New-onset Type 1 Diabetes Research Articles

8074 Investigating Viral Infections, Systemic Inflammation, and their Complex Interplay in Type 1 Diabetes Pathogenesis

Abstract Disclosure: K. Girdhar: None. E. Elko: None. A. Pina: None. M. Atkinson: None. J. Ludvigsson: None. J. Ladner: None. E. Altindis: None. Type 1 diabetes (T1D) is an autoimmune disorder characterized by the immune-mediated destruction of insulin-producing beta cells. The etiological factors triggering the immunogenicity of endogenous β-cell antigens remain a focal point of investigation. Viral infections, particularly enteroviruses, coxsackieviruses, and rotaviruses, have been proposed as potential contributors to T1D onset and progression. However, the causal relationship between viral infections and T1D pathogenesis remains elusive. To address this, we conducted an in-depth analysis of viral infection histories of T1D patients and pediatric T1D progressors compared to the controls. To this end, we employed highly multiplexed serology using PepSeq sequencing, an in vitro platform designed for conducting proteomic assays against customizable targets via DNA-barcoded peptides. Utilizing samples from the All Babies in Sweden (ABIS) study (n=58) and the TrialNet study (n=116 new-onset T1D, n=25 established T1D, n=128 controls), we assessed seropositivity against 79 different human viruses. Contrary to previous reports, no significant differences were identified in viral infection histories between T1D individuals and controls. Subsequent analyses of enriched Peptide Count and Viral Homology Search (VHS) species provided further confirmation of the absence of distinctions in T1D progression. Next, we determined whether there are any differences in the markers of systematic inflammation in spite of their similar viral history profile. Therefore, we employed Luminex assays to investigate cytokine profiles in established T1D individuals (n=25). While we could not identify any differences when we compared T1D patients to controls, we identified notable sex-specific differences. Anti-inflammatory cytokines (IL-4, IL-13, IL-22) were lower in female T1D patients compared to female controls. Likewise, female T1D patients had higher pro-inflammatory cytokines (IL-17E, TNF-β). On the other hand, male T1D patients exhibited increased levels of epidermal growth factor and platelet-derived growth factor compared to male controls, with IL-22 uniquely elevated. Our findings challenge the direct association between viral infections and T1D, highlighting the importance of investigating alternative factors. Moreover, the observed sex-specific cytokine alterations underscore the complex interplay between immune responses and T1D, emphasizing the need for sex-specific therapeutic strategies. This research contributes valuable insights into the intricate dynamics of viral infections, systemic inflammation, and their potential roles in T1D pathogenesis. Presentation: 6/2/2024

RNA Splicing Events in Circulation Distinguish Individuals with and without New-Onset Type 1 Diabetes.

Alterations in RNA splicing may influence protein isoform diversity that contributes to or reflects the pathophysiology of certain diseases. Whereas specific RNA splicing events in pancreatic islets have been investigated in models of inflammation in vitro, how RNA splicing in the circulation correlates with or is reflective of T1D disease pathophysiology in humans remains unexplored. To use machine learning to investigate if alternative RNA splicing events differ between individuals with and without new-onset type 1 diabetes (T1D) and to determine if these splicing events provide insight into T1D pathophysiology. RNA deep sequencing was performed on whole blood samples from two independent cohorts: a training cohort consisting of 12 individuals with new-onset T1D and 12 age- and sex-matched nondiabetic controls and a validation cohort of the same size and demographics. Machine learning analysis was used to identify specific isoforms that could distinguish individuals with T1D from controls. Distinct patterns of RNA splicing differentiated participants with T1D from unaffected controls. Notably, certain splicing events, particularly involving retained introns, showed significant association with T1D. Machine learning analysis using these splicing events as features from the training cohort demonstrated high accuracy in distinguishing between T1D subjects and controls in the validation cohort. Gene Ontology pathway enrichment analysis of the retained intron category showed evidence for a systemic viral response in T1D subjects. Alternative RNA splicing events in whole blood are significantly enriched in individuals with new-onset T1D and can effectively distinguish these individuals from unaffected controls. Our findings also suggest that RNA splicing profiles offer the potential to provide insights into disease pathogenesis.

Plasma proteomics in children with new-onset type 1 diabetes identifies new potential biomarkers of partial remission

Partial remission (PR) occurs in only half of people with new-onset type 1 diabetes (T1D) and corresponds to a transient period characterized by low daily insulin needs, low glycemic fluctuations and increased endogenous insulin secretion. While identification of people with newly-onset T1D and significant residual beta-cell function may foster patient-specific interventions, reliable predictive biomarkers of PR occurrence currently lack. We analyzed the plasma of children with new-onset T1D to identify biomarkers present at diagnosis that predicted PR at 3 months post-diagnosis. We first performed an extensive shotgun proteomic analysis using Liquid Chromatography-Tandem-Mass-Spectrometry (LCMS/MS) on the plasma of 16 children with new-onset T1D and quantified 98 proteins significantly correlating with Insulin-Dose Adjusted glycated hemoglobin A1c score (IDAA1C). We next applied a series of both qualitative and statistical filters and selected protein candidates that were associated to pathophysiological mechanisms related to T1D. Finally, we translationally verified several of the candidates using single-shot targeted proteomic (PRM method) on raw plasma. Taken together, we identified plasma biomarkers present at diagnosis that may predict the occurrence of PR in a single mass-spectrometry run. We believe that the identification of new predictive biomarkers of PR and β-cell function is key to stratify people with new-onset T1D for β-cell preservation therapies.

Association between COVID-19 and the incidence of type 1 diabetes in Portugal – a registry study

BackgroundViral respiratory infections may precipitate type 1 diabetes (T1D). A possible association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, and the incidence of T1D is being determined. This study was carried out using Portuguese registries, aiming at examining temporal trends between COVID-19 and T1D.MethodsHospital data, comparing the incidence before and during the COVID-19 pandemic, from children and young adults diagnosed with new-onset T1D, was acquired beginning in 2017 and until the end of 2022. Data was obtained from nine different Portuguese hospital units. The impact of the COVID-19 pandemic, beginning in March 2020, was assessed comparing the annual numbers of new-onset T1D cases. The annual median levels of glucose, glycated hemoglobin (HbA1c) and fasting C-peptide at T1D diagnosis were compared. The annual number of diabetic ketoacidosis (DKA) episodes among new T1D cases was also assessed at two centers.ResultsIn total, data from 574 newly diagnosed T1D patients was analyzed, including 530 (92.3%) children. The mean ages for child and adult patients were 9.1 (SD 4.4) and 32.8 (SD 13.6) years, respectively. 57.8% (331/573) were male, one patient had unknown sex. The overall median (25–75 percentiles) levels of glucose, HbA1c and fasting C-peptide at diagnosis were 454 mg/dL (356–568), 11.8% (10.1–13.4) and 0.50 µg/L (0.30–0.79), respectively. DKA at T1D diagnosis was present in 48.4% (76/157). For eight centers with complete 2018 to 2021 data (all calendar months), no overall significant increase in T1D cases was observed during the COVID-19 pandemic, i.e. 90 cases in 2018, 90 cases in 2019, 112 in 2020 and 100 in 2021 (P for trend = 0.36). Two of the centers, Faro (CHUA) and Dona Estefânia (CHULC) hospitals, did however see an increase in T1D from 2019 to 2020. No significant changes in glucose (P = 0.32), HbA1c (P = 0.68), fasting C-peptide (P = 0.20) or DKA frequency (P = 0.68) at the time of T1D diagnosis were observed over the entire study period.ConclusionThe T1D incidence did not increase significantly, when comparing the years before and during the COVID-19 pandemic, nor did key metabolic parameters or number of DKA episodes change.

Clinical features, biomarkers and diabetic ketoacidosis at diagnosis of type 1 diabetes among children and adolescents in Sana’a, Yemen

IntroductionThere is little published information on type 1 diabetes (T1D) in children in Yemen. We aimed to identify the clinical characteristics, biomarkers and diabetic ketoacidosis (DKA) at diagnosis of T1D...

Early Onset of Type 1 Diabetes in Kuwait: Distinct Clinical, Metabolic, and Immunological Characteristics.

Exploring early-onset diabetes in terms of describing characteristics at time of diagnosis might aid in a better understanding of etiology and may have implications on management and prevention. The aim of this study was to investigate the prevalence of early-onset type 1 diabetes (T1D) in Kuwait as well as describe their baseline clinical, biochemical, and immunological characteristics. Medical records of children newly diagnosed with T1D and registered in the Childhood-Onset Diabetes electronic Registry (CODeR) in Kuwait between 2017 and 2022 were reviewed. Early-onset T1D was defined as diagnosis at age younger than 6 years. 2,051 children were registered with new-onset T1D between 2017 and 2022, of which 657 (32.0%) were diagnosed at early onset. There has been a trend of slight increase in the percentage of early-onset T1D after 2020 (15.2%) with a prevalence of 18.4% and 20.2% in 2021 and 2022, respectively (p = 0.056). Age at onset was inversely related to admission to the pediatric intensive care unit (OR = 0.90, 95% CI: 0.85, 0.95, p < 0.0001) and was directly related to positive celiac autoimmunity (p = 0.022), higher hemoglobin A1C (p < 0.0001), and C-peptide levels (p < 0.0001). However, age at onset of T1D was inversely related to the higher vitamin D levels (p < 0.0001). These findings reinforce the need for increased attention to be given to study the development of T1D in children of younger age. This in turn will support special management and prevention measures targeted toward this vulnerable age group.

Incidence of type 1 diabetes in Sardinian children aged 0–14 years has almost doubled in the last twenty years. On top of the world

AimsThe primary objectives were to investigate the incidence rate (IR) of type 1 diabetes (T1D) in Sardinian children aged 0–14 years in 2019–2022 and to examine the temporal trend from 1989-1999. MethodsData from new-onset T1D patients aged 0–14 years who were residents of Sardinia were collected from all pediatric diabetology clinics. The overall, sex- and age specific (groups 0–4, 5–9, and 10–14 years), and calendar year IRs were calculated. The standardized IR (SIR) was also calculated using the direct method. Poisson regression was used to estimate the temporal trend in the SIRs from 1989-1999 to 2019–2022. ResultsIn 2019–2022, 512 patients aged 0–14 years were diagnosed with T1D in Sardinia. The overall IR was 73.9 per 100,000 person-years (95 % CI 67.6–80.0). Since 1989, the SIR has increased by 2.3 % per year (CI 1.7–2.8, p < 0.0001). The frequency of ketoacidosis at onset was 26.4 %, with no significant differences among the four years. ConclusionsThe incidence of T1D in Sardinia, unlike in other countries such as Finland, has almost doubled in the last 20 years, and currently, it appears to be the highest in the world.

Bioengineered Artificial Extracellular Vesicles Presenting PD-L1 and Gal-9 Ameliorate New-Onset Type 1 Diabetes.

An important factor in the development of Type 1 diabetes (T1D) is the deficiency of inhibitory immune checkpoint ligands, specifically programmed cell death ligand 1 (PD-L1) and Galectin-9 (Gal-9), in β-cells. Hence, modulation of the pancreas infiltrated T lymphocytes by exogenous PD-L1 or Gal-9 is an ideal approach for treating the new-onset T1D. Herein, we genetic engineered the macrophage cells to generate artificial extracellular vesicles (aEVs) overexpressing PD-L1 and Gal-9, which could restrict the islets autoreactive T lymphocytes and protect β-cells from destruction. Intriguingly, overexpressing Gal-9 spurred macrophage polarization to M2 phenotype with immune suppressive attribute. Alternatively, both of PD-L1 and Gal-9 presenting aEVs (PD-L1-Gal-9 aEVs) favorably adhere to T cells via the interaction of programmed cell death protein 1 (PD-1)/PD-L1 or T cell immunoglobulin mucin 3 (TIM-3)/Gal-9. Moreover, PD-L1-Gal-9 aEVs prominently promoted effector T cell apoptosis and splenic regulatory T cells (Treg) cells differentiation in vitro. Virtually, PD-L1-Gal-9 aEVs efficaciously reversed the new-onset hyperglycemia in the NOD mice, prevented T1D progress, and declined the proportion and activation of CD4+ and CD8+ T cells infiltrating the pancreas notably, which together contributed to preserving the residual β-cells survival and mitigating the hyperglycemia.

A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes.

CD4+CD25hiCD127lo/-FOXP3+ regulatory T cells (Tregs) play a key role in preventing autoimmunity. In autoimmune type 1 diabetes (T1D), adoptive transfer of autologous polyclonal Tregs has been shown to be safe in adults in phase 1 clinical trials. We explored factors contributing to efficacy of autologous polyclonal expanded Tregs (expTregs) in a randomized phase 2 multi-center, double-blind, clinical trial (Sanford/Lisata Therapeutics T-Rex phase 2 trial, ClinicalTrials.gov NCT02691247). One hundred ten treated children and adolescents with new-onset T1D were randomized 1:1:1 to high-dose (20 × 106 cells/kilogram) or low-dose (1 × 106 cells/kilogram) treatments or to matching placebo. Cytometry as well as bulk and single-cell RNA sequencing were performed on selected expTregs and peripheral blood samples from participants. The single doses of expTregs were safe but did not prevent decline in residual β cell function over 1 year compared to placebo (P = 0.94 low dose, P = 0.21 high dose), regardless of age or baseline C-peptide. ExpTregs were highly activated and suppressive in vitro. A transient increase of activated memory Tregs was detectable 1 week after infusion in the high-dose cohort, suggesting effective transfer of expTregs. However, the in vitro fold expansion of expTregs varied across participants, even when accounting for age, and lower fold expansion and its associated gene signature were linked with better C-peptide preservation regardless of Treg dose. These results suggest that a single dose of polyclonal expTregs does not alter progression in T1D; instead, Treg quality may be an important factor.

Transient albuminuria in the setting of short-term severe hyperglycemia in type 1 diabetes

In a cohort of 1817 children with type 1 diabetes (T1D), short-term hyperglycemia was associated with transient albuminuria (11 % during new-onset T1D without diabetic ketoacidosis (DKA), 12 % during/after DKA, 6 % during routine screening). Our findings have implications regarding future risk of diabetic kidney disease and further investigation is needed.

Family History of Type 2 Diabetes and Its Association with Beta Cell Function and Lipid Profile in Newly Diagnosed Pediatric Patients with Type 1 Diabetes

ABSTRACT Objective The objective of this study was to explore the associations between a family history of type 2 diabetes (T2D) and beta-cell function, as well as lipid profile, in pediatric patients newly diagnosed with type 1 diabetes (T1D). Methods A retrospective analysis was conducted on children under 14 years of age who were newly diagnosed with T1D at the Children’s Hospital of Zhejiang University between August 2018 and August 2022. Clinical features, metabolic profiles, beta-cell function, and lipid profile were evaluated. Results A total of 316 children were diagnosed with new-onset T1D. Among them, 28.2% had a family history of T2D. Patients with T1D who had a family history of T2D experienced a later onset of the disease (p = 0.016), improved HOMA2-%B levels (p = 0.003), and increased concentrations of HDL-C (p = 0.005). In addition, no statistically significant differences in age at onset, HOMA2-%B levels, or HDL-C were found when assessing the interaction between family history of T2D and type of diabetes mellitus (autoimmune T1D/idiopathic T1D). Conclusion A family history of T2D may contribute to the heterogeneity of T1D patients in terms of HOMA2-%B levels and lipid profile. This highlights the significance of taking into account T2D-related factors in the diagnosis and treatment of T1D.

Child Opportunity Index and clinical characteristics at diabetes diagnosis in youth: type 1 diabetes versus type 2 diabetes

IntroductionAmong youth with type 1 diabetes (T1D), longitudinal poor glycemic control is associated with adverse socioeconomic conditions at the neighborhood level. Child Opportunity Index (COI), which encompasses measures of education,...

The COVID-19 Pandemic Increased the Incidence of New-Onset Type One Diabetes in Children.

Background: The impact of the COVID-19 pandemic on the incidence rate of childhood type 1 diabetes (T1D) is controversial. Our aim was to analyze the incidence of new-onset T1D among children aged 0-17 before and during the COVID-19 pandemic in Israel. Methods: Data obtained from the national T1D registry for children aged 0-17 were analyzed for the pre-pandemic (1997-2019) and pandemic (2020-2022) periods. In the pre-pandemic period, 7246 children with newly diagnosed T1D were compared with 1490 children diagnosed during the pandemic period. Results: T1D incidence significantly increased in the 0-17 age group from a mean of 12.9/105 (pre-pandemic) to 17.7/105 and 16.7/105 during the first two years of the pandemic (2020 and 2021, respectively) (p = 0.0001). Stratifying by age group (0-4, 5-9, 10-14, and 15-17) revealed a significant increase in the 5-9, 10-14, and 15-17 groups, both in 2020 (p = 0.0001) and in 2021 (p = 0.0001). The incidence rate in the 0-4 age group showed no change in the first year of the pandemic (2020) (p = 0.4). However, in the second year of the pandemic (2021), there was a significant increase from 6.3/105 in the pre-pandemic period to 9.1/105 (p = 0.001). Anti-COVID-19 vaccination in 2022 led to a significant decrease in the incidence rates in the 10-14 and 15-17 age groups (p = 0.03 and p = 0.02, respectively). Conclusion: The COVID-19 pandemic was associated with a significant increase in the incidence of new-onset T1D in prepubertal and pubertal children. Anti-COVID-19 vaccination decreased the incidence rate significantly only in pubertal children.

Circulating hsa-miR-320a and its regulatory network in type 1 diabetes mellitus.

Increasing evidence from human and animal model studies indicates the significant role of microRNAs (miRNAs) in pancreatic beta cell function, insulin signaling, immune responses, and pathogenesis of type 1 diabetes (T1D). We aimed, using next-generation sequencing, to screen miRNAs from peripheral blood mononuclear cells of eight independent Kuwaiti-Arab families with T1D affected siblings, consisting of 18 T1D patients and 18 unaffected members, characterized by no parent-to-child inheritance pattern. Our analysis revealed 20 miRNAs that are differentially expressed in T1D patients compared with healthy controls. Module-based weighted gene co-expression network analysis prioritized key consensus miRNAs in T1D pathogenesis. These included hsa-miR-320a-3p, hsa-miR-139-3p, hsa-miR-200-3p, hsa-miR-99b-5p and hsa-miR-6808-3p. Functional enrichment analysis of differentially expressed miRNAs indicated that PI3K-AKT is one of the key pathways perturbed in T1D. Gene ontology analysis of hub miRNAs also implicated PI3K-AKT, along with mTOR, MAPK, and interleukin signaling pathways, in T1D. Using quantitative RT-PCR, we validated one of the key predicted miRNA-target gene-transcription factor networks in an extended cohort of children with new-onset T1D positive for islet autoantibodies. Our analysis revealed that hsa-miR-320a-3p and its key targets, including PTEN, AKT1, BCL2, FOXO1 and MYC, are dysregulated in T1D, along with their interacting partners namely BLIMP3, GSK3B, CAV1, CXCL3, TGFB, and IL10. Receiver Operating Characteristic analysis highlighted the diagnostic potential of hsa-miR-320a-3p, CAV1, GSK3B and MYC for T1D. Our study presents a novel link between hsa-miR-320a-3p and T1D, and highlights its key regulatory role in the network of mRNA markers and transcription factors involved in T1D pathogenesis.

Analiza učestalosti i dužine trajanja kliničke remisije u pacijenata sa novootkrivenim tipom 1 dijabetesa

Introduction: Clinical remission (CR) phase, in other words, euglycaemia, in the absence of insulin therapy (complete CR) or with a reduced daily dose of insulin (partial CR) can be achieved in some patients with new-onset type 1 diabetes (T1D) after the introduction of insulin therapy. Unfortunately, there is still not enough information about the factors influencing the induction and duration of remission. Material and methods: This research included 62 patients with the diagnosis of new-onset T1D, who were treated at the Clinic of Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia in 2019 and 2020. Demographic, clinical and laboratory data were acquired from medical records. Descriptive statistical methods, Fisher's exact probability test, Pearson's chi-square test, Student's t test, Mann Whitney U test and Spearman's correlation coefficient were used for statistical analysis. Results: Clinical remission was inducted in 46.8% of patients and its average duration was 11.2 months. Patients with CR had remarkably lower HbA1c values (9.9 ± 2.8 vs 11.8 ± 2.4%; p=0.007) and lost less weight (4 vs 12 kg, p&lt;0.001) compared to patients without CR. Additionally, C peptide levels at the beginning and 6 minutes after the glucagon test were remarkably higher in patients with CR compared to patients without CR (p&lt;0.001). At the same time, remarkably more patients with CR had autoantibodies detected compared to those without CR (GAD 100% vs 72.4% i IA2-2A 81.8% vs 34.5%; p=0.001). The duration of CR was remarkably correlated with the level of C peptide at the beginning and 6 minutes after the glucagon test (p&lt;0.001). Conclusion: Patients with CR (46.8%) had better metabolic control, less weight loss, better endogenous insulin reserve capacity and less frequent presence of autoantibodies to beta cell antigens at disease onset. At the same time, the duration of CR was associated with an initially better, preserved, endogenous insulin reserve.

Tracking DNA-based antigen-specific T cell receptors during progression to type 1 diabetes.

T cells targeting self-proteins are important mediators in autoimmune diseases. T cells express unique cell-surface receptors (TCRs) that recognize peptides presented by major histocompatibility molecules. TCRs have been identified from blood and pancreatic islets of individuals with type 1 diabetes (T1D). Here, we tracked ~1700 known antigen-specific TCR sequences, islet antigen or viral reactive, in bulk TCRβ sequencing from longitudinal blood DNA samples in at-risk cases who progressed to T1D, age/sex/human leukocyte antigen-matched controls, and a new-onset T1D cohort. Shared and frequent antigen-specific TCRβ sequences were identified in all three cohorts, and viral sequences were present across all ages. Islet sequences had different patterns of accumulation based upon antigen specificity in the at-risk cases. Furthermore, 73 islet-antigen TCRβ sequences were present in higher frequencies and numbers in T1D samples relative to controls. The total number of these disease-associated TCRβ sequences inversely correlated with age at clinical diagnosis, indicating the potential to use disease-relevant TCR sequences as biomarkers in autoimmune disorders.

“It changed everything we do”: A mixed methods study of youth and parent experiences with a pilot exercise education intervention following new diagnosis of type 1 diabetes

AimsThis pilot study delivered a comprehensive exercise education intervention to youth with new-onset type 1 diabetes (T1D) and their parents to increase knowledge and confidence with physical activity (PA) shortly after diagnosis. MethodsYouth initiated continuous glucose monitoring (CGM) and PA trackers within 1 month of diagnosis. Youth and their parents received the 4-session intervention over 12 months. Participants completed self-report questionnaires at baseline, 6- and 12-months. Surveys were analyzed using linear mixed effects models. Semi-structured interviews and focus groups explored experiences with the exercise education intervention. Groups and interviews were audio-recorded, transcribed, and analyzed using content analysis. ResultsA total of 16 parents (aged 46 ± 7 years; 88 % female; 67 % non-Hispanic White) and 17 youth (aged 14 ± 2 years; 41 % female; 65 % non-Hispanic White) participated. Worry about hypoglycemia did not worsen throughout the study duration. Parents and youth reported increased knowledge and confidence in managing T1D safely and preventing hypoglycemia during PA following receiving the tailored exercise education intervention. ConclusionThis study assessed a novel structured exercise education program for youth and their parents shortly following T1D diagnosis. These results support the broad translation and acceptability of a structured exercise education program in new-onset T1D.

The Effect of COVID-19 on Type 1 Diabetes Occurrence among Children and Adolescents: A Multicenter Prospective Observational Cohort Study in Israel

Aim. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pediatric occurrence of type 1 diabetes (T1D) is inconclusive. We aimed to assess associations between seroprevalences of the distinct anti-SARS-CoV-2 antibodies and T1D occurrence in children and adolescents. Methods. This multicenter prospective observational cohort comprised children diagnosed with T1D between October 2020 and July 2022 and unrelated children who performed endocrine tests (control group) in a 1 : 3 ratio. Anti-SARS-CoV-2 antibodies, including anti-S, anti-N, and neutralizing antibodies, were assessed in each group. Results. The cohort included 51 children with T1D and 182 children in the control group. The median (interquartile range) age was 11.4 (8.2, 13.3) years, with 45% being female. Increases were not observed in the seroprevalence of any of the anti-SARS-CoV-2 antibodies among the children with new-onset T1D compared to the control group. Among the T1D group, anti-S seroprevalence was higher among those without diabetic ketoacidosis (DKA) than in those with DKA upon T1D diagnosis (72% vs. 42%, p = 0.035 ). After adjustment to vaccination status, this difference was not statistically significant. Additionally, anti-N antibodies and neutralizing antibodies did not differ between the DKA and the non-DKA groups. None of the anti-SARS-CoV-2 antibodies were associated with any of the glycemic parameters. Conclusions. This study is the first to assess several distinct anti-SARS-CoV-2 antibodies in new-onset T1D, and our findings do not support an association between SARS-CoV-2 infection and the occurrence of T1D in children and adolescents. Since autoimmunity may emerge years after a viral infection, we recommend conducting follow-up epidemiological studies to assess whether there is a change in the incidence of T1D following the SARS-CoV-2 pandemic.

FRI608 Secondary Prevention Of Diabetes Type 1 With Oral Calcitriol And Analogs, The Precal Study

Abstract Disclosure: D.T. Papadimitriou: None. E. Dermitzaki: None. P. Christopoulos: None. M. Papagianni: None. K. Kleanthous: None. C. Marakaki: None. A. Papadimitriou: None. G. Mastorakos: None. Type 1 diabetes (T1D) hits about 1:300 with rising incidence affecting increasingly younger children. Population screening at ages 2 and 6 yrs with T1D associated autoantibodies (T1Ab) has been recently proven sensitive. While potential treatments to prevent or delay T1D are currently in development, a population based cost-effective preventive strategy is still lacking. Hence, 2000 IU cholecalciferol daily in a large birth cohort study published in 2001 reduced by 80% the risk of T1D in 1 yr. A pilot clinical trial 10 yrs ago, demonstrated negativation of T1Ab within 0.6 (0.4-2.1) yrs under oral calcitriol in 12 children. To further pursue this hypothesis, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). Between 2010-2022, 50 children (26 boys, 24 girls) aged 0.65-16,37 yrs identified as at high risk for T1D were included: 44 were positive for T1Ab (Insulin auto-antibodies, IAA; anti-tyrosinase abs, IA2, anti-glutamic decarboxylase abs, GAD; islet auto-abs, ICA; anti-Zn8 if available) and 6 with negative T1Abs had predisposing HLA A DQ DR haplotypes and genotypes. Nine were diagnosed with varied impaired glucose tolerance (IGT) ( all T1Ab+), 4 with pre-T1D (3 T1Ab+ and 1 HLA+), and 9 had new-onset T1D (all T1Ab+). Serum T1Ab levels and fasting plasma glucose, HbA1c, c-peptide, Ca (tolerated ≤11.5 mg/dl), P, ALP, Ca/Cr 2-hr urine morning sample, 25(OH)D, 1-25(OH)2D with renal ultrasound in cases with hypercalcemia/hypercalciuria (tolerated ≤50%, or at the upper normal for age) were determined before and q3-6 months after initiation of calcitriol (0.05 mcg/Kg/day) 0.25-0.5 x 1-3/day or its synthetic analogue, paricalcitol (thrice the calcitriol dose) 1-4 mcg x 1-3/day p.o. under cholecalciferol repletion. Measurements are given as median and range. Available data on 42 (7 dropouts, 1 follow-up &amp;lt; 3 m). All 26 without pre-T1D/T1D followed 3.06 (0.5-10) yrs negativized T1Ab (15 IAA, 3 IA2, 4 ICA, 2 GAD, 1 IAA/GAD, 1 ICA/GAD) within 0.57 (0.32-1.3) yrs or did not progress to T1D [5 +HLA, follow-up 3 (1-4) yrs]. From 4 pre-T1D, 1 negativized T1Ab (follow-up 1 yr), 1 with +HLA did not progress to T1D (follow-up 3.3 yrs) and 2 with +T1Ab developed T1D in 6m/3yrs. Three out of 8 children with T1D at presentation progressed immediately to overt disease, 5 showed complete remission for 1 yr (1m-2yrs). Five with +T1Ab relapsed and negativized again after resuming therapy. Four (aged &amp;lt; 3 yrs) negativized anti-TPO/TG, and 2 anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Calcitriol, and it’s less-calcemic analogue paricalcitol were 100% effective and reasonably safe in negativizing T1Ab in healthy children, possibly preventing the otherwise probably inevitable evolution towards clinical development of T1D, at least if started soon enough after seroconversion. Presentation: Friday, June 16, 2023

THU277 Deletion Or inhibition Of Ornithine Decarboxylase Protects Islet β-cell Health And Is Associated With Preserved Residual C-peptide In Persons With Recent Onset Type 1 Diabetes

Abstract Disclosure: B. Hammoud: None. L.A. DiMeglio: None. A. Kulkarni: None. A. Hull: None. S. Woerner: None. S. Cabrera: None. L.D. Mastrandrea: None. F. Ouyang: None. S.N. Perkins: None. C. Evans-Molina: None. T.L. Mastracci: None. S.A. Tersey: None. S. Sarkar: None. E. Nakayasu: None. B. Webb-Robertson: None. E. Gerner: None. R.G. Mirmira: None. E.K. Sims: None. Inhibition of polyamine biosynthesis using α-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, reduces β cell stress and type 1 diabetes (T1D) incidence in preclinical animal models. However, the cellular and molecular mechanisms by which polyamines promote β-cell stress and the tolerability and effectiveness of their depletion by DFMO in humans with T1D remain unknown. We hypothesized that β-cell protection from stress occurs via cell-autonomous effects of polyamine depletion. To test this hypothesis, we generated β-cell specific knockout of ornithine decarboxylase in mice, performed comprehensive proteomics and transcriptomics on human islets treated with DFMO under inflammatory conditions in vitro, and performed a clinical study of DFMO tolerability, safety, and efficacy in persons with new-onset T1D. β-cell-specific deletion of the gene encoding ornithine decarboxylase in mice demonstrated protection of these animals against toxin (streptozotocin)-induced β-cell loss and hyperglycemia, implicating a cell-autonomous role for ornithine decarboxylase in β-cell stress. RNA sequencing and proteomics analyses of human islets exposed to a cytokine mix (1000 U/mL IFNγ + 50 U/mL IL-1β) +/- 5 mM DFMO identified 130 differentially regulated transcripts and 701 differentially regulated proteins. Pathway analysis implicated endosomal transport, vesicle organization and regulation of exocytosis, mRNA processing, and antigen cross presentation as mechanisms underlying DFMO effects on the islet response. To test DFMO in humans, we performed a 3-site randomized, placebo-controlled, double masked dose-ranging study of 3 months daily oral DFMO in persons with recent-onset T1D (&amp;lt;100 days). Dosing at 125, 250, 500, 750 or 1000 mg/m2/day was tested in 41 persons (12-34 y/o, 59% male, mean HbA1c 7.3%), with 6-10 participants/dosing group. Only mild and moderate adverse effects (AEs) were noted. Possible drug-related AEs included mild-moderate gastrointestinal symptoms, headache, upper respiratory infections, a pump site infection, and anemia. Urinary levels of the ODC product putrescine were decreased (p=0.05) in the 1000 mg/m2 dosing group. Compared to placebo, individuals receiving 750 and 1000 mg/m2 doses had significantly higher mixed-meal C-peptide area under the curve values at the 6-month post-randomization visit (p&amp;lt;0.05 vs. placebo). In conclusion, β-cell ODC inhibition protects β-cell health and function in the context of the proinflammatory T1D milieu. A 3-month course of oral DFMO was well tolerated with a favorable AE profile in persons with recent-onset T1D. Higher doses were associated with greater β-function compared to placebo. DFMO may have utility as a β-cell preservation therapy in recent-onset T1D. Presentation: Thursday, June 15, 2023