Teplizumab, an anti-CD3 monoclonal antibody, is approved for delaying progression to stage 3 type 1 diabetes (T1D) in individuals with stage 2 disease (1) and has been evaluated in a series of new onset T1D clinical trials. As its use expands, prompt recognition and management of treatment-related adverse effects, particularly cytokine release syndrome (CRS), is increasingly important.

Introduction and Objective: Teplizumab (TPZ), an anti-CD3 monoclonal antibody, is approved in the US to delay stage 3 T1D onset in individuals aged ≥8 years (y) with stage 2 T1D. We present screening and real-world treatment (Tx) patterns from individuals in the US who received TPZ according to their age group. Methods: TEPLI-REAL (NCT06892002) was a chart review study including 24 sites in the US. Eligible individuals had ≥1 day of TPZ Tx and were followed until data abstraction. Results: Median follow-up was 14.6 months (mo). The median age of individuals (n=101) at TPZ initiation was 13.0 y (range 8-62); 75 (74%) were <18 y. For youth, islet autoantibody (IA) testing was most requested by a pediatric endocrinologist (endoc; n=36; 48%) and performed by Autoimmunity Screening for Kids/TrialNet (n=27; 36%) research programs; 74 (99%) had ≥2 IAs (GADA: 73 [97%], IAA: 38 [61%], IA-2A: 49 [78%], and ZnT8A: 56 [85%]). At screening, 67 (90%) had HbA1c tests (median 5.8%; range 4.8-11.5), 36 (49%) had oral glucose tolerance tests (OGTTs), and 7 (9%) had continuous glucose monitoring (CGM) data. The median (range) time between stage 2 confirmation and TPZ initiation was 3.5 (0.6-119.6) mo. TPZ Tx occurred most commonly in hospitals (n=33; 44%), and 71 (95%) completed 14 days of Tx. For adults, IA testing was most requested by an adult endoc (n=9; 35%) and performed at a commercial laboratory (n=10; 38%); 26 (100%) had ≥2 IAs (GADA: 25 [100%], IAA: 7 [33%], IA-2A: 18 [69%], and ZnT8A: 17 [71%]). At screening, 20 (77%) had HbA1c tests (median 6.1%; range 4.7-13.8), 13 (50%) had OGTTs, and none had CGM data. The median (range) time between stage 2 confirmation and TPZ initiation was 6.4 (1.5-184.6) mo in adults. Most TPZ Tx occurred in infusion centers (n=19; 73%), and 23 (88%) completed 14 days of Tx. Conclusion: This TEPLI-REAL US cohort provides important insights into the care pathway of youth and adults who were treated with TPZ in clinical practice. Disclosure M. Tuffaha: None. J. Felton: Advisory Panel; Ended; Sanofi. Other - Gave educational lectures.; Ended; Sanofi, Med Learning Group, LLC. T.E. Graham: Research Support; Current; Eli Lilly and Company, Novo Nordisk, Abbott Diagnostics, Tandem Diabetes Care, Inc., Sanofi, Novartis Pharmaceuticals Corporation. Advisory Panel; Current; Ascendis Pharma A/S. Research Support; Current; Ascendis Pharma A/S. Advisory Panel; Current; Sanofi. Research Support; Current; Sequel Med Tech. K. Simmons: None. A. Tirosh: Advisory Panel; Current; Medtronic. Research Support; Current; Medtronic. Speaker's Bureau; Ended; Sanofi. Advisory Panel; Ended; Sanofi. Research Support; Current; Sanofi. Speaker's Bureau; Ended; Novo Nordisk A/S, Eli Lilly and Company. Consultant; Current; DreaMed Diabetes, Ltd., Radella Pharma. M. Bonnemaire: Employee; Current; Sanofi. Stock/Shareholder; Current; Sanofi. C.B. Manzano Salgado: Employee; Current; Sanofi. Employee; Ended; IQVIA Inc. T.A. Dex: Stock/Shareholder; Current; Sanofi, Pfizer Inc., Teva Pharmaceutical Industries Ltd. F. Kleinjung: Employee; Current; Sanofi. J.M. Gwinnutt: Employee; Current; IQVIA Inc. F. Negreiro: Employee; Current; IQVIA Inc. J.H. Zaccai: Employee; Current; Sanofi. S.E. Gitelman: Advisory Panel; Current; Sanofi, SAB Biotherapeutics, Inc., Eli Lilly and Company, Genentech, Inc. Research Support; Current; Sanofi, SAB Biotherapeutics, Inc., GentiBio. Other - Member, DSMB; Current; Diamyd. Advisory Panel; Current; AnaptysBio, Inc.

There is significant interest in antigen specific approaches both to delay type 1 diabetes in pre-clinical stages and after diagnosis to support tolerance. We conducted a Phase 1 trial of a non-integrating DNA plasmid constructed to secrete the type 1 diabetes antigen pre-proinsulin (PPI) and the immune modulatory cytokines transforming growth factor β1 (TGF-β1), interleukin-10 (IL-10), and interleukin-2 (IL-2). In this placebo controlled, double-masked study of 47 adults with stage 3 type 1 diabetes, we showed that the drug is safe and well tolerated, with most reported adverse events (AE) categorized as grade 1 and with no clinically significant difference in AE amongst treatment groups. There were no untoward metabolic or immune effects. We found pharmacodynamic evidence of treatment, as demonstrated by a dose dependent type 1 interferon (IFN) signature. Plasmid DNA, representing a pharmocokinetic measure, was detected in the two highest dosing groups. We did not find global or antigen-specific immune cell changes following treatment with a DNA plasmid expressing pre-proinsulin, IL-2, IL-10 and TGF-β1, nor did we detect IL-2, IL-10 or TGF-b1 driven immune changes. Our results support further trials of this novel tolerizing antigen construct.

OBJECTIVE Posttransplant type 1 diabetes (T1D) is typically attributed to transferred donor autoimmunity. We investigated a distinct etiology in a patient who developed diabetes following haploidentical hematopoietic cell transplantation, assessing whether autoimmunity originated from donor or residual host cells. RESEARCH DESIGN AND METHODS Leveraging HLA disparity between the haploidentical donor and recipient, we used HLA class II tetramers to enumerate islet-specific CD4+ T cells in peripheral blood restricted by shared versus recipient-only HLA alleles. RESULTS Tetramer analysis revealed an expanded population of islet-specific T cells in the recipient. The donor showed no such expansion. Despite 99% donor T-cell chimerism, >80% of the islet-specific T cells were restricted by recipient-unique HLA alleles, suggesting they originated from the residual host fraction. CONCLUSIONS T1D in this patient was most likely driven by residual recipient-derived T cells. Their survival despite myeloablative conditioning and repeated immunotherapy underscores the remarkable durability of established islet autoimmunity.

What is this summary about? This is a plain language summary of a survey on experiences and views of (1) adults who were treated with teplizumab in early type 1 diabetes (T1D) and (2) caregivers of children who were treated with teplizumab in early T1D. Teplizumab is a treatment currently approved to delay the onset of stage 3 T1D in adults and children aged 8 years and older with stage 2 T1D. The survey collected information on: Characteristics and personal and family health history of the respondents.Experiences with finding out they or the child they care for had early T1D (screening and diagnosis).Thoughts and feelings before and after receiving treatment with teplizumab.Expectations for future health. This survey is the first to ask about the real-world experiences (outside of a clinical trial) of adults treated with teplizumab and caregivers of children treated with teplizumab. What were the results? Most people agreed with the statement that they were grateful for the chance to receive teplizumab (or for the child they care for to receive teplizumab).Most people also thought teplizumab would make their T1D easier to manage.Most people still worried about their condition getting worse and kept a close eye on their glucose levels after treatment with teplizumab.Even though they were concerned, they would recommend teplizumab to others and make the same decision for treatment if another family member had early T1D. What do the results of the survey mean? This survey captured the experiences and views of adults who received teplizumab or caregivers of children who received teplizumab. These findings are important for people who are considering screening for T1D or treatment with teplizumab, people who want to understand the possible consequences of having a screening test result showing early T1D, and clinicians who are considering teplizumab for their patients.

At present, no disease-modifying therapies are available for individuals who have been newly diagnosed with type 1 diabetes, despite promising results from decades of clinical trials initiated at stage 3 disease onset. Historically, clinical trials have used changes in the C-peptide AUC (AUCCp) during a mixed meal tolerance test (MMTT) as the primary endpoint; however, this measure does not always correlate with clinical outcomes. We analysed 4930 MMTT data points from 799 participants in nine Phase II stage 3 type 1 diabetes trials to determine whether a model-derived physiological measure of in vivo beta cell glucose sensitivity (βGS) could augment clinical trial strategies in type 1 diabetes. Older age and higher BMI were associated with maintenance of βGS (defined as loss <10

Introduction and Objective: Teplizumab (TPZ), an anti-CD3 monoclonal antibody, is approved in several countries to delay stage 3 type 1 diabetes (T1D) onset in individuals aged ≥8 years with stage 2. This is the first comprehensive study to characterize and follow individuals who received TPZ in the real world (RW). Methods: In the chart review study, TEPLI-REAL (NCT06892002), all individuals with ≥1 day of TPZ treatment at 27 participating sites were followed until data abstraction. Results: Among 110 individuals (US: n=101; Israel: n=9), 54% were female, 83% were White, 57% had a family history of T1D, 10% had Hashimoto’s, 4% had celiac disease. Median age was 13 years (range 8-62; 74% <18 years) at TPZ initiation. Median number of positive islet autoantibodies (IA) per individual was 3; 99% had ≥2 IA. Individuals were identified with dysglycemia first (41%), IA first (36%), or both at the same time (23%). Median HbA1c for these subgroups was 6.1% (n=41), 5.6% (n=32), and 6.0% (n=23), respectively, at or near screening. The median follow-up was 14.3 months. Most (94%) completed 14 days of TPZ. More than 70% remained in stage 2 T1D. Probability of remaining free of stage 3 per diagnostic pathway is shown in Figure. Conclusion: This RW study shows high TPZ infusion completion in those ≥8 years and provides insights into treatment from different diagnostic pathways. Disclosure S.E. Gitelman: Advisory Panel; Current; Sanofi, SAB Biotherapeutics, Inc., Eli Lilly and Company, Genentech, Inc. Research Support; Current; Sanofi, SAB Biotherapeutics, Inc., GentiBio. Other - Member, DSMB; Current; Diamyd. Advisory Panel; Current; AnaptysBio, Inc. K. Simmons: None. T.E. Graham: Research Support; Current; Eli Lilly and Company, Novo Nordisk, Abbott Diagnostics, Tandem Diabetes Care, Inc., Sanofi, Novartis Pharmaceuticals Corporation. Advisory Panel; Current; Ascendis Pharma A/S. Research Support; Current; Ascendis Pharma A/S. Advisory Panel; Current; Sanofi. Research Support; Current; Sequel Med Tech. J. Felton: Advisory Panel; Ended; Sanofi. Other - Gave educational lectures.; Ended; Sanofi, Med Learning Group, LLC. A. Tirosh: Advisory Panel; Current; Medtronic. Research Support; Current; Medtronic. Speaker's Bureau; Ended; Sanofi. Advisory Panel; Ended; Sanofi. Research Support; Current; Sanofi. Speaker's Bureau; Ended; Novo Nordisk A/S, Eli Lilly and Company. Consultant; Current; DreaMed Diabetes, Ltd., Radella Pharma. M. Bonnemaire: Employee; Current; Sanofi. Stock/Shareholder; Current; Sanofi. C.B. Manzano Salgado: Employee; Current; Sanofi. Employee; Ended; IQVIA Inc. T.A. Dex: Stock/Shareholder; Current; Sanofi, Pfizer Inc., Teva Pharmaceutical Industries Ltd. F. Kleinjung: Employee; Current; Sanofi. J.M. Gwinnutt: Employee; Current; IQVIA Inc. F. Negreiro: Employee; Current; IQVIA Inc. J.H. Zaccai: Employee; Current; Sanofi. M. Tuffaha: None.

Identifying individuals at high risk of type 1 diabetes (T1D) is crucial as disease-delaying medications are available. Here we report a microRNA (miRNA)-based dynamic (responsive to the environment) risk score developed using multicenter, multiethnic and multicountry ('multicontext') cohorts for T1D risk stratification. Discovery (wet and dry lab) analysis identified 50 miRNAs associated with functional β cell loss, which is a hallmark of T1D. These miRNAs measured across n = 2,204 individuals from four contexts (4C: Australia, Denmark, Hong Kong SAR People's Republic of China, India) led to a four-context, miRNA-based dynamic risk score (DRS) that effectively stratified individuals with and without T1D. Generative artificial intelligence was used to create an enhanced four-context, miRNA-based DRS, which offered good predictive power (area under the curve = 0.84) for T1D stratification in a separate multicontext validation dataset (n = 662), and accurately predicted future exogenous insulin requirement at 1 hour of islet transplantation. In a clinical trial assessing the imatinib drug therapy, baseline miRNA signature, rather than clinical characteristics, distinguished drug responders from nonresponders at 1 year. This study harnessed machine learning/generative artificial intelligence approaches, identifying and validating a miRNA-based DRS for T1D discrimination and treatment efficacy prediction.

is not a required field for Obituaries

Objective:Identify microbial and microbiota-associated metabolites in monozygotic (MZ) and dizygotic (DZ) twins discordant for type 1 diabetes (T1D) to gain insight into potential environmental factors that may influence T1D. Research Design and Methods:Serum samples from 39 twins discordant for T1D were analyzed using a semi-targeted metabolomics approach via liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS). Statistical analyses identified significant metabolites (p < 0.1) within three groups: All twins (combined group), MZ twins, and DZ twins. Results:Thirteen metabolites were identified as significant. 3-indoxyl sulfate and 5-hydroxyindole were significantly reduced in T1D individuals across all groups. Carnitine was reduced, and threonine, muramic acid, and 2-oxobutyric acid were significantly elevated in both All and MZ groups. Allantoin was significantly reduced and 3-methylhistidine was significantly elevated in All and DZ groups. Conclusions:Metabolite dysregulation associated with gut dysbiosis was observed. However, further validation of our findings in a larger cohort is needed. Article Highlights:Why did we undertake this study? We believed this cohort of twins discordant for type 1 diabetes (T1D) would allow for control over genetic variability to examine environmental factors.What is the specific question(s) we wanted to answer? We aimed to identify differences in microbial and microbiota-associated metabolites in twins discordant for T1D to examine the effect of the gut microbiome on T1D.What did we find? Thirteen metabolites were identified as significantly different.What are the implications of our findings? Our results show the dysregulation of several microbial metabolites in twin pairs, suggesting that the gut microbiome plays a role in the pathogenesis of T1D.

AIMS:This study surveyed individuals and caregivers of children who received teplizumab at stage 2 type 1 diabetes (T1D) to garner real-world experiences and their health outlook for the future following treatment with the first approved disease-modifying immune therapy for delaying the onset of Stage 3 T1D. MATERIALS AND METHODS:This was a cross-sectional, observational, online survey (conducted September-October 2024) of adults (≥18 years) and caregivers of children (8-17 years) who received teplizumab while participating in the US COMPASS patient support program. Questions pertained to demographics, health history, T1D screening, the decision to take teplizumab, treatment, post-treatment experience, outlook on prognosis and self-reported health status. All data were summarized using descriptive statistics. RESULTS:A total of 47/116 invited individuals responded (30 adults, 17 caregivers of children). Almost half of respondents had a family history of T1D, and 36% reported autoimmune comorbidities. The top reason for both screening for T1D and receiving teplizumab was for a chance at delaying Stage 3 T1D. Although respondents expressed continued concern over diabetes progression, 87% felt grateful to receive teplizumab, 72% felt it would help slow down the disease, 60% felt it would make T1D easier to manage and most (>80%) would recommend treatment/make the same decision for another family member. CONCLUSIONS:Individuals living with or caring for someone who received teplizumab felt grateful for the opportunity to delay disease or make it easier to manage following teplizumab, with most agreeing they would recommend teplizumab and make the same decision for family in their situation. PLAIN LANGUAGE SUMMARY:Type 1 diabetes (T1D) happens when the body destroys cells in the pancreas that make insulin. This ultimately causes high blood sugar. People with T1D often worry about the long-term effects of the disease. Teplizumab is the first FDA-approved treatment that delays the onset of high blood sugar in people in the early stages of T1D-when there are signs of cell damage and mild increases in blood sugar. We surveyed adults (N = 30) and caregivers (N = 17) of children treated with teplizumab about their journey before and after treatment. More than half of adults were initially told they might have a different type of diabetes, usually type 2, before being accurately diagnosed with early-stage T1D. Doctors specializing in diabetes were most often the ones who recommended screening for T1D. The most common reason to screen was a chance for more time before the onset of high blood sugar. Greater than 80% of people were grateful they or their child had the opportunity to receive teplizumab, and most would recommend it to others in a similar situation. After receiving teplizumab, most people still worried about their blood sugar and measured it frequently. Most thought that teplizumab would delay the disease progression to symptoms, and more than half thought teplizumab would make T1D easier to manage. These findings are the first to describe the journey of adults and caregivers of children treated with teplizumab, their reasons for screening, and their beliefs about the future.

Teplizumab is approved in the USA and seven other countries to delay stage 3 type 1 diabetes onset in individuals ≥8 years of age with stage 2 type 1 diabetes. As part of a US Food and Drug Administration post-marketing requirement, this study evaluated the safety, tolerability and pharmacokinetics of teplizumab in children aged <8 years with stage 2 type 1 diabetes. The PETITE-T1D trial is a 2 year single-arm, open-label, multicentre study of 23 children <8 years of age with stage 2 type 1 diabetes. Participants received a 14 day teplizumab course. A prespecified interim analysis was performed after 15 participants completed 1 year of follow-up and included all 23 participants. Primary endpoints included treatment-emergent adverse events (TEAEs), TEAEs causing treatment discontinuation, and serious adverse events (SAEs). Other endpoints assessed immunogenicity, pharmacokinetics, pharmacodynamics and time from study treatment to stage 3 type 1 diabetes. Mean participant age was 4.8 years (range 1.7–6.8). Median follow-up duration was 51.9 weeks (range 3.9–77.1). All participants experienced one or more TEAE, with most being mild to moderate. No grade 4 or 5 TEAEs were reported. Three participants (13

We investigated serum metabolites in monozygotic (MZ) and dizygotic (DZ) twins discordant for type 1 diabetes (T1D) to explore potential environmental factors, with a focus on differences in gut microbiota-associated metabolites that may influence T1D. Serum samples from 39 twins discordant for T1D were analyzed using a semi-targeted metabolomics approach via liquid chromatography-high-resolution tandem mass spectrometry. Statistical analyses identified significant metabolites (P < 0.1) within three groups: all twins (combined group [All]), MZ twins, and DZ twins. Thirteen metabolites exhibited significant differences between individuals with T1D and those without T1D. Across all groups, 3-indoxyl sulfate and 5-hydroxyindole were significantly reduced in individuals with T1D. Carnitine was reduced, and threonine, muramic acid, and 2-oxobutyric acid were significantly elevated in both All and MZ groups. Allantoin was significantly reduced and 3-methylhistidine was significantly elevated in All and DZ groups. These findings suggest metabolite dysregulation associated with gut dysbiosis was observed. However, further validation of our findings in a larger cohort is needed. ARTICLE HIGHLIGHTS:We believed this cohort of twins discordant for type 1 diabetes (T1D) would allow for control over genetic variability to examine environmental factors. We aimed to identify differences in microbial and microbiota-associated metabolites in twins discordant for T1D to examine the effect of the gut microbiome on T1D. Thirteen metabolites were identified as significantly different. Our results show dysregulation of several microbial metabolites in twin pairs, suggesting the role of the gut microbiome in T1D pathogenesis.

We report the first case of imatinib use in an adolescent with diabetes and suggest that it impacts the natural course of disease. A 14-year-old male patient presented in diabetic ketoacidosis (DKA) and was diagnosed with presumed autoantibody-negative type 1 diabetes (T1D) as well as myeloid neoplasm with platelet-derived growth factor receptor beta (PDGFRB) rearrangement. After starting exogenous insulin and imatinib, he experienced a 1.7-point reduction in glycated hemoglobin (HbA1c) and a 71% reduction in insulin requirement with sustained partial diabetes remission. Our case suggests imatinib as a potential therapeutic agent for pediatric T1D.

Background & Aims: Teplizumab is an anti-CD3 mAb approved for delaying onset of Stage 3 T1D in people ≥8 years old with Stage 2 T1D. In the PROTECT study intent-to-treat (ITT) population, teplizumab demonstrated significantly greater β‑cell function preservation vs placebo (PBO; least-squares mean difference of C-peptide ln(AUC+1) change from baseline to Week 78 between teplizumab and PBO was 0.13 pmol/mL; p<0.001). In the ITT population, insulin dose was lower with teplizumab vs PBO from Week 12. Here we explore reduction in insulin dose and sustained glycemic control in the per-protocol (PP) population. Methods: The Phase 3 PROTECT study (NCT03875729) of 8-17-year-olds with Stage 3 T1D, diagnosed ≤6 weeks, randomized participants 2:1 to two 12-day courses of teplizumab or PBO. The PP population excluded those who received incorrect treatment, took prohibited medications, became pregnant, or had <80% treatment compliance. Results: In the PP analysis, teplizumab showed consistent results in reduced insulin dose, and greater % time in range (TIR) vs the PBO group (Table); HbA1c levels were not significantly different between groups. Conclusions: Participants treated with teplizumab showed greater β-cell function preservation and clinically relevant metabolic outcomes including lower insulin doses and greater TIR vs PBO. Disclosure K.C. Herold: Consultant; Sanofi. C. Dayan: Consultant; Provention Bio, Inc., Sanofi. Other Relationship; Dompé. Advisory Panel; Avotres Inc., Amgen Inc. L. Chatenoud: Consultant; Provention Bio, Inc., Sanofi. S.E. Gitelman: Advisory Panel; Abata Therapeutics, Avotres Inc., Genentech, Inc., GentiBio, SAB Biotherapeutics, Inc., Sanofi. Z. Sumnik: None. K.M. Simmons: Advisory Panel; Provention Bio, Inc. Consultant; Provention Bio, Inc. Research Support; Provention Bio, Inc., Novartis AG. Consultant; Medtronic. A. Szypowska: Speaker's Bureau; Abbott. Advisory Panel; Dexcom, Inc., Medtronic. Speaker's Bureau; Sanofi, Novo Nordisk. Advisory Panel; SYNOPIS Pharma, Proglikemia. Research Support; Provention Bio, Inc. L. Knecht: Employee; Sanofi, Provention Bio, Inc. E. Niemoeller: Employee; Sanofi-Aventis Deutschland GmbH. Stock/Shareholder; Sanofi. W. Tian: Employee; Sanofi. E.L. Ramos: None. Funding Provention Bio, a Sanofi company

CD4 + CD25 hi CD127 lo/− FOXP3 + regulatory T cells (T regs ) play a key role in preventing autoimmunity. In autoimmune type 1 diabetes (T1D), adoptive transfer of autologous polyclonal T regs has been shown to be safe in adults in phase 1 clinical trials. We explored factors contributing to efficacy of autologous polyclonal expanded T regs (expT regs ) 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 × 10 6 cells/kilogram) or low-dose (1 × 10 6 cells/kilogram) treatments or to matching placebo. Cytometry as well as bulk and single-cell RNA sequencing were performed on selected expT regs and peripheral blood samples from participants. The single doses of expT regs 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. ExpT regs were highly activated and suppressive in vitro. A transient increase of activated memory T regs was detectable 1 week after infusion in the high-dose cohort, suggesting effective transfer of expT regs . However, the in vitro fold expansion of expT regs 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 T reg dose. These results suggest that a single dose of polyclonal expT regs does not alter progression in T1D; instead, T reg quality may be an important factor.

In 2015, introduction of a disease staging system offered a framework for benchmarking progression to clinical type 1 diabetes. This model, based on islet autoantibodies (stage 1) and dysglycaemia (stage 2) before type 1 diabetes diagnosis (stage 3), has facilitated screening and identification of people at risk. Yet, there are many limitations to this model as the stages combine a very heterogeneous group of individuals; do not have high specificity for type 1 diabetes; can occur without persistence (ie, reversion to an earlier risk stage); and exclude age and other influential risk factors. The current staging system also infers that individuals at risk of type 1 diabetes progress linearly from stage 1 to stage 2 and subsequently stage 3, whereas such movements are often more complex. With the approval of teplizumab by the US Food and Drug Administration in 2022 to delay type 1 diabetes in people at stage 2, there is a need to refine the definition and accuracy of type 1 diabetes staging. Theoretically, we propose that a type 1 diabetes risk calculator should incorporate any available demographic, genetic, autoantibody, metabolic, and immune data that could be continuously updated. Additionally, we call to action for the field to increase the breadth of knowledge regarding type 1 diabetes risk in non-relatives, adults, and individuals from minority populations.