Effectiveness of the MyDiaMate application in reducing diabetes distress in adults with type 1 diabetes: Study protocol of the multi-national, randomised-controlled MyREMEDY trial.

AIMS: Diabetes distress is common among people with type 1 diabetes (T1D), negatively affecting quality of life, self management, and diabetes outcomes. E-health-based interventions could be an effective and low-cost way to improve the psychological care for people with T1D experiencing diabetes distress. The MyREMEDY study aims to test the effectiveness of the online unguided self-help intervention MyDiaMate in decreasing diabetes distress in adults with T1D. MyDiaMate is based on Cognitive Behavioural Therapy and consists of eight modules, each focusing on a different aspect of living with T1D that is often experienced as burdensome (e.g. hypoglycaemia, fatigue). METHODS: The effectiveness of MyDiaMate will be tested through a randomised-controlled trial across four European countries (the Netherlands, Germany, Spain and the United Kingdom). Six hundred and sixty adults (N = 165 per country) with T1D will be recruited and randomised with a balance of 2:1 into the intervention and care as usual groups. Intervention group members receive access to MyDiaMate for 6 months, care as usual group members receive access after 3 months for 3 months. Participants fill in questionnaires at 0 (baseline), 3 (effectiveness) and 6 months (follow-up). Primary outcome is diabetes distress at 3 months. Secondary outcomes are emotional well-being, psychological self-efficacy in relation to diabetes, social engagement, fatigue, and glycaemic outcomes. Moreover, logdata of MyDiaMate use is passively collected. Linear mixed model analyses will be used to test the effectiveness of MyDiaMate along with identifying which user subgroup benefits most from MyDiaMate use. TRIAL REGISTRATION: Clinicaltrials.gov NCT06308549.

Modified streptozotocin-induced diabetic model in rodents.

Streptozotocin (STZ)-induced type I diabetes mellitus (DM) models have been pivotal in diabetes research due to their ability to mimic the insulin-dependent hyperglycemia akin to human type I diabetes. However, these models often suffer from poor induction rates and low survival post-STZ induction, especially in long-term experiments, necessitating insulin supplementation, which introduces additional variables to experiments. To address this, we present a novel modification to the STZ-induced DM model in C57BL/6J mice to improve survival rates without insulin supplementation. Our method involves non-fasting, low-dose STZ injections dissolved in pH-neutral phosphate buffer saline instead of acidic sodium citrate buffer, administered over 5 days. We observed hyperglycemia induction in 94.28% of mice within a week post-injection, with stable high blood glucose levels, stable body weight, and minimal mortality up to 21 weeks. Notably, omitting 10% sucrose in water and fasting did not affect hyperglycemia induction. Our findings suggest that the modified protocol not only decreases the experimental effort of the researchers, but reduces animal stress and mortality, thus enhancing experimental outcomes and animal welfare. By optimizing the STZ-induced DM model in C57BL/6J mice, our study provides a valuable resource for researchers aiming to study diabetes and its complications while minimizing experimental variability and animal usage.

Relationship between type 1 diabetes and autoimmune diseases in european populations: A two-sample Mendelian randomization study.

Background: Previous studies have suggested an association between Type 1 diabetes (T1D) and autoimmune diseases (AIDs), but the causal relationship remains unclear. Therefore, this study utilizes publicly available Genome-Wide Association Studies (GWAS) databases and employs a two-sample Mendelian Randomization (MR) approach to explore the causal relationships between T1D and systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). Methods: Summary GWAS data for T1D, SLE, RA, and IBD were downloaded from open GWAS databases and the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). We employed a series of methods to select instrumental variables closely related to T1D. To enhance the reliability of our conclusions, we applied multiple robust analytical methods, with the inverse variance weighted (IVW) method as the primary approach. Validation and meta-analysis were conducted using the FinnGen consortium. Additionally, we assessed heterogeneity, pleiotropy, and sensitivity to ensure the robustness of our conclusions. Results: A potential causal association was found between T1D and SLE (OR = 1.37, 95% CI = 1.26 - 1.49, P < 0.001), which was further confirmed by meta-analysis. Similarly, a potential causal association was found between T1D and RA (OR = 1.32, 95% CI = 1.17 - 1.50, P < 0.001), and this was also confirmed by meta-analysis. Although the association between T1D and IBD showed P < 0.05, the leave-one-out test did not pass, and further meta-analysis indicated no significant statistical association between them. Conclusion: Our study reveals the relationships between T1D and three clinically common autoimmune diseases (SLE, RA, and IBD). This research supplements previous studies and provides a reference for future clinical work.

Regulatory CD4+ T cells redirected against pathogenic CD8+ T cells protect NOD mice from development of autoimmune diabetes.

Introduction: In this study, we report a novel therapeutic approach redirecting antigen-specific CD4+ T cells recognizing a hybrid insulin peptide (BDC2.5 T cell receptor (TCR) transgenic CD4+ T cells) to attract and suppress islet-specific CD8+ T cells T cells in the non-obese diabetic (NOD) mouse model, and prevent the development of autoimmune diabetes. Methods: Purified BDC2.5 CD4+ T cells were induced to differentiate into regulatory T cells (Tregs). The Tregs were then electroporated with mRNA encoding chimeric human ß2 microglobulin (hß2m) covalently linked to insulin B chain amino acids 15-23 (designated INS-eTreg) or islet-specific glucose-6-phosphatase related protein (IGRP) peptide 206-214 (designated IGRP-eTreg). Immunoregulatory functions of these engineered regulatory T cells (eTregs) were tested by in vitro assays and in vivo co-transfer experiments with ß-cell-antigen-specific CD8+ T cells in NOD.Scid mice or by adoptive transfer into young, pre-diabetic NOD mice. Results: These eTregs were phenotyped by flow cytometry, and shown to have high expression of FoxP3, as well as other markers of Treg function, including IL-10. They suppressed polyclonal CD4+ T cells and antigen-specific CD8+ T cells (recognizing insulin or IGRP), decreasing proliferation and increasing exhaustion and regulatory markers in vitro. In vivo, eTregs reduced diabetes development in co-transfer experiments with pathogenic antigen-specific CD8+ T cells (INS-CD8+ or IGRP-CD8+ cells) into NOD.Scid mice. Finally, when the eTreg were injected into young NOD mice, they reduced insulitis and prevented spontaneous diabetes in the recipient mice. Conclusion: Our results suggest a novel therapeutic strategy to protect NOD mice by targeting antigen-specific cytotoxic CD8+ T cells, using redirected antigen-specific CD4+ Treg cells, to suppress autoimmune diabetes. This may suggest an innovative therapy for protection of people at risk of development of type 1 diabetes.

Autoimmune diseases refractory to corticosteroids and immunosuppressants.

Corticosteroids and immunosuppressive drugs can alleviate the symptoms of most autoimmune diseases and induce remission by restraining the autoimmune attack and limiting the damage to the target tissues. However, four autoimmune non-degenerative diseases-adult advanced type 1 diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, and advanced primary biliary cholangitis-are refractory to these drugs. This article suggests that the refractoriness of certain autoimmune diseases is due to near-total loss of secreting cells coupled with the extremely low regenerative capacity of the affected tissues. The near-complete destruction of cells responsible for secreting insulin, thyroid hormones, or biliary HCO3 - diminishes the protective effects of immunosuppressants against further damage. The slow regeneration rate of these cells hinders tissue recovery, even after drug-induced immune suppression, thus preventing remission. Although the liver can fully regenerate after injury, severe primary biliary cholangitis may impair this ability, preventing liver recovery. Consequently, these four autoimmune diseases are resistant to immunosuppressive drugs and corticosteroids. In contrast, early stages of type 1 diabetes and early primary biliary cholangitis, where damage to secreting cells is partial, may benefit from immunosuppressant treatment. In contrast to these four diseases, chronic degenerative autoimmune conditions like multiple sclerosis may respond positively to corticosteroid use despite the limited regenerative potential of the affected tissue (the central nervous system). The opposite is true for acute autoimmune conditions like Guillain-Barré syndrome.

The role of islet autoantigen-specific T cells in the onset and treatment of type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM), a complex chronic disease with an intricate etiology and pathogenesis, involves the recognition of self-antigens by pancreatic islet autoantigen-specific T cells and plays crucial roles in both early- and late-stage destruction of beta cells, thus impacting disease progression. Antigen-specific T cells regulate and execute immune responses by recognizing particular antigens, playing broad roles in the treatment of various diseases. Immunotherapy targeting antigen-specific T cells holds promising potential as a targeted treatment approach. This review outlines the pathogenesis of diabetes, emphasizing the pivotal role of pancreatic islet autoantigen-specific T cells in the progression and treatment of T1DM. Exploring this avenue in research holds promise for identifying novel therapeutic targets for effectively managing diabetes.

Whole Exome Sequencing in Children With Type 1 Diabetes Before Age 6 Years Reveals Insights Into Disease Heterogeneity.

Aims: This study is aimed at comparing whole exome sequencing (WES) data with the clinical presentation in children with type 1 diabetes onset ≤ 5 years of age (EOT1D). Methods: WES was performed in 99 unrelated children with EOT1D with subsequent analysis to identify potentially deleterious rare variants in MODY genes. High-resolution HLA class II haplotyping, SNP genotyping, and T1D-genetic risk score (T1D-GRS) were also evaluated. Results: Eight of the ninety-nine EOT1D participants carried a potentially deleterious rare variant in a MODY gene. Rare variants affected five genes: GCK (n = 1), HNF1B (n = 2), HNF4A (n = 1), PDX1 (n = 2), and RFX6 (n = 2). At diagnosis, these children had a mean age of 3.0 years, a mean HbA1c of 10.5%, a detectable C-peptide in 5/8, and a positive islet autoantibody in 6/7. Children with MODY variants tend to exhibit a lower number of pancreatic autoantibodies and a lower fasting C-peptide compared to EOT1D without MODY rare variants. They also carried at least one high-risk DR3-DQ2 or DR4-DQ8 haplotype and exhibited a T1D-GRS similar to the other individuals in the EOT1D cohort, but higher than healthy controls. Conclusions: WES found potentially deleterious rare variants in MODY genes in 8.1% of EOT1D, occurring in the context of a T1D genetic background. Such genetic variants may contribute to disease precipitation by a ß-cell dysfunction mechanism. This supports the concept of different endotypes of T1D, and WES at T1D onset may be a prerequisite for the implementation of precision therapies in children with autoimmune diabetes.

Parents' and children's experiences of participating in a randomized controlled clinical trial: AIDIT-QS.

Participation in a paediatric, complex randomized controlled trial (RCT) might add to the family burden when a child is diagnosed with a severe disease. Although important, there are only a limited number of papers describing this aspect of research from the family point of view. This study explored parents' and children's experiences of participation in a research study shortly after the child had been diagnosed with type 1 diabetes. Sixteen parents (nine mothers, seven fathers) and nine children were interviewed by an independent researcher about their inducement, the decision-making process within the family which led to their participation, and their experience of having done so. The result showed that the parents wanted to contribute to improve treatment for children with diabetes in general but also specifically for their own child. Older children were more involved in the decision making than the younger children. Study information needs to be communicated clearly and effectively since decision-making based on information of a clinical trial directly after the child's diabetes onset proved difficult. Being randomized to the intervention group in this specific study was considered somewhat burdensome. However, parental participants in both intervention and control group claimed that they would recommend participation in research studies to other parents in a similar situation, and so did the children. There was no difference between the mothers' and fathers' experiences.

Parents' expectations: A predominant driving force for the parents was the expectation that the study outcome could lead to something good for both their own child and other children with type 1 diabetes.Children's perspective on participation: Older children appreciated being involved in the decision-making process and valued their role in potentially helping others with diabetes. However, younger children were less involved and often relied on their parents for decision-making.Personal benefits: Both children and parents considered it important to gain something for themselves; by participating, they could benefit from more advanced technology and more rigorous follow-ups.Importance of control group: It was important for the families' motivation for completing the study that the researchers conveyed that the control group was as important for the outcome of the study as the intervention group.Future treatments: The parents felt that participation in the clinical trial could eventually lead to new treatments that could help their own child.Perceived safety: The fact that the clinical trial was considered well-planned and safe and implied no risk for the child made it easier to agree to participation.Effective communication: Since the onset of diabetes is emotionally stressful, and diabetes treatment itself is demanding, effective communication about the content of such a clinical trial is necessary, otherwise families may not understand what they are agreeing to.Burden on the intervention group: This clinical trial was somewhat burdensome for the intervention group to participate in; nevertheless, all of the families remained committed to their reasons for participating and completed the study.

Prediction of Incident Diabetic Retinopathy in Adults With Type 1 Diabetes Using Machine Learning Approach: An Exploratory Study.

BACKGROUND: Early detection and intervention are crucial for preventing vision-threatening diabetic retinopathy (DR) in adults with type 1 diabetes (T1D). This exploratory study uses machine learning on continuous glucose monitoring (CGM) data to identify factors influencing DR and predict high-risk individuals for timely intervention. METHODS: Between June 2018 and March 2022, adults with T1D with incident DR or no retinopathy (control) were identified. The CGM data were collected retrospectively for up to seven years before the date of defining incident DR or no retinopathy. A mixture of three machine learning algorithms was trained and evaluated in two different scenarios, using different glycemic features extracted from CGM traces (scenario 1), and the two principal components (two PCs; exposure to hyperglycemia and hypoglycemia risk) of those features (scenario 2). Classifiers were evaluated through 10-fold cross-validation using the receiver operating characteristic area under the curve (AUC-ROC) to select the best classification model. RESULTS: The CGM data of 30 adults with incident DR (mean±SD age of 21.2±9.4 years, glycated hemoglobin [HbA1c] of 8.6%±1.0%, and body mass index [BMI] of 24.5±4.8 kg/m2) and 30 adults without DR (age of 41.8±14.7 years, HbA1c of 7.0%±0.9%, and BMI of 26.2±3.6 kg/m2) were included in this analysis. In scenario 2, classifiers outperformed scenario 1, resulting in an average AUC-ROC increase to 0.92 for two of three models, indicating that the two PCs captured vital classification data, representing the most discriminative aspects and enhancing model performance. CONCLUSION: Machine learning approaches using CGM data may have potential to aid in identifying adults with T1D at risk of DR.

Twelve-Month Real-World Use of an Advanced Hybrid Closed-Loop System Versus Previous Therapy in a Dutch Center For Specialized Type 1 Diabetes Care.

BACKGROUND: Complexity of glucose regulation in persons with type 1 diabetes (PWDs) necessitates increased automation of insulin delivery (AID). This study aimed to analyze real-world data over 12 months from PWDs who started using the MiniMed 780G (MM780G) advanced hybrid closed-loop (aHCL) AID system at the Diabeter clinic, focusing on glucometrics and clinical outcomes. METHODS: Persons with type 1 diabetes switching to the MM780G system were included. Clinical data (e.g. HbA1c, previous modality) was collected from Diabeter's electronic health records and glucometrics (time in range [TIR], time in tight range [TITR], time above range [TAR], time below range [TBR], glucose management indicator [GMI]) from CareLink Personal for a 12-month post-initiation period of the MM780G system. Outcomes were age-stratified, and the MM780G system was compared with previous use of older systems (MM640G and MM670G). Longitudinal changes in glucometrics were also evaluated. RESULTS: A total of 481 PWDs were included, with 219 having prior pump/sensor system data and 334 having monthly longitudinal data. After MM780G initiation, HbA1c decreased from 7.6 to 7.1% (P < .0001) and the percentage of PWDs with HbA1c <7% increased from 30% to 50%. Glucose management indicator and TIR remained stable with mean GMI of 6.9% and TIR >70% over 12 months. Age-stratified analysis showed consistent improvements of glycemic control across all age groups, with older participants achieving better outcomes. Participants using recommended system settings achieved better glycemic outcomes, reaching TIR up to 77% and TTIR up to 55%. CONCLUSIONS: Use of MM780G system results in significant and sustained glycemic improvements, consistent across age groups and irrespective of previous treatment modalities.

Psychological distress in Aotearoa New Zealand adults with type 1 diabetes.

The psychological burden of type 1 diabetes (T1D) can negatively impact health outcomes. This study evaluates the prevalence of low mood (WHO-5), disordered eating (DEPS-R), diabetes distress (PAID) and fear of hypoglycaemia (HFS-II), in a sample of 250 New Zealand adults (8.4% Maori/91.6% non-Maori; 43.6% female/56.4% male) with T1D using validated tools. Maori and female patients indicated low mood, with lower median WHO-5 scores than non-Maori (p = 0.027) and males (p = 0.002). Maori were more likely to score in the clinical range on the WHO-5, DEPS-R, PAID and HFS-II (all p < 0.05). HbA1c was correlated with emotional well-being (rs = -0.189), diabetes distress (rs = 0.223) and disordered eating (rs = 0.389; all p < 0.001) whilst DEPS-R correlated with age (rs = -0.232) and BMI (rs = 0.343; both p ≤ 0.001). Thus, diabetes-related psychological distress is common in New Zealand adults with T1D, particularly for Maori, females and those with elevated HbA1c levels.

Relationship Between C-Peptide Levels, Clinical Features, and Serum Data in a Brazilian Type 1 Diabetes Population with Large Variations in Genomic Ancestry.

Type 1 diabetes (T1D) is a chronic disease characterized by the immune-mediated destruction of the pancreatic beta cells responsible for insulin production. The secreted insulin and C-peptide are equimolar. Due to its longer half-life, C-peptide has become a safer means of assessing the pancreatic reserve. C-peptide levels were evaluated in a population of patients with T1D, focusing on the relationship between this variable and other factors. In addition, the influence of C-peptide on metabolic control and microvascular complications was investigated. This cross-sectional study included 95 patients who had been diagnosed with T1D at least five years earlier. These patients were evaluated using a clinical demographic survey, anthropometric data, laboratory tests, and fundoscopy. This study showed that 29.5% of patients had residual insulin secretion, which correlated directly with their age at diagnosis. No statistically significant differences in metabolic control or microvascular complications were observed between the C-peptide level groups. In addition, our results indicate that ancestry does not influence the persistence of residual C-peptide function in our highly mixed population. It is recommended that future research consider incorporating new variables, such as HLA and pancreatic autoimmunity, as factors that may influence residual ß-cell function.

Autoimmune Health Crisis: An Inclusive Approach to Addressing Disparities in Women in the United States.

Autoimmune diseases are identified by the chronic inflammation and tissue damage resulting from unregulated immune responses throughout the body. Systemic lupus erythematosus, type 1 diabetes mellitus, and Hashimoto's thyroiditis are among the 80+ characterized conditions, 80% of which are diagnosed in women. The compounded effects of biological sex and hormones; social identities, such as age, race, and gender; and other determinants on health highlight a pressing need for an inclusive approach to address disparities for women living with autoimmune diseases. Such an approach must recognize and incorporate intersectional experiences of diverse populations of women into biomedical research, clinical practice, and policy solutions. Research must prioritize inclusive designs, data collection, and representation of women in clinical studies. Clinical care must focus on developing guidelines and promoting patient-provider interactions that meet a range of demographic needs. Health care policies must support financial investments in research and equitable access to care. This review provides an overview of the impacts of autoimmune diseases on women's health through an intersectional lens, identifies persistent gaps in addressing the unique needs of women, and proposes recommendations for a comprehensive, equity-focused approach to mitigate disparities and better serve all women at risk for or living with autoimmune diseases.

Sodium-Glucose Co-transporter-2 Inhibitors in Type 1 Diabetes Mellitus: The Framework for Recommendations for Their Potential Use.

The growing prevalence of overweight/obesity, the persistence of inadequate glycemic control among the majority of affected individuals, and the still unacceptably high risk of cardiovascular morbidity and mortality among population with type 1 diabetes mellitus (T1D), impose an urgent need for the introduction of non-insulin glucose-lowering agents in the therapeutic armamentarium. Given that their antihyperglycemic mechanism of action is independent of endogenous insulin secretion and that the observed cardio-renal benefits are unrelated to their glucose-lowering properties, one can speculate that the use of sodium-glucose co-transporter-2 inhibitors (SGLT2is) could provide benefits in T1D, similar to the ones observed among individuals with type 2 diabetes mellitus, chronic kidney disease (CKD), and heart failure. Available evidence from randomized controlled trials suggests that treatment with SGLT2is as adjunct to insulin in T1D results in modest reductions in glycated hemoglobin and body weight. Additionally, SGLT2is ameliorate albuminuria, and thus delay or prevent the development of CKD in T1D. However, use of SGLT2is is associated with an increased risk of diabetic ketoacidosis (DKA) in T1D. This commentary aims at providing a framework for practical recommendations regarding the potential use of SGLT2is in adults with T1D, based on the individual's risk level for DKA development, the presence of inadequate glycemic control and related cardio-renal complications.

Can a mobile application improve glucose-related and patient-reported outcome measures (PROMs) in people with type 1 diabetes mellitus? A randomized controlled trial using the mySugr® app.

PURPOSE: Mobile applications (apps) have proven to be highly effective tools to empower patients with type 1 diabetes mellitus (T1DM) and enable them to achieve better self-care, quality of life (QOL), and glycemic control. The aim of the study is to examine whether mySugr®, an app for diabetes management, together with teleconsultations, can have a positive impact on these factors and, thereby, replace current clinical care. METHODS: This study concerns an exploratory randomized clinical trial of 12 months' duration. People with T1DM using multiple daily injections were randomized to usual care (bolus calculator, five face-to-face visits) or intervention (mySugr® app, three face-to-face visits, and two teleconsultations). The main outcome was increase in empowerment assessed with the Diabetes Empowerment Scale Short Form questionnaire (DES-SF-S). Secondary outcomes were change in additional glucose-related (blood glucose monitoring, mean blood glucose, standard deviation, coefficient of variation (CV), and high and low blood glucose index) and patient-reported outcome measures (PROMs) (self-management, QOL, and distress). RESULTS: A total of 25 out of 28 participants completed the study (52% men, age 44.52 years, diabetes duration 21.28 years). At 12 months, no significant differences were identified in the change of DES-SF-S and additional PROMs between arms. Similarly, no differences were observed in glucose-related outcomes except for the change in CV at 9 (control - 1.87 ± 4.98 vs. intervention 5.89 ± 11.33, p = 0.008) and 12 months (control - 2.33 ± 3.54 vs. intervention 5.12 ± 11.32, p = 0.018). Adherence to and satisfaction with the app were high. CONCLUSION: Patients with diabetes using the mySugr® app and teleconsultation achieved similar results to those following usual care in empowerment, other PROMs, and most glucose-related outcomes, thus supporting its use in combination with face-to-face visits. The RCT was registered with ClinicalTrials.gov (NCT03819335, first registration 28/01/2019).

ATN blood biomarkers are related to digital cognitive assessment in type 1 diabetes.

INTRODUCTION: Associations between amyloid-tau-neurodegeneration (ATN) plasma biomarkers and cognition have not been characterized in adults with type 1 diabetes (T1D). METHODS: Using data from participants in the Glycemic Variability and Fluctuations in Cognitive Status in Adults with T1D (GluCog) study (N = 114), we evaluated associations between phosphorylated tau (pTau)181, pTau217, ß-amyloid 42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) and self-administered digital cognitive tests, adjusting for age, sex, education, comorbidities (e.g., kidney disease), and glycemic indices. RESULTS: Higher concentrations of pTau181 and GFAP were associated with slower responses on working memory tasks (pTau181: ß = 0.261; p = 0.007; GFAP: ß = 0.175, p = 0.036), and higher ß-amyloid 42/40 ratio was associated with better vocabulary (ß = 0.260, p = 0.009). Discussion: Digital cognitive performance was associated with several ATN plasma biomarkers in T1D adults. Prospective studies are needed to understand the utility of these biomarkers in T1D. Highlights: There is an increase in life expectancy for individuals with type 1 diabetes (T1D).Few studies investigate the relationship between T1D and neurodegeneration.We characterize the relation between ATN plasma biomarkers and cognitive function.Digital cognitive performance was associated with plasma biomarkers in T1D adults.

Possible Glycemic Effects of Vagus Nerve Stimulation Evaluated by Continuous Glucose Monitoring in People with Diabetes and Autonomic Neuropathy: A Randomized, Sham-Controlled Trial.

Objective: Autonomic neuropathy is associated with dysglycemia that is difficult to control. We investigated if transcutaneous vagus nerve stimulation (tVNS) could improve glycemic levels. Methods: We randomized 145 individuals with type 1 diabetes (T1D) (n = 70) or type 2 diabetes (T2D) (n = 75) and diabetic autonomic neuropathy (DAN) to self-administered treatment with active cervical tVNS (n = 68) or sham (n = 77) for 1 week (4 daily stimulations) and 8 weeks (2 daily stimulations), separated by a wash-out period of at least 2 weeks. Continuous glucose monitoring (CGM) indices were measured for 104 participants starting 5 days prior to intervention periods, during the 1-week period, and at end of the 8-week period. Primary outcomes were between-group differences in changes in coefficient of variation (CV) and in time in range (TIR 3.9-10 mmol/L). Secondary outcomes were other metrics of CGM and HbA1c. Results: For the 1-week period, median [interquartile range] changes of CV from baseline to follow-up were -1.1 [-4.3;2.0] % in active and -1.5 [-4.4;2.5] % in sham, with no significance between groups (P = 0.54). For TIR, the corresponding changes were 2.4 [-2.1;7.4] % in active and 5.1 [-2.6;8.8] in sham group (P = 0.84). For the 8-week treatment period, changes in CV and TIR between groups were also nonsignificant. However, in the subgroup analysis, persons with T1D receiving active tVNS for 8 weeks had a significant reduction in CV compared with the T1D group receiving sham stimulation (estimated treatment effect: -11.6 [95% confidence interval -20.2;-2.0] %, P = 0.009). None of the changes in secondary outcomes between treatment groups were significantly different. Conclusions: Overall, no significant changes were observed in CGM metrics between treatment arms, while individuals with T1D and DAN decreased their CV after 8 weeks of tVNS treatment.

Autoimmune CD4+ T cells fine-tune TCF1 expression to maintain function and survive persistent antigen exposure during diabetes.

Self-reactive T cells experience chronic antigen exposure but do not exhibit signs of exhaustion. Here, we investigated the mechanisms for sustained, functioning autoimmune CD4+ T cells despite chronic stimulation. Examination of T cell priming showed that CD4+ T cells activated in the absence of infectious signals retained TCF1 expression. At later time points and during blockade of new T cell recruitment, most islet-infiltrating autoimmune CD4+ T cells were TCF1+, although expression was reduced on a per T cell basis. The Tcf7 locus was epigenetically modified in circulating autoimmune CD4+ T cells, suggesting a pre-programmed de novo methylation of the locus in early stages of autoimmune CD4+ T cell differentiation. This mirrored the epigenetic profile of recently recruited CD4+CD62L+ T cells in the pancreas. Collectively, these data reveal a unique environment during autoimmune CD4+ T cell priming that allows T cells to fine-tune TCF1 expression and maintain long-term survival and function.

Beyond the insulin pump: Unraveling diabetes tech dependency.

The use of technology for Type 1 diabetes (T1D) has significantly developed in the last 20 years leading to several benefits in life-style management but also to potentially overreliance and addiction to such life changing devices. Insulin pumps (CSII) being small, discreet and sophisticated, offer features such as customizable basal rates, bolus calculators and integration with Continuous Glucose Monitoring (CGM) systems becoming a must have for diabetic patients. Indeed CGM, firstly introduced in the late 1990s and now being highly sophisticated provide trends and patterns hence allowing a better management of T1D. In this review we inquire the multifactorial aspects of dependency on diabetes technology, focusing not only on the benefits and the advancements these automations offer, but also the challenges, limits and possible risks associated with overreliance on them. Specifically, the impact that early introduction to technology had on patients, the dependency on CSII and CGM, the importance of learning and self-management skills and strategies for addressing unexpected events.