Loss to Follow-Up: Patients with Type 1 Diabetes During the SARS-CoV-2 Pandemic.

The SARS-CoV-2 (severe acute respiratory syndrome related coronavirus 2) pandemic revealed many flaws in our health care system. This review aims to explore the significance of loss to follow-up on patients with type 1 diabetes during the pandemic, the morbidity and mortality associated, and strategies to prevent loss to follow-up or to re-engage patients in longitudinal care. [Pediatr Ann. 2024;53(7):e254-e257.].

COVID-19 and Type 1 Diabetes.

The coronavirus disease 2019 (COVID-19) pandemic brought about several challenges for pediatric patients that were considerably different than those for adult patients. While adult patients had severe illness with associated respiratory and multiorgan failure and subsequent death, pediatric patients typically had milder disease. There were increases in postinfection complications, including an increased incidence of new-onset type 1 diabetes (T1D) following COVID-19 infection, particularly in adolescent patients. Currently, there is increasing concern that COVID-19 infection may be contributing to the development of T1D. This review will provide an overview of COVID-19, T1D, and the increased incidence noted during the pandemic, and the proposed mechanism of development of T1D in this specific patient demographic. Future studies will be needed to understand the long-term impact of the COVID-19 pandemic on T1D in children and adolescents. [Pediatr Ann. 2024;53(7):e244-e248.].

COVID-19 and Diabetes: An Epidemiologic Overview.

Past literature on the development of type 1 diabetes (T1D) and type 2 diabetes (T2D) has emphasized the influence of exogenous factors, including viral infections, in the development of these conditions. The coronavirus disease 2019 (COVID-19) pandemic again highlighted the complicated connection between viral infection and the development of diabetes. The complex interplay of proinflammatory, genetic, and socioeconomic factors can help explain the increased incidence of T1D and T2D during the pandemic. Proposed pathophysiological mechanisms connecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to T1D include the expression of angiotensin enzyme 2 receptors on pancreatic islet cells, resultant proinflammatory states, and potential transient damage caused by viral entry. The intricate web of genetic factors, social determinants of health (including the rise of obesity), and the impact of proinflammatory states during SARS-CoV-2 infection on insulin resistance suggests mechanisms linking SARS-CoV-2 infection to the development of diabetes. [Pediatr Ann. 2024;53(7):e258-e263.].

The Role of Cytokines and T Cells as Mediators of Inflammatory Pathology in Type 1 Diabetes and COVID-19.

During the coronavirus disease 2019 (COVID-19) pandemic, reports of individuals experiencing new-onset type 1 diabetes (T1D) began to appear in the literature. This spurred subsequent epidemiological studies that demonstrated an increase in new diagnosis of T1D compared to prepandemic. Development of T1D is characterized by the development of an inappropriate T cell response directed against pancreatic beta-cells, leading to eventual loss of insulin secretion. This T cell response occurs in genetically susceptible individuals and may be triggered by viral illnesses. Abnormal cytokine production is another element of the pathogenesis of T1D. Infection with severe acute respiratory syndrome related coronavirus 2 induces a profound increase in the production of inflammatory cytokines and causes significant T-cell dysregulation. These disruptions of the immune system may be linked to the development of T1D following COVID-19. [Pediatr Ann. 2024;53(7):e264-e268.].

INfluenza VaccInation To mitigate typE 1 Diabetes (INVITED): a study protocol for a randomised, double-blind, placebo-controlled clinical trial in children and adolescents with recent-onset type 1 diabetes.

INTRODUCTION: Children and adolescents with recent-onset type 1 diabetes (T1D) commonly maintain a certain level of insulin production during the remission phase, which can last months to years. Preserving ß-cell function can reduce T1D complications and improve glycaemic control. Influenza vaccination has pleiotropic effects and administration of the vaccine during the early phases of T1D may offer ß-cell protection. This study aims to assess the effect of influenza vaccination on preserving ß-cell function in children and adolescents with recent-onset T1D. METHODS AND ANALYSIS: The INfluenza VaccInation To mitigate typE 1 Diabetes trial is a randomised, double-blind, placebo-controlled, multicentre trial in paediatric patients with recent-onset T1D aged 7-17 years. 100 participants will be randomised in a 1:1 ratio to receive either a standard inactivated quadrivalent influenza vaccine or a placebo within 14 days of diagnosis. The primary outcome is a difference in mean change (from baseline to 12 months) in C-peptide level between groups during a 2-hour mixed-meal tolerance test. Secondary outcomes include mean change (from baseline to 6 months) in C-peptide levels, haemoglobin A1c, ambulatory glucose profiles and insulin requirements. Exploratory outcomes are diabetes-related autoantibodies, inflammatory markers and serum haemagglutinin inhibition antibody titres against the influenza viruses. The current treatment for T1D is largely symptomatic, relying on insulin administration. There is a pressing need for novel pharmacological approaches aimed at modulating the immune system to preserve residual ß-cell function. Existing immunotherapies are cost-prohibitive and associated with multiple side effects, whereas influenza vaccination is inexpensive and generally well tolerated. A positive outcome of this study holds potential for immediate implementation into standard care for children and adolescents with recent-onset T1D and may guide future research on immune modulation in T1D. ETHICS AND DISSEMINATION: Ethical approval was obtained from Danish Health Authorities prior to participant enrollment. The trial results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05585983 and EudraCT Number 2022-500906-17-01.

Case report: management of a young male patient with diabetic ketoacidosis and thyroid storm.

This report describes a case of concomitant diabetic ketoacidosis (DKA) and thyroid storm (TS) in a 20-year-old male patient that presented both diagnostic and management challenges owing to their intricate interrelationship in endocrine-metabolic disorders. The patient, previously diagnosed with type 1 diabetes mellitus (T1DM) and hyperthyroidism, was admitted to the emergency department with symptoms of DKA and progressive exacerbation of TS. Initial treatment focused on correcting DKA; as the disease progressed to TS, it was promptly recognized and treated. This case emphasizes the rarity of simultaneous occurrence of DKA and TS, as well as the challenges in clinical diagnosis posed by the interacting pathophysiological processes and overlapping clinical manifestations of DKA and TS. The patient's treatment process involved multiple disciplines, and after treatment, the patient's critical condition of both endocrine metabolic diseases was alleviated, after which he recovered and was eventually discharged from the hospital. This case report aims to emphasize the need for heightened awareness in patients with complex clinical presentations, stress the possibility of concurrent complications, and underscore the importance of prompt and collaborative treatment strategies.

Identification of functional enhancer variants associated with type I diabetes in CD4+ T cells.

Type I diabetes is an autoimmune disease mediated by T-cell destruction of ß cells in pancreatic islets. Currently, there is no known cure, and treatment consists of daily insulin injections. Genome-wide association studies and twin studies have indicated a strong genetic heritability for type I diabetes and implicated several genes. As most strongly associated variants are noncoding, there is still a lack of identification of functional and, therefore, likely causal variants. Given that many of these genetic variants reside in enhancer elements, we have tested 121 CD4+ T-cell enhancer variants associated with T1D. We found four to be functional through massively parallel reporter assays. Three of the enhancer variants weaken activity, while the fourth strengthens activity. We link these to their cognate genes using 3D genome architecture or eQTL data and validate them using CRISPR editing. Validated target genes include CLEC16A and SOCS1. While these genes have been previously implicated in type 1 diabetes and other autoimmune diseases, we show that enhancers controlling their expression harbor functional variants. These variants, therefore, may act as causal type 1 diabetic variants.

Glycemic variability through the perspective of the glycemia risk index and time in range and their association with glycated hemoglobin A1c in pediatric patients on sensor-augmented pump therapy.

Introduction: From the introduction of continuous glucose monitoring (CGM) in treatments of type 1 diabetes, particularly its integration with insulin pumps, there has been a quest for new parameters that describe optimal glycemic control. As of the consensus reached in 2019, the ambulatory glucose profile (AGP) has become the standard, with time in range (TIR) emerging as a fundamental parameter for metabolic control assessment. However, with technological advancements, new parameters, such as the glycemia risk index (GRI), have been introduced and clinically utilized. Therefore, exploring the relationships between traditional and novel parameters to understand metabolic control comprehensively is imperative. Materials and methods: This study was conducted at the Pediatric Clinic of the University Hospital of the Republic of Srpska Banja Luka between January and July 2023. The participants were randomly selected, with the inclusion criteria specifying an age greater than eight years and a diabetes type 1 duration exceeding two years. All participants were required to use a sensor-augmented insulin pump for the next three months (90 days), irrespective of prior use, with the suspend-before-low option activated. Results: Of the 35 participants, 30 completed the study, 14 (46.7%) of whom were male. The mean age of the subjects was 14.90 ± 2.88 years, and the mean duration of diabetes was 7.83 ± 4.76 years. Over the 90-day period, HbA1c increased to an average of 7.31%. The analysis revealed significant effects of TIR (ß=-0.771) and GRI (ß=0.651) on HbA1c. Furthermore, GRI and TIR strongly correlated (ß=-0.953). Discussion and conclusion: New parameters generated from the ambulatory glucose profile (AGP) can help clinicians create a complete picture of a patient's metabolic control in relation to HbA1c levels. Additionally, the GRI is a mathematically tailored parameter that incorporates all components of the ambulatory glucose profile and demonstrates strong correlations with laboratory-measured HbA1c and TIR. The GRI potentially can become a valuable statistical parameter for evaluating and managing patients in routine clinical practice.

Multi-omics analysis reveals drivers of loss of ß-cell function after newly diagnosed autoimmune type 1 diabetes: An INNODIA multicenter study.

AIMS: Heterogeneity in the rate of ß-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease-modifying clinical trials. Integrative analyses of baseline multi-omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rates of disease progression after type 1 diabetes diagnosis. METHODS: We collected samples in a pan-European consortium that enabled the concerted analysis of five different omics modalities in data from 97 newly diagnosed patients. In this study, we used Multi-Omics Factor Analysis to identify molecular signatures correlating with post-diagnosis decline in ß-cell mass measured as fasting C-peptide. RESULTS: Two molecular signatures were significantly correlated with fasting C-peptide levels. One signature showed a correlation to neutrophil degranulation, cytokine signalling, lymphoid and non-lymphoid cell interactions and G-protein coupled receptor signalling events that were inversely associated with a rapid decline in ß-cell function. The second signature was related to translation and viral infection was inversely associated with change in ß-cell function. In addition, the immunomics data revealed a Natural Killer cell signature associated with rapid ß-cell decline. CONCLUSIONS: Features that differ between individuals with slow and rapid decline in ß-cell mass could be valuable in staging and prediction of the rate of disease progression and thus enable smarter (shorter and smaller) trial designs for disease modifying therapies as well as offering biomarkers of therapeutic effect.

An automatic deep reinforcement learning bolus calculator for automated insulin delivery systems.

In hybrid automatic insulin delivery (HAID) systems, meal disturbance is compensated by feedforward control, which requires the announcement of the meal by the patient with type 1 diabetes (DM1) to achieve the desired glycemic control performance. The calculation of insulin bolus in the HAID system is based on the amount of carbohydrates (CHO) in the meal and patient-specific parameters, i.e. carbohydrate-to-insulin ratio (CR) and insulin sensitivity-related correction factor (CF). The estimation of CHO in a meal is prone to errors and is burdensome for patients. This study proposes a fully automatic insulin delivery (FAID) system that eliminates patient intervention by compensating for unannounced meals. This study exploits the deep reinforcement learning (DRL) algorithm to calculate insulin bolus for unannounced meals without utilizing the information on CHO content. The DRL bolus calculator is integrated with a closed-loop controller and a meal detector (both previously developed by our group) to implement the FAID system. An adult cohort of 68 virtual patients based on the modified UVa/Padova simulator was used for in-silico trials. The percentage of the overall duration spent in the target range of 70-180 mg/dL was 71.2 % and 76.2 % , < 70 mg/dL was 0.9 % and 0.1 % , and > 180 mg/dL was 26.7 % and 21.1 % , respectively, for the FAID system and HAID system utilizing a standard bolus calculator (SBC) including CHO misestimation. The proposed algorithm can be exploited to realize FAID systems in the future.

Clinical serum lipidomic profiling revealed potential lipid biomarkers for early diabetic retinopathy.

Diabetic retinopathy (DR) is a serious complication of diabetes featuring abnormal lipid metabolism. However, the specific lipid molecules associated with onset and progression remain unclear. We used a broad-targeted lipidomics approach to assess the lipid changes that occur before the proliferative retinopathy stage and to identify novel lipid biomarkers to distinguish between patients without DR (NDR) and with non-proliferative DR (NPDR). Targeted lipomics analysis was carried out on serum samples from patients with type I diabetes, including 20 NDRs and 20 NPDRs. The results showed that compared with the NDR group, 102 lipids in the NPDR group showed specific expressions. Four lipid metabolites including TAG58:2-FA18:1 were obtained using the Least Absolute Shrink And Selection Operator (LASSO) and Support Vector Machine Recursive Feature Elimination (SVM-RFE) methods. The four-lipid combination diagnostic models showed good predictive ability in both the discovery and validation sets, and were able to distinguish between NDR patients and NPDR patients. The identified lipid markers significantly improved diagnostic accuracy within the NPDR group. Our findings help to better understand the complexity and individual differences of DR lipid metabolism.

Emergent inequity of glycaemic metrics for Maori children with type 1 diabetes is negated by early use of continuous glucose monitoring.

AIM: We investigated if continuous glucose monitoring (CGM) in children with type 1 diabetes (T1D) within 12 months of being diagnosed modifies the development of glycaemic outcome inequity on the basis of either ethnicity or socio-economic status (SES). METHOD: De-identified clinical and SES data from the KIWIDIAB data network were collected 12 months after diagnosis in children under 15 years diagnosed with T1D between 1 October 2020 and 1 October 2021. RESULTS: There were 206 children with new onset T1D: CGM use was 56.7% for Maori and 77.2% for Europeans. Mean (SD) HbA1c was 62.4 (14.2) mmol/mol at 12 months post diagnosis, but Maori were 9.4mmol/mol higher compared to Europeans (p<0.001). For those without CGM, Maori had an HbA1c 10.8 (95% CI 2.3 to 19.4, p=0.013) mmol/mol higher than Europeans, whereas there was no evidence of a difference between Maori and Europeans using CGM (62.1 [9.3] mmol/mol vs 58.5 [12.4] mmol/mol p=0.53 respectively). Comparing quintiles of SES, HbA1c was 10.8 (95% CI 4.7 to 16.9, p<0.001) mmol/mol higher in the lowest quintile of SES compared to the highest. CONCLUSION: These observational data suggest CGM use ameliorates the ethnic disparity in HbA1c at 12 months in new onset T1D.

Protein glycation products associate with progression of kidney disease and incident cardiovascular events in individuals with type 1 diabetes.

BACKGROUND: Despite improved glycemic treatment, the impact of glycation on pathological consequences may persist and contribute to adverse clinical outcomes in diabetes. In the present study we investigated the association between serum protein glycation products and progression of kidney disease as well as incident major adverse cardiovascular events (MACE) in type 1 diabetes. METHODS: Fructosamine, advanced glycation end products (AGEs), and methylglyoxal-modified hydro-imidazolone (MG-H1) were measured from baseline serum samples in the FinnDiane study (n = 575). Kidney disease progression was defined as steep eGFR decline (> 3 mL/min/1.73 m2/year) or progression of albuminuria (from lower to higher stage of albuminuria). MACE was defined as acute myocardial infarction, coronary revascularization, cerebrovascular event (stroke), and cardiovascular death. RESULTS: Fructosamine was independently associated with steep eGFR decline (OR 2.15 [95% CI 1.16-4.01], p = 0.016) in the fully adjusted model (age, sex, baseline eGFR). AGEs were associated with steep eGFR decline (OR 1.58 per 1 unit of SD [95% CI 1.07-2.32], p = 0.02), progression to end-stage kidney disease (ESKD) (HR 2.09 per 1 unit of SD [95% CI 1.43-3.05], p < 0.001), and pooled progression (to any stage of albuminuria) (HR 2.72 per 1 unit of SD [95% CI 2.04-3.62], p < 0.001). AGEs (HR 1.57 per 1 unit of SD [95% CI 1.23-2.00], p < 0.001) and MG-H1 (HR 4.99 [95% CI 0.98-25.55], p = 0.054) were associated with incident MACE. MG-H1 was also associated with pooled progression (HR 4.19 [95% CI 1.11-15.89], p = 0.035). Most AGEs and MG-H1 associations were no more significant after adjusting for baseline eGFR. CONCLUSIONS: Overall, these findings suggest that protein glycation products are an important risk factor for target organ damage in type 1 diabetes. The data provide further support to investigate a potential causal role of serum protein glycation in the progression of diabetes complications.

Partnered Recruitment: Engaging Individuals With Lived Experience in the Recruitment of Co-Design Participants.

BACKGROUND: Young adults with type 1 diabetes (T1D) face complex health challenges, including a heightened risk for distress. To counter this distress, there is a need to develop accessible, acceptable comprehensive care solutions that integrate diabetes and mental health care to enhance self-efficacy and counter mental health challenges in this population. OBJECTIVE: To describe the engagement of individuals with lived experience of T1D and mental health challenges in the development of a recruitment strategy to support the co-design of an innovative integrated care programme. RESULTS: Seven individuals with lived experience formed a Partner Advisory Council (PAC) to recruit young adults (18-29 years old) living with T1D, their friends or family and health researchers and professionals in co-design interviews (n = 19) and co-design events (n = 12). The PAC played a key role in developing a comprehensive recruitment strategy, overcoming traditional barriers and stigmas in the design of an integrated model of care. CONCLUSION: Assuming the presence of mental health challenges in young adults living with T1D during recruitment had far-reaching impacts on the development of a whole-person and integrated diabetes and mental health care solution. The efficient recruitment of this sample provided invaluable insights into the nuanced challenges experienced by young adults with T1D, the individual skills developed in response to their mental health challenges and the ways that this understanding can shape future programming to support mental health, quality of life and well-being. The ongoing involvement of the PAC as co-researchers underscores the enduring impact of patient engagement in developing integrated care solutions. PATIENT OR PUBLIC CONTRIBUTION: The co-design of the TECC-T1D3 model was enriched by the invaluable contributions of individuals with lived experience. This included the engagement of a diverse PAC in the recruitment of participants in co-design interviews and co-design events. PAC members actively participated in research decision-making with their insights informing a robust recruitment strategy. Beyond recruitment, PAC members continue to serve as co-researchers, shaping ongoing research and actively contributing to the TECC-T1D3 project. Six PAC members are co-authors on this manuscript.

Possible involvement of sialidase and sialyltransferase activities in a stage-dependent recycling of sialic acid in some organs of type 1 and type 2 diabetic rats.

Background: Type 1 (T1D) and type 2 (T2D) diabetes lead to an aberrant metabolism of sialoglycoconjugates and elevated free serum sialic acid (FSSA) level. The present study evaluated sialidase and sialyltranferase activities in serum and some organs relevant to diabetes at early and late stages of T1D and T2D. Methods: Sialic acid level with sialidase and sialyltransferase activities were monitored in the serum, liver, pancreas, skeletal muscle and kidney of diabetic animals at early and late stages of the diseases. Results: The FSSA and activity of sialidase in the serum were significantly increased at late stage of both T1D and T2D while sialic acid level in the liver was significantly decreased in the early and late stages of T1D and T2D, respectively. Furthermore, the activity of sialidase was significantly elevated in most of the diabetes-relevant organs while the activity of sialyltransferase remained largely unchanged. A multiple regression analysis revealed the contribution of the liver to the FSSA while pancreas and kidney contributed to the activity of sialidase in the serum. Conclusions: We concluded that the release of hepatic sialic acid in addition to pancreatic and renal sialidase might (in)directly contribute to the increased FSSA during both types of diabetes mellitus.

Association between HLA alleles and haplotypes with age at diagnosis of type 1 diabetes in an admixed Brazilian population: A nationwide study.

To investigate the potential relationship between HLA alleles and haplotypes and the age at diagnosis of type 1 diabetes (T1DAgeD) in an admixed Brazilian population. This nationwide study was conducted in public clinics across 12 Brazilian cities. We collected demographic and genetic data from 1,600 patients with T1D. DNA samples were utilised to determine genomic ancestry (GA) and perform HLA typings for DRB1, DQA1 and DQB1. We explored allele and haplotype frequencies and GA in patients grouped by T1DAgeD categories (<6 years, ≥6-<11 years, ≥11-<19 years and ≥19 years) through univariate and multivariate analyses and primary component analyses. Additionally, we considered self-reported colour-race and identified a familiar history of T1D in first-degree relatives. The homozygosity index for DRB1~DQA1~DQB1 haplotypes exhibited the highest variation among T1DAgeD groups, and the percentages of Sub-Saharan African and European ancestries showed opposite trends in principal component analysis (PCA) analyses. Regarding the association of alleles and haplotypes with T1DAgeD, risk alleles such as HLA-DQB1*03:02g, -DQA1*03:01g, -02:01g, DRB1*04:05g and -04:02g were more frequently observed in heterozygosity or homozygosity in T1D patients with an early disease onset. Conversely, alleles such as DRB1*07:01g, -13:03g, DQB1*06:02g and DQA1*02:01 were more prevalent in older T1D patients. The combination DR3/DR4.5 was significantly associated with early disease onset. However, gender, GA, familiar history of T1D and self-reported colour-race identity did not exhibit significant associations with the onset of T1D. It is worth noting that the very common risk haplotype DRB1*03:01g~DQA1*05:01g~DQB1*02:01g did not differentiate between T1DAgeD groups. In the admixed Brazilian population, the high-risk haplotype DRB1*04:05~DQA1*03:01~DQB1*03:02 was more prevalent in individuals diagnosed before 6 years of age. In contrast, the protective alleles DQA1*01:02g, DQB1*06:02g, DRB1*07:01g and DRB1*13:03g and haplotypes DRB1*13:03g~DQA1*05:01g~DQB1*03:01g and DRB1*16:02g~DQA1*01:02g~DQB1*05:02g were more frequently observed in patients diagnosed in adulthood. Notably, these associations were independent of factors such as sex, economic status, GA, familiar history of T1D and region of birth in Brazil. These alleles and haplotypes contribute to our understanding of the disease onset heterogeneity and may have implications for early interventions when detected in association with well-known genomic risk or protection factors for T1D.

Diabetes, glycemic profile and risk of vitiligo: A Mendelian randomization study.

BACKGROUD: Previous observational studies have shown that vitiligo usually co-manifests with a variety of dysglycemic diseases, such as Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM). Mendelian randomization (MR) analysis was performed to further evaluate the causal association between fasting plasma glucose, glycosylated hemoglobin (HbA1c), T1DM, T2DM and vitiligo. MATERIALS AND METHODS: We used aggregated genome-wide association data from the Integrative Epidemiology Unit (IEU) online database of European adults vitiligo; HbA1c data were from IEU. Fasting blood glucose data were obtained from the European Bioinformatics Institute (EBI). T1DM and T2DM data were from FinnGen. We used bidirectional two-sample and multivariate MR analyses to test whether dysglycemic measures (fasting blood glucose, HbA1c), diabetes-related measures (T1DM, T2DM) are causatively associated with vitiligo. Inverse variance weighting (IVW) method was used as the main test method, MR-Egger, Weighted mode and Weighted median were used as supplementary methods. RESULTS: We found no statistically significant evidence to support a causal association between dysglycemic traits and vitiligo, but in the correlation analysis of diabetic traits, our data supported a positive causal association between T1DM and vitiligo (p = 0.018). In the follow-up multivariate MR analysis, our results still supported this conclusion (p = 0.016), and suggested that HbA1c was not a mediator of T1DM affecting the pathogenesis of vitiligo. No reverse causality was found in any of the reverse MR Analyses of dysglycemic traits and diabetic traits. CONCLUSIONS: Our findings support that T1DM is a risk factor for the development of vitiligo, and this conclusion may explain why the co-presentation of T1DM and vitiligo is often seen in observational studies. Clinical use of measures related to T1DM may be a new idea for the prevention or treatment of vitiligo.

Bromodomain Protein Inhibition Protects ß-Cells from Cytokine-Induced Death and Dysfunction via Antagonism of NF-κB Pathway.

Cytokine-induced ß-cell apoptosis is a major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding its underlying mechanisms, few drugs have been translated to protect ß-cells in T1D. Epigenetic modulators such as bromodomain-containing BET (bromo- and extra-terminal) proteins are important regulators of immune responses. Pre-clinical studies have demonstrated a protective effect of BET inhibitors in an NOD (non-obese diabetes) mouse model of T1D. However, the effect of BET protein inhibition on ß-cell function in response to cytokines is unknown. Here, we demonstrate that I-BET, a BET protein inhibitor, protected ß-cells from cytokine-induced dysfunction and death. In vivo administration of I-BET to mice exposed to low-dose STZ (streptozotocin), a model of T1D, significantly reduced ß-cell apoptosis, suggesting a cytoprotective function. Mechanistically, I-BET treatment inhibited cytokine-induced NF-kB signaling and enhanced FOXO1-mediated anti-oxidant response in ß-cells. RNA-Seq analysis revealed that I-BET treatment also suppressed pathways involved in apoptosis while maintaining the expression of genes critical for ß-cell function, such as Pdx1 and Ins1. Taken together, this study demonstrates that I-BET is effective in protecting ß-cells from cytokine-induced dysfunction and apoptosis, and targeting BET proteins could have potential therapeutic value in preserving ß-cell functional mass in T1D.

Scavengers in islets fuel diabetic autoimmunity.

Autoreactive lymphocytes that infiltrate the pancreatic islet environment and target ß cells are primary drivers of type 1 diabetes. In this issue of Immunity, Srivastava et al.1 examine the role of the islet microenvironment in autoimmunity and find that the scavenging receptor CXCL16 on islet-resident macrophages uptakes oxidized low-density lipoproteins and promotes the differentiation and survival of infiltrating pathogenic CD8+ T cells.