Timing of Immunotherapy in Type 1 Diabetes: The Earlier, the Better?

Background: Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by progressive destruction of the pancreatic beta cells, leading to a lifelong dependence on insulin. It is associated with an increased morbidity and mortality from diabetes-related complications and a significant treatment burden. However, there has been substantial progress in therapeutic strategies that can affect the course of the disease. Summary: This review addresses advances in immunotherapy aimed at preserving residual beta-cell function in individuals with a recent onset of T1D and arresting the disease in pre-symptomatic stages. Recent and ongoing clinical trials have investigated the efficacy and safety of various immunotherapeutic strategies aimed at targeting several mechanisms of autoimmunity, which are thought to be important in disease pathogenesis, and therapies that also address beta-cell health. So far, T-cell-directed therapies that led to a favourable balance between T-effector cell depletion or modulation and preservation or expansion of regulatory T cells have shown the most success. Furthermore, regarding the timing of intervention, teplizumab was the first immunomodulatory agent to demonstrate a significant delay in disease progression in high-risk individuals before clinical onset. Key Messages: As more targeted immune interventions with potentially fewer side effects are closer to the translation into clinical practice, some new challenges may need to be addressed. The use of combination approaches that include immunotherapeutic strategies targeting different aspects of the immune system and interventions that improve beta-cell health may be required, along with the use of individualized patient-tailored approaches, a move towards early intervention, and a focus on patient-reported outcome measures.

Increased formation of neutrophil extracellular traps (NETs) is associated with gut leakage in type 1 diabetes (T1D). To explore the mechanism of how enteropathy exacerbated by NETs triggers pancreatic autoimmunity in T1D, we carried out a correlation analysis for NET formation with gut barrier functions and autoimmunity in nonobese diabetic (NOD) mice. Inducing chronic colitis or knocking out of peptidyl arginine deiminase type 4 (PAD4) in NOD mice were used to further study the effect of NET formation on the progression of T1D. Microbial alterations in Deferribacteres and Proteobacteria, along with the loss of gut barrier function, were found to be associated with increased endotoxin and abnormal formation of NETs in NOD mice. Both DSS-induced colitis and knockout of PAD4 in NOD mice indicated that PAD4-dependent NET formation was involved in the aggravation of gut barrier dysfunction, the production of autoantibodies, and the activation of enteric autoimmune T cells, which then migrated to pancreatic lymph nodes (PLNs) and caused self-damage. The current study thus provides evidence that PAD4-dependent NET formation is engaged in leaky gut triggering pancreatic autoimmunity and suggests that either degradation of NETs or inhibition of NET formation may be helpful for innovative therapeutic interventions in T1D.

The Review of Diabetic Studies,2005,2,4,187-189.DOI:10.1900/RDS.2005.2.187Published:February 2006Type:CommentaryAuthors:Damien Bresson, and Matthias von Herrath Author(s) affiliations:Damien Bresson and Matthias von Herrath La Jolla Institute for Allergy and Immunology, Department of Developmental Immunology 3, 10355 Science Center Drive, San Diego, California 92121, USA. Abstract:The article by Drs. Chatenoud and Bach [1] is in many aspects sophisticated as well as surging. It summarizes the latest findings on immunotherapy of type 1 diabetes (T1D) regarding the application of CD3 antibodies by scrutinizing four prevailing concepts that could mislead the further development of such therapies. Inasmuch these concepts, i.e. antigenspecific therapies, initiation of immunotherapy before diabetes onset, combining several agents and, finally, caution regarding the generalization of results obtained from NOD mice, still remain burning issues in diabetes research, the article contributes valuably to the path of finding the optimal intervention strategy. The authors present criticism to the four concepts and take a clear stand of the promise of antigen-nonspecific immunotherapy in the establishment of long-term remission. Insofar, the article inspires to a more intensive discussion to include aspects that could be able to enrich the discussion on these critical concepts. Firstly, it is noticeable that the outcomes of several investigations do not confirm the role of anti-CD3 alone as a cure for T1D in humans [2-4]. If we act on this assumption, then either additional therapies and combinations will be needed or another holistic approach to cure the disease must be taken into consideration. Another critical issue in anti-CD3 therapy is the dose of administration. The dose that is currently being used in clinical trials is probably close to the maximum that can be ethically given. This is because of the initial cytokine release syndrome and the transient EBV reactivation that occurs in many patients due to the systemically immunosuppressive properties of anti- CD3 [5-8]. In order to avoid high doses, more frequent administrations of anti-CD3 or administration during the prediabetic phase could be beneficial, although we do not know whether this strategy will be safe. In this regard, we may consider why the NOD animal model could be misleading. Although anti-CD3 did not completely protect from diabetes when given to prediabetic NOD mice, it did in other diabetes models, such as the streptozotocin-treated CD1 mice [9] and the rat insulin promoter-lymphocytic choriomeningitis virus (RIPLCMV) model [10]. Therefore, maybe due to its multiple immune defects, the NOD mouse might not accurately reflect the immune status of the average prediabetic patient. Keywords:NilView:PDF (174.19 KB)

Although the MTNR1B single nucleotide polymorphism rs10830963 has been strongly associated with the onset of type 2 diabetes (T2D), its association with the progression and prognosis of T2D has been understudied. We conducted this prospective analysis based on the UK Biobank cohort study. Microvascular complications (MIC) of T2D in this study included diabetic retinopathy, diabetic neuropathy, and diabetic kidney disease. Macrovascular complications (MAC) of T2D included diabetic coronary artery disease, diabetic cerebrovascular disease, and diabetic peripheral vascular disease. The multi-state model was used to analyze the association between the polymorphism of rs10830963 and the trajectory of T2D. The accelerated failure time (AFT) model was used to assess the association between rs10830963 and the onset of T2D and T2D comorbidities. A total of 283,531 middle- and old-age participants were included. During a median follow-up of 13.7 years, 11,947 participants developed T2D, 1556 participants developed MIC, 1797 participants developed MAC, and 618 participants died. In the additive model, the G risk allele of rs10830963 was significantly associated with an increased risk of the transition from T2D-free to T2D (HR = 1.050, 95% CI: 1.020, 1.079) and a decreased risk of the transition from T2D to MIC (HR = 0.918, 95% CI: 0.850, 0.992), particularly from T2D to diabetic retinopathy (HR = 0.882, 95% CI: 0.782, 0.995). Besides, the G risk allele of rs10830963 accelerated the transition from T2D-free to T2D (Time Ratio [TR] = 0.966, 95% CI: 0.947, 0.986) and slowed down the transition from T2D to MIC (TR = 1.067, 95% CI: 1.030, 1.105). The MTNR1B single nucleotide polymorphism rs10830963 was associated with an increased risk of T2D and a decreased risk of MIC, particularly diabetic retinopathy among T2D individuals. Our results highlight that rs10830963 might play differential roles in the onset and progression of T2D.

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

Immune intervention with T regulatory cells: Past lessons and future perspectives for type 1 diabetes

We remember George Eisenbarth for his many contributions to the scientific understanding of the pathogenesis of type 1 diabetes (T1D). In this article we frame our discussion of Dr. Eisenbarth's legacy, citing quotations from a noted scientific philosopher of the modern era, David Hume:

School-partnered interventions with clinical diabetes centers may help optimize child T1D health outcomes. Such interventions are under-studied and published examples are short-term with mixed benefit. We aimed to discover factors affecting implementation of T1D interventions in school to better design future programs. We conducted semi-structured interviews with school nurses (SN) in Pennsylvania (n=20) and West Virginia (n=10). Transcripts were coded by two reviewers using a consensus-driven approach. Major themes were aligned with an implementation science framework. SN represented various geographic settings (52% rural, 41% suburban, 7% urban) and years of experience (24% <5, 21% 5-10, 28% 11-20, 27% >20 years). SN from both states perceived factors to influence implementation of T1D interventions in school related to four themes. Theme 1 Motivating Factors: T1D interventions are prioritized as these students have complex medical needs and there is a dearth of available resources for school staff. Theme 2 Facilitators: Schools have existing structures which could support T1D interventions, including procedures to assemble multidisciplinary teams and expanded use of video conferencing since the pandemic. Theme 3 Challenges: Variable parent engagement and limited school health staffing may interfere with schools’ ability to participate in interventions. Theme 4 Peer Influence: Communication between school districts can influence adoption of interventions and should be considered when approaching school leaders. Differences in state policy for school health and insulin administration affected SN perceptions for who should lead interventions and funding for SN. Individual, school, and state-level factors will affect implementation of school-partnered T1D interventions. Understanding the unique systems for school health and working with key stakeholders may help tailor strategies to promote sustainable interventions in schools and improve T1D outcomes. Disclosure C. March: None. E. Naame: None. S. Alfinito: None. J. Rankine: None. L.M. Siminerio: Research Support; Becton, Dickinson and Company, Sanofi. Advisory Panel; embecta, Bayer Inc. T.M. Kazmerski: None. A. Albanese-O'Neill: None. A. Lyon: None. E. Miller: Other Relationship; Wolters Kluwer Health. I. Libman: None. Funding National Institutes of Health (K23DK135800)

Type 2 diabetes (T2D) has become a significant global health threat, yet its precise causes and mechanisms remain unclear. This study aims to identify gene expression patterns specific to T2D pancreatic islet cells and to explore the potential role of pancreatic stellate cells (PSCs) in T2D progression through regulatory networks involving lncRNA-mRNA interactions. In this study, we screened for upregulated genes in T2D pancreatic islet samples using bulk sequencing (bulkseq) datasets and mapped these gene expression profiles onto three T2D single-cell RNA sequencing (scRNAseq) datasets. The identified T2D-specific gene features were further validated in an additional T2D scRNAseq dataset, a T1D scRNAseq dataset, and a T2D bulkseq dataset. To investigate regulatory networks, we analyzed the potential lncRNA-mRNA interactions within T2D peripheral blood mononuclear cell (PBMC) bulkseq data. Our analysis identified a specific gene panel-COL1A2, VCAN, and SULF1-that was consistently upregulated in T2D pancreatic islet samples. Expression of this gene panel was strongly associated with the activation of pancreatic stellate cells (PSCs), suggesting a unique T2D-specific signature characterized by COL1A2hi/VCANhi/SULF1hi PSCs. This signature was exclusive to T2D and was not observed in Type 1 diabetes (T1D) samples, indicating a distinct role for activated PSCs in T2D progression. Furthermore, we identified six long non-coding RNAs (lncRNAs) that potentially interact with the COL1A2hi/VCANhi/SULF1hi PSCs. These lncRNAs were mapped to a lncRNA-mRNA network, suggesting they may modulate immune responses and potentially reshape the immune microenvironment in T2D. Our findings highlight the potential immune-regulatory role of PSCs in T2D and suggest that PSC-related lncRNA-mRNA networks could serve as novel therapeutic targets for T2D treatment. This research provides insights into PSCs as a modulator in T2D progression, paving the way for innovative treatment strategies.

Background: Type 2 diabetes (T2D) is a global metabolic condition associated with complications of multiple organs, including the bone. However, the exact impact of T2D on bone along the disease progression, particularly in the early phase, remains largely unknown. Methods: Four-week and sixteen-week high-fat diet (HFD) feeding-induced T2D mouse models were established, and the glucose metabolic status was examined. Bone mass was evaluated by micro-computed tomography (micro-CT), and immunofluorescent (IF) staining was performed for bone histomorphometry with enzyme-linked immunosorbent assay (ELISA) determining serum markers. RNA sequencing analysis was performed to examine the transcriptome of bone, and single-cell RNA-sequencing (scRNA-seq) analysis was further applied. Bone marrow mesenchymal stem cells (BMMSCs) were isolated and analyzed for functional behaviors. Results: The occurrence of glucose metabolic disorders was confirmed at both four weeks and sixteen weeks of HFD feeding, showing increased blood glucose levels with impaired glucose tolerance and insulin sensitivity. Notably, early T2D osteoporosis symptoms were detected at four weeks, especially in the trabecular bone, demonstrating reduced bone mass and mineral density. Histological analysis confirmed that bone remodeling and immune-related inflammation were also altered in T2D mice, remarkably at the early phase, mainly reflected by suppressed bone formation, stimulated bone resorption, increased macrophages, and elevated tumor necrosis factor-alpha (TNF-α) levels. Transcriptomic sequencing further demonstrated significant yet distinct changes in the gene expression profile of bone during T2D progression, which confirmed the histological findings. Notably, overlapping genes with altered expression at four weeks and sixteen weeks of T2D compared to the respective control were identified, and bone marrow scRNA-seq analysis indicated many of them were expressed in BMMSCs, suggesting BMMSCs critically involved in T2D osteoporosis. Dysregulated molecular profiles and functional abnormalities of BMMSCs in T2D mice were validated by ex vivo assays, showing early and persistent occurrence of impaired colony-forming and proliferative capacities with biased differentiation potential. Conclusions: These findings elucidate the bone lesion phenotype in T2D, particularly at the early phase, uncover changes in gene expression profiles of bone during T2D progression, and clarify the functional alterations in bone stem cells, providing a basis for subsequent research and the development of treatment strategies.

Corrigendum to 'What type 1 diabetes endotype is most suitable for anti-CD3 antibodies prevention trials?' [JDC, Vol. 39, Issue 10, October 2025, 109132

What type 1 diabetes endotype is most suitable for anti-CD3 antibodies prevention trials?

Immune intervention at diagnosis of type 1 diabetes (T1D) aims to prevent or reverse the disease by blocking autoimmunity, thereby preserving/restoring beta-cell mass and function. Recent clinical trials of non-specific and of antigen-specific immune therapies have demonstrated the feasibility of modulation of islet-specific autoimmunity in patients with partial prevention of loss of insulin secretion. In a series of review articles published in this issue of the journal, some of the most promising approaches of immune intervention in T1D are presented. Here we outline the rationale of such interventions and future prospects in this area.

Type 2 diabetes (T2D) is a heterogenous disease, and conventionally, peripheral insulin resistance (IR) was thought to precede islet β-cell dysfunction, promoting progression from prediabetes to T2D. New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression. Oxidative stress, defined as the generation of reactive oxygen species (ROS), is mediated by hyperglycemia alone or in combination with lipids. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs. Under metabolic-related stress conditions, EV-mediated cross-talk between β-cells and skeletal muscle likely trigger mitochondrial anomalies leading to prediabetes and T2D. This article reviews the underlying molecular mechanisms in ROS-related pathogenesis of prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress. Further, this review will describe the potential of various therapeutic avenues for attenuating oxidative damage, reversing prediabetes and preventing progression to T2D.

After a century of extensive scientific investigations, there is still no curative or disease-modifying treatment available that can provide long-lasting remission for patients diagnosed with type 1 diabetes (T1D). Although T1D has historically been regarded as a classic autoimmune disorder targeting and destroying pancreatic islet β-cells, significant research has recently demonstrated that β-cells themselves also play a substantial role in the disease's progression, which could explain some of the unfavorable clinical outcomes. We offer a thorough review of scientific and clinical insights pertaining to molecular mechanisms behind pathogenesis and the different therapeutic interventions in T1D covering over 20 possible pharmaceutical intervention treatments. The interventions are categorized as immune therapies, treatments targeting islet endocrine dysfunctions, medications with dual modes of action in immune and islet endocrine cells, and combination treatments with a broader spectrum of activity. We suggest that these collective findings can provide a valuable platform to discover new combinatorial synergies in search of the curative disease-modifying intervention for T1D. SIGNIFICANCE STATEMENT: This research delves into the underlying causes of T1D and identifies critical mechanisms governing β-cell function in both healthy and diseased states. Thus, we identify specific pathways that could be manipulated by existing or new pharmacological interventions. These interventions fall into several categories: (1) immunomodifying therapies individually targeting immune cell processes, (2) interventions targeting β-cells, (3) compounds that act simultaneously on both immune cell and β-cell pathways, and (4) combinations of compounds simultaneously targeting immune and β-cell pathways.