Background:A contemporary description and estimates for rates of chronic kidney disease (CKD) in type 1 diabetes are needed to inform risk reduction strategies. The study aim was to assess prevalence and severity of CKD based on a population with type 1 diabetes receiving care at a large United States health system. Methods:Type 1 diabetes was identified through the Providence health system electronic health records during 2013-2022. Prevalent CKD was defined cross-sectionally by ≥ 90-day persistence of estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, urine albumin-to-creatinine ratio ≥30 mg/g, or urine protein-to-creatinine ratio ≥0.15 g/g. Multivariable logistic regression models analyzed variable associations with CKD and severe kidney disease (eGFR < 45 mL/min/1.73 m2, dialysis, or transplant). Findings:The study population (N = 23,589) was 48.6% female with a mean ± SD age of 38 ± 17 years. CKD prevalence was 27.1%. Higher odds of CKD were found for females (odds ratio: 1.36 [95% confidence interval]: 1.26-1.47); age 60-79 years (reference 12-17 years; 2.22 [1.83-2.69]); Asian (reference White; 1.71 [1.20-2.44]), Black or African American (1.76 [1.45-2.14]), and Other race (1.33 [1.04-1.71]) populations. CKD odds were higher with hypertension, heart failure, and atherosclerotic cardiovascular disease. Severe kidney disease was present in 10.8% with higher odds among Black or African American (2.08 [1.23-3.54]) and Native Hawaiian or Pacific Islander (2.62 [1.28-5.38]) populations. Interpretation:CKD was present in nearly one of three persons with type 1 diabetes with higher risks for females, older adults, racial and ethnic minorities, and those with cardiovascular diseases. Severe kidney disease was found in over one-tenth and more likely in Black or African American and Native Hawaiian or Pacific Islander populations. Focus on disproportionately affected groups who may benefit from monitoring and interventions to improve clinical outcomes will be important for public health and health system strategies to reduce risks of CKD and severe kidney disease in type 1 diabetes. Funding:This work was supported in part by CDC project numbers 75D301-21-P-12254 and 75D301-23-C-18264, and in part by Brigham Research Institute.

Two major accomplishments in the field of prediction and prevention have had important implications for type 1 diabetes (T1D), as well as other immune-mediated diseases such as inflammatory bowel disease (IBD). First, individuals destined to develop T1D can now be identified by testing for the presence of autoantibodies, long before signs or symptoms of clinical disease. Second, there is now an FDA-approved therapy to delay disease progression. These accomplishments were made possible by more than 4 decades of multicenter research, sustained commitments from funders, a culture of collaboration that enabled international standardization of autoantibody measurements, and common entry criteria and outcome measures for clinical trials. Robust data find that essentially everybody with 2 or more autoantibodies will eventually progress to clinical disease. This concept is now codified as stages of T1D, whereby those with multiple autoantibodies are considered to have early-stage disease. This provided a pathway for regulatory approval by clarifying that therapy was aimed at treating people with disease in contrast to preventing disease in healthy individuals and has helped antibody-positive individuals understand risk. Translating these scientific accomplishments into clinical practice remains challenging, but the availability of an approved therapy to delay T1D onset suggests that such translation is on the horizon for T1D and ultimately for other immune-mediated diseases.

Background/Aims Type 1 Diabetes TrialNet (TrialNet) conducted a placebo randomized trial in children and adults with pre-clinical type 1 diabetes (T1D) to test whether hydroxychloroquine (HCQ) could delay or prevent progression to clinical T1D. Study regulators required more frequent monitoring for retinal toxicity than is recommended by clinical guidelines and we evaluated the impact of this monitoring. Methods We obtained the outcome of all eye exams from TrialNet and focused on exams that were recommended for follow up outside the protocol or for repeat testing within the trial. Results No HCQ related retinal toxicity was found, but increased frequency of monitoring led to additional testing due to incomplete exams or technical difficulties, and incidental findings prompted the need for follow up outside the study. Conclusion Our analysis suggests that increased frequency of retinal monitoring provided no benefit, created additional burdens, and that future trials testing HCQ in a pre-clinical T1D population could safely follow standard clinical guidelines for retinal surveillance. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Clinical Trials [NCT03428945][1] ### Funding Statement The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), through the cooperative agreements U01 DK061042, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, UC4 DK085466, U01 DK085476, U01 DK085504, U01 DK085509, U01 DK103282, U01 DK106984, U01 DK106993, U01 DK106994, U01 DK107013, U01 DK107014. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The University of Miami central IRB gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03428945&atom=%2Fmedrxiv%2Fearly%2F2025%2F01%2F29%2F2025.01.28.25321283.atom

Introduction & Objective: Islet antigen reactive (IAR) T cells play an important role in pancreatic β-cell destruction in type 1 diabetes (T1D) and are clonally expanded after T1D diagnosis, indicative of in vivo antigen exposure. The objective of this study was to determine if clonal expansion of IAR CD4 T cells occurs prior to T1D onset and is associated with risk for disease progression. Methods: The study included prospective blood samples collected from islet autoantibody (Aab) positive individuals enrolled in the TrialNet Pathways to Prevention and Long Term Investigative Follow-up in TrialNet studies. IAR CD4 T cells were isolated using a CD154 activation assay from PBMC samples of a cross-sectional cohort of Aab negative (n=6), 1 Aab+ >18y (n=6), 1 Aab+ <14y (n=3), and >1 Aab+ (n=6) donors with increasing risk for progression to T1D. Cells were analyzed by single-cell RNA-sequencing to identify T cell receptor α/β pairs and full transcript profiles. Clonal expansion was visualized using circos plots and analyzed using Simpson’s diversity. Transcript profiles were analyzed by unsupervised clustering and differential gene expression using Seurat v4. Results: Clonal expansion of IAR CD4 T cells was observed primarily in the >1 Aab+ at-risk group compared to the single Aab+ or Aab negative groups. The transcript profiles of IAR CD4 T cells formed clusters based on differentiation status from naïve to T effector memory phenotypes and revealed an enrichment of T effector memory cells in >1 Aab+ at-risk subjects. Conclusion: These results suggest that IAR CD4 T cell clonal expansion and enrichment of an effector memory transcript profile may accompany the progression to multiple Aab and increased risk for development of T1D. Further studies with longitudinal samples from subjects progressing from single to multiple Aab and T1D onset will validate and extend these findings to determine if IAR CD4 T cells are a biomarker of disease progression. T.H. Edwards: Employee; Wavely Diagnostics, Inc. J. Chen: None. M. Dufort: None. R. Hartley: None. C. Speake: None. C. Greenbaum: Other Relationship; Sanofi, Takeda Pharmaceutical Company Limited, Bristol-Myers Squibb Company, Imcyse. P. Linsley: None. K. Cerosaletti: Research Support; GentiBio, Cour Pharmaceuticals. American Diabetes Association (1-19-ICTS-006)

Type 1 diabetes is a chronic autoimmune disease in which destruction of pancreatic β-cells causes life-threatening metabolic dysregulation. Numerous approaches are envisioned for new therapies, but limitations of current clinical outcome measures are significant disincentives to development efforts. C-peptide, a direct byproduct of proinsulin processing, is a quantitative biomarker of β-cell function that is not cleared by the liver and can be measured in the peripheral blood. Studies of quantitative measures of β-cell function have established a predictive relationship between stimulated C-peptide as a measure of β-cell function and clinical benefits. C-peptide levels at diagnosis are often high enough to afford glycemic control benefits associated with protection from end-organ complications of diabetes, and even lower levels offer protection from severe hypoglycemia in type 1 diabetes, as observed in large prospective cohort studies and interventional trials of islet transplantation. These observations support consideration of C-peptide not just as a biomarker of β-cell function but also as a specific, sensitive, feasible, and clinically meaningful outcome defining β-cell preservation or restoration for clinical trials of disease-modifying therapies. Regulatory acceptance of C-peptide as a validated surrogate for demonstration of efficacy would greatly facilitate development of disease-modifying therapies for type 1 diabetes. Article Highlights

The approval of teplizumab to delay the onset of type 1 diabetes is an important inflection point in the decades-long pursuit to treat the cause of the disease rather than its symptoms. The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop of the Diabetes Mellitus Interagency Coordinating Committee titled “Evolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes” to review this accomplishment and identify future goals. Speakers representing Type 1 Diabetes TrialNet (TrialNet) and the Immune Tolerance Network emphasized that the ability to robustly identify individuals destined to develop type 1 diabetes was essential for clinical trials. The presenter from the U.S. Food and Drug Administration described how regulatory approval relied on data from the single clinical trial of TrialNet with testing of teplizumab for delay of clinical diagnosis, along with confirmatory evidence from studies in patients after diagnosis. The workshop reviewed the etiology of type 1 diabetes as a disease involving multiple immune pathways, highlighting the current understanding of prognostic markers and proposing potential strategies to improve the therapeutic response of disease-modifying therapies based on the mechanism of action. While celebrating these achievements funded by the congressionally appropriated Special Diabetes Program, panelists from professional organizations, nonprofit advocacy/funding groups, and industry also identified significant hurdles in translating this research into clinical care.

Background Essentially all individuals with multiple autoantibodies will develop clinical type 1 diabetes. Multiple autoantibodies (AABs) and normal glucose tolerance define stage 1 diabetes; abnormal glucose tolerance defines stage 2. However, the rate of progression within these stages is heterogeneous, necessitating personalized risk calculators to improve clinical implementation.Methods We developed 3 models using TrialNet's Pathway to Prevention data to accommodate the reality that not all risk variables are clinically available. The small model included AAB status, fasting glucose, hemoglobin A1c, and age, while the medium and large models added predictors of disease progression measured via oral glucose tolerance testing.Findings All models markedly improved granularity regarding personalized risk missing from current categories of stages of type 1 diabetes. Model-derived risk calculations are consistent with the expected reduction of risk with increasing age and increase in risk with higher glucose and lower insulin secretion, illustrating the suitability of the models. Adding glucose and insulin secretion data altered model predicted probabilities within stages. In those with high 2-hour glucose, a high C-peptide markedly decreased predicted risk; a lower C-peptide obviated the age-dependent risk of 2-hour glucose alone, providing a more nuanced estimate of the rate of disease progression within stage 2.Conclusion While essentially all those with multiple AABs will develop type 1 diabetes, the rate of progression is heterogeneous and not explained by any individual single risk variable. The model-based probabilities developed here provide an adaptable personalized risk calculator to better inform decisions about how and when to monitor disease progression in clinical practice.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.

Introduction & Objective: Electronic health records (EHR) are a valuable source of real-world data for clinical research. Reliable methods are needed to identify type 1 diabetes (T1D) by EHR. The study aim was to develop an EHR algorithm for T1D using diagnosis codes and clinical characteristics validated by manual chart review. Methods: Data from the Center for Kidney Disease Research, Education, and Hope (CURE-CKD) Registry were used to identify persons ≥12 years of age with T1D by diagnosis codes, ketoacidosis encounters, insulin pump and short-acting insulin use during 2013-2022. Manual chart review was performed on a subset of 100 participants to verify selection criteria; 40 from “very likely” category, 40 from “likely” category, and 20 from “unlikely”. Results: T1D cohorts (N=31,695) were divided into likelihood categories based on confirming criteria (Figure). The cohort was 48.5% female and 75.7% White race identity. Their mean±SD for age was 42±19 years with HbA1c 8.2±2.1% and BMI 27.5±6.3 kg/m2. Positive predictive values were 100% for very likely, 98% for likely, and 40% for unlikely categories. Conclusions: T1D can be reliably identified by the CURE-CKD algorithm using clinical EHR data. Pending further validation, this algorithm can be used for T1D cohort selection in real-world studies of epidemiology, diagnosis, and treatment. Disclosure C. Greenbaum: Other Relationship; Sanofi, Takeda Pharmaceutical Company Limited, Bristol-Myers Squibb Company, Imcyse. C.L. Reynolds: None. C. Jones: None. L. Kornowske: None. K.B. Daratha: None. R.Z. Alicic: Advisory Panel; Bayer Inc., Boehringer-Ingelheim. Research Support; AstraZeneca, Bayer Inc., AstraZeneca, Novo Nordisk, Traveere Pharmaceuticals. J.J. Neumiller: Advisory Panel; Bayer Inc., Boehringer-Ingelheim, Eli Lilly and Company, Proteomics International. K.R. Tuttle: Consultant; Lilly Diabetes. Research Support; Boehringer-Ingelheim. Consultant; AstraZeneca. Research Support; Novo Nordisk, Bayer Inc., Traveere Pharmaceuticals. Consultant; Pfizer Inc. Funding CDC (75D301-21-P-12254)

Context The value of continuous glucose monitoring (CGM) for monitoring autoantibody (AAB)-positive individuals in clinical trials for progression of type 1 diabetes (T1D) is unknown.Objective Compare CGM with oral glucose tolerance test (OGTT)-based metrics in prediction of T1D.Methods At academic centers, OGTT and CGM data from multiple-AAB relatives were evaluated for associations with T1D diagnosis. Participants were multiple-AAB-positive individuals in a TrialNet Pathway to Prevention (TN01) CGM ancillary study (n = 93). The intervention was CGM for 1 week at baseline, 6 months, and 12 months. Receiver operating characteristic (ROC) curves of CGM and OGTT metrics for prediction of T1D were analyzed.Results Five of 7 OGTT metrics and 29/48 CGM metrics but not HbA1c differed between those who subsequently did or did not develop T1D. ROC area under the curve (AUC) of individual CGM values ranged from 50% to 69% and increased when adjusted for age and AABs. However, the highest-ranking metrics were derived from OGTT: 4/7 with AUC similar to 80%. Compared with adjusted multivariable models using CGM data, OGTT-derived variables, Index60 and DPTRS (Diabetes Prevention Trial-Type 1 Risk Score), had higher discriminative ability (higher ROC AUC and positive predictive value with similar negative predictive value).Conclusion Every 6-month CGM measures in multiple-AAB-positive individuals are predictive of subsequent T1D, but less so than OGTT-derived variables. CGM may have feasibility advantages and be useful in some settings. However, our data suggest there is insufficient evidence to replace OGTT measures with CGM in the context of clinical trials.

Genome-wide association studies have identified numerous loci with allelic associations to Type 1 Diabetes (T1D) risk. Most disease-associated variants are enriched in regulatory sequences active in lymphoid cell types, suggesting that lymphocyte gene expression is altered in T1D. Here we assay gene expression between T1D cases and healthy controls in two autoimmunity-relevant lymphocyte cell types, memory CD4 + /CD25 + regulatory T cells (Treg) and memory CD4 + /CD25 - T cells, using a splicing event-based approach to characterize tissue-specific transcriptomes. Limited differences in isoform usage between T1D cases and controls are observed in memory CD4 + /CD25 - T-cells. In Tregs, 402 genes demonstrate differences in isoform usage between cases and controls, particularly RNA recognition and splicing factor genes. Many of these genes are regulated by the variable inclusion of exons that can trigger nonsense mediated decay. Our results suggest that dysregulation of gene expression, through shifts in alternative splicing in Tregs, contributes to T1D pathophysiology.

Objective: Innate immune responses may be involved in the earliest phases of type 1 diabetes. Research Design and Methods: To test whether blocking innate immune cells modulated progression of the disease we randomized 273 individuals with stage 1 type 1 diabetes to treatment with hydroxychloroquine (n=183, 5 mg/kg/d to a maximum of 400 mg) or placebo (n=90) and assessed whether hydroxychloroquine treatment delayed or prevented progression to stage 2 T1D (i.e. two or more islet autoantibodies with abnormal glucose tolerance). Results: After median follow up of 23.3 months, the trial was stopped prematurely by the Data Safety Monitoring Board because of futility. There were no safety concerns in the hydroxychloroquine arm, including in annual ophthalmologic exams. Preplanned secondary analyses showed a transient decrease in the glucose average area under the curve to oral glucose in the hydroxychloroquine-treated arm at month 6 and a reduced titer of anti-GAD and anti-insulin autoantibodies and acquisition of positive autoantibodies in the hydroxychloroquine arm (p=0.032). Conclusions: We conclude that hydroxychloroquine does not delay the progression to stage 2 type 1 diabetes in individuals with stage 1 disease. Drug treatment reduces the acquisition of additional autoantibodies and the titers of autoantibodies to GAD and insulin.

Studies of new therapies to preserve insulin secretion in early type 1 diabetes require several years to recruit eligible subjects and to see a treatment effect; thus, there is interest in alternative study designs to speed this process. Most people with longstanding type 1 diabetes no longer secrete insulin. However, studies from pancreata of those with longstanding T1D show that beta cells staining for insulin can persist for decades after diagnosis, and this is paralleled in work showing proinsulin secretion in individuals with longstanding disease; collectively this suggests that there is a reserve of alive but "sleeping" beta cells. Here, we designed a novel clinical trial platform to test whether a short course of therapy with an agent known to have effects in type 1 diabetes with residual endogenous insulin could transiently induce insulin secretion in those who no longer produce insulin. A therapy that transiently "wakes up" sleeping beta cells might be tested next in a fully powered trial in those with endogenous insulin secretion. In this three-arm non-randomized pilot study, we tested three therapies known to impact disease: two beta-cell supportive agents, liraglutide and verapamil, and an immunomodulatory agent, golimumab. The golimumab treated arm was not fully enrolled due to uncertainties about immunotherapy during the COVID-19 pandemic. Participants had mixed-meal tolerance test (MMTT)-stimulated C-peptide below the quantitation limit (<0.02 ng/mL) at enrollment and received 8 to 12 weeks of therapy. At the completion of therapy, none of the individuals achieved the primary outcome of MMTT-stimulated C-peptide ≥ 0.02 ng/mL. An exploratory outcome of the verapamil arm was MRI-assessed pancreas size, diffusion, and longitudinal relaxation time, which showed repeatability of these measures but no treatment effect. The liraglutide and golimumab arms were registered on clinicaltrials.gov under accession number NCT03632759 and the verapamil arm under accession number NCT05847413. Trail registration: Protocols are registered in ClinicalTrials.gov under accession numbers NCT03632759 and NCT05847413.

Type 1 diabetes mellitus (T1DM) can be predicted, and immune therapy can alter the progression of the disease. The FDA’s approval of teplizumab as the first disease-modifying therapy for T1DM and the first therapy aimed at delaying the clinical onset of any immune-mediated disease represents a paradigm shift in the treatment of T1DM.