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BACKGROUND: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification. METHODS: To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument. RESULTS: We identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings. CONCLUSIONS: While the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Inflammation and oxidative stress in pancreatic islets amplify the appearance of various posttranslational modifications to self-proteins. In this study, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in NOD mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase β subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found that carbonylated P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin-to-insulin ratios. Autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Moreover, we identify autoreactive CD4+ T-cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and in creating autoantigenic forms of insulin in type 1 diabetes.

BackgroundType 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes.MethodsWe did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (

The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.

Type 1 diabetes treatment stands at a crucial and exciting crossroad since the 2022 U.S. Food and Drug Administration approval of teplizumab to delay disease development. In this article, we discuss four major conceptual and practical issues that emerged as key to further advancement in type 1 diabetes research and therapies. First, collaborative networks leveraging the synergy between the type 1 diabetes research and care community members are key to fostering innovation, know-how, and translation into the clinical arena worldwide. Second, recent clinical trials in presymptomatic stage 2 and recent-onset stage 3 disease have shown the promise, and potential pitfalls, of using immunomodulatory and/or β-cell protective agents to achieve sustained remission or prevention. Third, the increasingly appreciated heterogeneity of clinical, immunological, and metabolic phenotypes and disease trajectories is of critical importance to advance the decision-making process for tailored type 1 diabetes care and therapy. Fourth, the clinical benefits of early diagnosis of β-cell autoimmunity warrant consideration of general population screening for islet autoantibodies, which requires further efforts to address the technical, organizational, and ethical challenges inherent to a sustainable program. Efforts are underway to integrate these four concepts into the future directions of type 1 diabetes research and therapy. Article Highlights: We discuss four key emphasis areas to pursue the ongoing acceleration of progress in type 1 diabetes research and care. Collaborations and communications should continue and expand between the research and care communities. Further clinical development of disease-modifying therapies is key. Identification of biomarkers of type 1 diabetes heterogeneity is needed for better disease stratification. Type 1 diabetes screening programs should be implemented in the general population. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) results from β-cell destruction due to autoimmunity. It has been proposed that β-cell loss is relatively quiescent in the early years after seroconversion to islet antibody positivity (stage 1), with accelerated β-cell loss only developing around 6–18 months prior to clinical diagnosis. This construct implies that immunointervention in this early stage will be of little benefit, since there is little disease activity to modulate. Here, we argue that the apparent lack of progression in early-stage disease may be an artifact of the modality of assessment used. When substantial β-cell function remains, the standard assessment, the oral glucose tolerance test, represents a submaximal stimulus and underestimates the residual function. In contrast, around the time of diagnosis, glucotoxicity exerts a deleterious effect on insulin secretion, giving the impression of disease acceleration. Once glucotoxicity is relieved by insulin therapy, β-cell function partially recovers (the honeymoon effect). However, evidence from recent trials suggests that glucose control has little effect on the underlying disease process. We therefore hypothesize that the autoimmune destruction of β-cells actually progresses at a more or less constant rate through all phases of T1D and that early-stage immunointervention will be both beneficial and desirable. Article Highlights: The process of autoimmune destruction of insulin-producing beta-cells in type 1 diabetes (T1D) begins long before the onset of clinical symptoms. Most studies in preclinical T1D have used an oral glucose tolerance test (OGTT) and concluded that β-cell loss occurs late; however, the OGTT underestimates β-cell function in the earliest preclinical stage (stage 1). Loss of β-cell function is said to accelerate around the time of clinical diagnosis, but this is likely attributable to glucotoxicity rather than an acceleration of the autoimmune process. We conclude that autoimmune-mediated β-cell loss is likely progressive throughout the preclinical period, and immunointervention efforts should focus on time points earlier in the process. [ABSTRACT FROM AUTHOR]

ObjectiveWe aimed to determine the effect of elevated BMI over time on the progression to type 1 diabetes in youth.Research design and methodsWe studied 1,117 children in the TrialNet Pathway to Prevention cohort (autoantibody-positive relatives of patients with type 1 diabetes). Longitudinally accumulated BMI above the 85th age- and sex-adjusted percentile generated a cumulative excess BMI (ceBMI) index. Recursive partitioning and multivariate analyses yielded sex- and age-specific ceBMI thresholds for greatest type 1 diabetes risk.ResultsHigher ceBMI conferred significantly greater risk of progressing to type 1 diabetes. The increased diabetes risk occurred at lower ceBMI values in children

Context Obesity is prevalent in type 1 diabetes (T1D) and is problematic with higher risk for diabetes complications. It is unknown to what extent gut microbiome changes are associated with obesity and T1D. Objective This work aimed to describe the gut microbiome and microbial metabolite changes associated with obesity in T1D. We hypothesized statistically significant gut microbial and metabolite differences in lean T1D youth (body mass index [BMI]: 5%-<85%) vs those with obesity (BMI: ≥95%). Methods We analyzed stool samples for gut microbial (using metagenomic shotgun sequencing) and short-chain fatty acid (SCFA) differences in lean (n = 27) and obese (n = 21) T1D youth in a pilot study. The mean ± SD age was 15.3 ± 2.2 years, glycated hemoglobin A1c 7.8 ± 1.3%, diabetes duration 5.1 ± 4.4 years, 42.0% female, and 94.0% were White. Results Bacterial community composition showed between sample diversity differences (β-diversity) by BMI group (P =.013). There was a higher ratio of Prevotella to Bacteroides in the obese group (P =.0058). There was a differential distribution of significantly abundant taxa in either the lean or obese groups, including increased relative abundance of Prevotella copri , among other taxa in the obese group. Functional profiling showed an upregulation of branched-chain amino acid (BCAA) biosynthesis in the obese group and upregulation of BCAA degradation, tyrosine metabolism, and secondary bile acid biosynthesis in the lean group. Stool SCFAs were higher in the obese vs the lean group (P <.05 for all). Conclusion Our findings identify a gut microbiome and microbial metabolite signature associated with obesity in T1D. These findings could help identify gut microbiome–targeted therapies to manage obesity in T1D. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Surviving beta cells in type 1 diabetes respond to inflammation by upregulating programmed death-ligand 1 (PD-L1) to engage immune cell programmed death protein 1 (PD-1) and limit destruction by self-reactive immune cells. Extracellular vesicles (EVs) and their cargo can serve as biomarkers of beta cell health and contribute to islet intercellular communication. We hypothesised that the inflammatory milieu of type 1 diabetes increases PD-L1 in beta cell EV cargo and that EV PD-L1 may protect beta cells against immune-mediated cell death. Methods: Beta cell lines and human islets were treated with proinflammatory cytokines to model the proinflammatory type 1 diabetes microenvironment. EVs were isolated using ultracentrifugation or size exclusion chromatography and analysed via immunoblot, flow cytometry and ELISA. EV PD-L1 binding to PD-1 was assessed using a competitive binding assay and in vitro functional assays testing the ability of EV PD-L1 to inhibit NOD CD8+ T cells. Plasma EV and soluble PD-L1 were assayed in the plasma of islet autoantibody-positive (Ab+) individuals or individuals with recent-onset type 1 diabetes and compared with levels in non-diabetic control individuals. Results: PD-L1 protein co-localised with tetraspanin-associated proteins intracellularly and was detected on the surface of beta cell EVs. Treatment with IFN-α or IFN-γ for 24 h induced a twofold increase in EV PD-L1 cargo without a corresponding increase in the number of EVs. IFN exposure predominantly increased PD-L1 expression on the surface of beta cell EVs and beta cell EV PD-L1 showed a dose-dependent capacity to bind PD-1. Functional experiments demonstrated specific effects of beta cell EV PD-L1 to suppress proliferation and cytotoxicity of murine CD8+ T cells. Plasma EV PD-L1 levels were increased in Ab+individuals, particularly in those positive for a single autoantibody. Additionally, in Ab+ individuals or those who had type 1 diabetes, but not in control individuals, plasma EV PD-L1 positively correlated with circulating C-peptide, suggesting that higher EV PD-L1 could be protective for residual beta cell function. Conclusions/interpretation: IFN exposure increases PD-L1 on the beta cell EV surface. Beta cell EV PD-L1 binds PD1 and inhibits CD8+ T cell proliferation and cytotoxicity. Circulating EV PD-L1 is higher in Ab+ individuals than in control individuals. Circulating EV PD-L1 levels correlate with residual C-peptide at different stages in type 1 diabetes progression. These findings suggest that EV PD-L1 could contribute to heterogeneity in type 1 diabetes progression and residual beta cell function and raise the possibility that EV PD-L1 could be exploited as a means to inhibit immune-mediated beta cell death. [ABSTRACT FROM AUTHOR]

The article "Safety and effects of acetylated and butyrylated high-amylose maize starch on youths recently diagnosed with type 1 diabetes: A pilot study" published in Diabetes, Obesity & Metabolism explores the impact of high-amylose maize starch (HAMS) on adolescents with type 1 diabetes. The study aimed to assess the safety of HAMS-AB consumption and its effects on the gut microbiome, metabolites, immune markers, and glycaemia. Results showed changes in the gut microbiome composition, metabolite profile, and immune markers associated with HAMS-AB consumption, suggesting potential benefits for T1D management. The study had strengths in assessing various markers and using a crossover design, but limitations included a small sample size and short duration of intake. Further research is needed to explore the potential benefits of HAMS-AB in a larger sample size. [Extracted from the article]

The year 2021 marks the centennial of Banting and Best's landmark description of the discovery of insulin. This discovery and insulin's rapid clinical deployment effectively transformed type 1 diabetes from a fatal diagnosis into a medically manageable chronic condition. In this Review, we describe key accomplishments leading to and building on this momentous occasion in medical history, including advancements in our understanding of the role of insulin in diabetes pathophysiology, the molecular characterization of insulin and the clinical use of insulin. Achievements are also viewed through the lens of patients impacted by insulin therapy and the evolution of insulin pharmacokinetics and delivery over the past 100 years. Finally, we reflect on the future of insulin therapy and diabetes treatment, as well as challenges to be addressed moving forward, so that the full potential of this transformative discovery may be realized. Decades of scientific accomplishment have transformed diabetes treatment; this Review describes key milestones in our understanding of the insulin molecule and looks to the future of insulin therapy., Author(s): Emily K. Sims [sup.1] [sup.2] [sup.3] , Alice L. J. Carr [sup.4] , Richard A. Oram [sup.4] [sup.5] , Linda A. DiMeglio [sup.1] [sup.2] [sup.3] , Carmella Evans-Molina [sup.1] [...]