin0-30 minutes), nor second-phase measures (c-peptide0-120 minutes, insulin0-120 minutes, and glucose0-120 minutes) showed a statistically significant difference between groups. The clamp acute c-peptide response to glucose, insulin sensitivity, c-peptide steady state, first-phase β-cell function, and second-phase β-cell function were similar between subject groups in both visits. Fasting proinsulin:c-peptide ratios, a biomarker of β-cell stress, were also similar between participant groups.Conclusion and Impact: Our data suggest that genetically at-risk autoantibody negative adult relatives of individuals with T1D do not demonstrate β-cell dysfunction compared to controls. Studies show that β-cell ER dysfunction preceding T1D onset is more striking in younger children. Thus, our findings may reflect the use of an adult study population. Alternatively, β-cell dysfunction in T1D may require initial autoimmune activation. This study will contribute to the growing understanding of risk factors contributing to T1D development.This project was funded, in part, with support from the Research Training Program in Diabetes and Obesity funded, in part by grant 3T32DK064466 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding also provided by JDRF grant 2-SRA-2017-498-M-B.

Type 1 diabetes and anxiety in adolescence. A case report

Introduction Type 1 diabetes (T1D) incidence is increasing around the world, being the third chronic medical condition in childhood. It is characterized by pancreatic β-cell loss which leads to insulin deficiency. Treatment includes insulin medication and lifestyle changes. Youngsters with T1D are at a high risk of psychological comorbidity (depression, anxiety, eating disorders), and especially anxiety symptoms have been correlated with worse diabetes control.ObjectivesOur purpose is to examine the impact of T1D in adolescence regarding a case report and literature review.MethodsWe present the case of a 14-year-old female with T1D onset and no psychiatric history. She is referred to our service three months after the T1D onset. Both her parents and the patient were anxious about the diagnostic implications and the treatment. The patient sometimes refused to follow insulin treatment and was angry and labile. Both family and individual assessment interviews were accomplished.ResultsRegarding our assessment and after coordination with endocrine service (doctor and nurse) we diagnosed an [F43.23] Adjustment Disorder (acute, with mixed anxiety and depressed mood). Following recent evidence Acceptance and Commitment Therapy and Family Therapy were the election treatment with good outcomes. The patient was released after 3 months of follow-up.Conclusions T1D treatment entails lifestyle changes and self-control, which may be stressful and challenging for adolescents and their families, causing mental health problems. Since learning self-care and emotional coping strategies can improve both psychological well-being and glucose management, an interdisciplinary approach including psychological care, especially on the onset, can be crucial.DisclosureNo significant relationships.

37-OR: Childhood Screening and Interception Strategies: An Economic Cohort Simulation Model

T1D screening and monitoring studies suggest opportunities for scaling up to public health population-based programs. Genetic Risk Scores (GRS) for T1D are also demonstrating the ability to identify those at higher risk of progressing to T1D as well as an increased opportunity for implementation into public health settings potential as a result of practical considerations, including falling gene sequencing costs.Previous studies have shown that screening and monitoring children for T1D progression significantly decreases DKA events at diagnosis, which has been shown to have both short- and long-term benefits. Furthermore, identification of those at higher risk of T1D provides an opportunity to intervene and delay T1D onset. A non-stochastic, state transition cohort simulation projected 20US births through adolescence. Data from previously collected natural history studies, including TEDDY, DIPP &amp; DAISY were used to model the patient journey. Children seroconverting to islet autoantibodies (IAB) each year and children with lower T1D risk were simulated as separate cohorts with distinct progressions. Interception strategies were layered over this natural history projection. Success of GRS screening followed by annual IAB and glucose monitoring to intercept T1D progression and reduce DKA events was explored. Therapeutic intervention to delay T1D onset was also simulated.Real-world benchmarks for newborn screening (85%) and patient follow-up (80%) as well as rapid T1D progression (&amp;lt;12 months) for some children limited maximum interception at dysglycemia to 52% of children progressing to T1D by age 15 using a GRS screening strategy. Short-term net incremental costs range reach $1.1B at current test costs or $225K per T1D case interception. Breakeven costs could be achieved with $40 IAB test cost and $5 GRS costs with a therapeutic to delay T1D onset by 3 years or possibly by including assessment potential long-term benefits of early intervention and improved glycemic control. Disclosure M.Trusheim: Other Relationship; CO BIO CONSULTING LLC. S.Kostense: Employee; Janssen Research &amp; Development, LLC. L.A.Ferrat: None. R.Mcqueen: Consultant; Merck &amp; Co., Inc., Monument Analytics, Research Support; Eli Lilly and Company. R.D.Neusner: Employee; Janssen Pharmaceuticals, Inc. R.A.Oram: Consultant; Janssen Research &amp; Development, LLC, Research Support; Randox R &amp; D. M.Rewers: Consultant; Janssen Research &amp; Development, LLC, Medscape, Provention Bio, Inc., Research Support; Dexcom, Inc., JDRF, Roche Diagnostics USA. J.L.Dunne: Employee; Janssen Research &amp; Development, LLC, JDRF.

Prevention of Type 1 Diabetes via a Lipid Nanoparticle-Based Oral Immunotherapy that Targets Selective Lymphoid Tissues

Abstract Type 1 diabetes (T1D) is an untreatable autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Antigen presenting cells (APCs) malfunctions and aberrant accumulation of type 1 interferons contribute to T1D, and the inhibition of inflammatory cytokines signaling via JAK inhibitors like Tofacitinib (Tofa) has shown promise in the prevention of the disease. However, maintenance of a therapeutic concentration of these drugs is challenging and their prolonged use leads to significant side effects. Our objective was to design a controlled and localized delivery of Tofa via lipid nanoparticles (LNp) and assess the impact of an oral short-term administration strategy on T1D development. We identified a LNp formulation with negligible toxicity, readily taken up by multiple immune cells, and with favorable Tofa encapsulation efficiency. Live animal imaging confirmed these particles have the unique property of accumulating in lymphoid tissues, particularly in pancreatic and mesenteric lymph nodes when administrated via oral gavage. Importantly, short-term administration (5 gavages once every other day) of Tofa-LNp early (3-week-old) or late (10-week-old) in disease prone NOD mice promoted a significant delay of T1D onset. Cell profiling and in vivo challenges indicated that this therapeutic effect is likely due to localized inhibition of APCs maturation and, surprisingly, promotion of anergy in diabetogenic T cells. Ex-vivo stimulation confirmed the hyporeactivity of these cells and adoptive transfer experiments confirmed their ability to act as reservoir of induced regulatory T cells. These results highlight the versatility of this novel LNp-based drug delivery strategy. This work was supported by grant 2-SRA-2016-310-S-B from the Juvenile Diabetes Research Foundation.

Outstanding improvement of the advanced lipoprotein profile in subjects with new-onset type 1 diabetes mellitus after achieving optimal glycemic control

AimsThe impact of glycemic optimization on lipoprotein subfraction parameters in apparently normolipidemic subjects with new-onset type 1 diabetes mellitus (T1D) was examined. MethodsWe evaluated the serum lipid and advanced lipoprotein profiles in twenty subjects at onset of T1D and twenty non-diabetic controls by laboratory methods and 1H NMR spectroscopy shortly after diabetes diagnosis (baseline), and after achieving optimal glycemic control (HbA1c ≤ 7.0%). ResultsAdvanced lipoprotein analysis revealed a significant reduction from baseline in serum concentrations of triglycerides (TG), cholesterol (C), and apolipoprotein (Apo)B-containing lipoproteins of treated subjects (VLDL-TG: −21%, IDL-TG: −30%, LDL-TG: −34%, LDL-TG: −36%, P < 0.05; VLDL-C: –23%, IDL-C: −44%, LDL-C: −16%; p < 0.05). Decreased VLDL and LDL lipids were mainly attributed to concomitant reductions in the concentration of medium-sized VLDL (–36%) and medium-sized LDL (–31%) and, to a lesser extent, to large-sized LDL (–14%). Notably, proatherogenic IDL characteristics and related surrogates of atherogenicity were resolved upon achievement of optimal glycemic status. Moreover, the concentration of HDL-TG was also reduced (−18%) at follow-up. ConclusionsOur data showed that the achievement of optimal glycemic control after T1D onset corrected hidden derangements in ApoB-containing lipoproteins (particularly IDL) and HDL-TG that are related to higher cardiovascular risk in poorly controlled T1D.

Long-term drench of exopolysaccharide from Leuconostoc pseudomesenteroides XG5 protects against type 1 diabetes of NOD mice via stimulating GLP-1 secretion.

Type 1 diabetes is an autoimmune disease that results in the specific destruction of insulin-producing beta cells in the pancreas. The aim of this study was to investigate the mechanism of exopolysaccharide from Leuconostoc pseudomesenteroides XG5 (XG5 EPS) against type 1 diabetes. Long-term drench of XG5 EPS delayed the onset of autoimmune diabetes and had fewer islets with high-grade infiltration (an insulitis score of 3 or 4) than untreated NOD mice. Oral administration of 50 mg kg-1 d-1 XG5 EPS increased the insulin and glucagon-like peptide-1 (GLP-1) levels of serum, stimulated GLP-1 secretion and upregulated gcg mRNA expression of colon in NOD mice. Moreover, oral administration of 50 mg kg-1 d-1 XG5 EPS significantly increased total short-chain fatty acids levels in the colon contents, especially those of acetic acid and butyric acid. In NCI-H716 cells, 500 and 1000 μmol L-1 sodium butyrate promoted the secretion of GLP-1 and upregulated the mRNA expression of gcg and PC3, while XG5 EPS and sodium acetate did not stimulate the GLP-1 secretion. Therefore, long-term drench of XG5 EPS delayed the onset of autoimmune diabetes, which may be directly correlated with the increase of butyrate in the colon of NOD mice. Long-term drench of 50 mg kg-1 d-1 XG5 EPS promoted the expression and secretion of GLP-1 by increasing the production of butyric acid, thereby delaying T1D onset in NOD mice. © 2021 Society of Chemical Industry.

HERV-W and Mycobacteriumavium subspecies paratuberculosis Are at Play in Pediatric Patients at Onset of Type 1 Diabetes.

The etiology of T1D remains unknown, although a variety of etiological agents have been proposed as potential candidates to trigger autoimmunity in susceptible individuals. Emerging evidence has indicated that endogenous human retrovirus (HERV) may play a role in the disease etiopathogenesis; although several epigenetic mechanisms keep most HERVs silenced, environmental stimuli such as infections may contribute to the transcriptional reactivation of HERV-Wand thus promote pathological conditions. Previous studies have indicated that also Mycobacterium avium subspecies paratuberculosis (MAP) could be a potential risk factor for T1D, particularly in the Sardinian population. In the present study, the humoral response against HERV-W envelope and MAP-derived peptides was analyzed to investigate their potential role in T1D etiopathogenesis, in a Sardinian population at T1D onset (n = 26), T1D (45) and an age-matched healthy population (n = 45). For the first time, a high serum-prevalence of anti-Map and anti-HERV-W Abs was observed in pediatric patients at onset of T1D compared to T1D patients and healthy controls. Our results support the hypothesis that external infections and internal reactivations are involved in the etiology of T1D, and that HERV-W activation may be induced by infectious agents such as MAP.

293-OR: IFN-a Evokes a Heterogeneous, Rapid ROS Response from a Subset of Human Islet Beta Cells in Situ

A large body of evidence reveals a web of complex, multifaceted genetic, and environmental factors that influences incidence of T1D. Among these, viral infection has been discussed as a factor implicated in onset. Production of type 1 interferons (IFN) is the archetypal immune response to viral infection. Indeed, at-risk children exhibit IFN-associated transcriptional profiles and IFN-stimulated genes are elevated in new onset T1D patients. IFN-α induces ER stress, substantial overexpression of HLA class 1, and insulitis in the islet. β-cells are known to be sensitive to reactive oxygen species (ROS) accumulation which may contribute to autoimmunogenicity in the IFN response. In order to detect the in vivo effects of IFN-α on the physiology of human islets, we conducted intravital microscopy studies of human islets transplanted in the mouse kidney - following transduction with a ratiometric fluorescent redox biosensor. These studies revealed that intravenous IFN-α elicited a mild overall accumulation of ROS in human islets, but rapid and pronounced accumulation of ROS in a subset of islet β-cells - a population of cells we termed, “ROSponders." Interestingly, the percentage of β-cells categorized as ROSponders was variable between donors (ranging from ~1% to 6% of all β-cells). Recent observations have drawn attention to the importance of β-cell expression and functional heterogeneity within the islet. Furthermore, recent work suggests that blockade of IFN-α signaling prior to clinical T1D manifestation may intercept autoimmunity and abort onset. Altogether, this work identifies novel heterogeneity of response to an inflammatory cytokine implicated in T1D onset and may inform future approaches to the treatment of T1D. Disclosure M. Arvin: None. C. Muralidharan: None. A. M. Conteh: None. M. M. Martinez irizarry: None. K. Orr: None. K. W. Dunn: None. A. K. Linnemann: None. Funding Human Islet Research Network (RRID:SCR_014393; UC4 DK104162); National Institutes of Health (3T32DK064466-18S1)