Search

Pancreatic islet transplantation is proposed as a cure for type 1 diabetes mellitus (T1D). Despite its success in optimal regulation of glucose levels, limitations in longevity of islet grafts still require innovative solutions. Inflammatory stress post-transplantation and loss of extracellular matrix attribute to the limited β-cell survival. Pancreatic stellate cells (PSCs), identified as pancreatic-specific stromal cells, have the potential to play a crucial role in preserving islet survival. Our study aimed to determine the effects of PSCs co-cultured with human CM β-cells and human islets under inflammatory stress induced by a cytokine cocktail of IFN-γ, TNF-α and IL-1β. Transwell culture inserts were utilized to assess the paracrine impact of PSCs on β-cells, alongside co-cultures enabling direct interaction between PSCs and human islets. We found that co-culturing PSCs with human CM β-cells and human cadaveric islets had rescuing effects on cytokine-induced stress. Effects were different under normoglycemic and hyperglycemic conditions. PSCs were associated with upregulation of β-cell mitochondrial activity and suppression of inflammatory gene expression. The rescuing effects exist both in indirect and direct co-culture methods. Furthermore, we tested whether PSCs have rescuing effects on human islets in conventional alginate-based microcapsules and in composite microcapsules composed of alginate-pectin collagen type IV, laminin sequence RGD, Nec-1, and amino acid. PSCs partially prevented cytokine-induced stress in both systems, but beneficial effects were stronger in composite capsules. Our findings show novel effects of PSCs on islet health. Islets and PSCs coculturing or co-transplantation might mitigate the inflammation stress and improve islet transplantation outcomes.

[This corrects the article DOI: 10.3389/fimmu.2023.1207108.].

Introduction and aim. Orthorexia nervosa is described as an obsession with consuming solely healthy foods accompanied by restrictive behaviors. Patients with chronic conditions frequently require dietary interventions alongside medication to manage symptoms and slow down disease progression. However, when dietary restrictions are taken to extremes, individuals may develop orthorexia nervosa, resulting in malnutrition and weight loss. This poses risks during treatment, where maintaining a balanced diet is vital. In this review we aim to display the prevalence of orthorexia nervosa in patients suffering from selected chronic diseases. Material and methods. A literature review was performed to investigate the prevalence of orthorexia nervosa among individuals with type 1 diabetes, inflammatory bowel disease, celiac disease, rheumatoid arthritis, and cancer. Description of the State of Knowledge. The occurrence of orthorexia reaches up to 7% in the general population, 72% in patients with type 1 diabetes mellitus, 77% in case of inflammatory bowel disease, 71% among individuals suffering from celiac disease, 75% in those with rheumatoid arthritis, and 50% in case of cancer. Orthorexia nervosa predominantly affects females who are younger, have higher levels of education, select organic foods, prepare their own meals, and have other concurrent chronic illnesses. The distress associated with diagnosis is considered the primary factor contributing to the development of this condition. Orthorexia ultimately leads to malnutrition, weight loss, impaired social functioning, and poses a risk of complications during the management of patients suffering from chronic diseases. Conclusion. The prevalence of orthorexia nervosa in patients suffering from the exhibited chronic illnesses is significantly higher compared to the general population. Therefore, early detection of this condition and intervention are necessary to improve patient management. Further research is needed to assess the frequency of orthorexia among individuals suffering from other chronic diseases. [ABSTRACT FROM AUTHOR]

Summary: Background: The possibility of preventing inflammatory bowel disease (IBD) is becoming more plausible due to advances in understanding preclinical disease and successful prevention trials in other immune‐mediated diseases, such as type 1 diabetes and rheumatoid arthritis. However, before that possibility becomes reality, several efforts need to occur in parallel and in a coordinated way. Aim: To propose some critical steps necessary for advancing the field of IBD prediction and prevention. Methods: We reviewed the current literature to identify the necessary steps toward a preventive strategy for IBD. Results: The first step should determine the most robust predictive biomarkers and validate them across independent cohorts, creating a multidimensional predictive tool. The second step is to gain a better understanding of the preferences of first‐degree relatives and people at risk for IBD, informing the implementation of screening and preventive strategies. Third, these efforts should contribute to the development of high‐risk clinics and establish the necessary networks for disease prevention trials. Conclusions: Advancing the field of IBD prediction and prevention will require a multifaceted approach, integrating biomarker discovery, understanding patient preferences, and establishing infrastructure for a collaborative network to support the practical implementation of IBD prevention strategies. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the five‐year incidence of diabetic retinopathy (DR) and associated risk markers in patients with type 1 diabetes in the national Danish DR‐screening programme. Methods: Based on national data, we included all 16 999 patients with type 1 diabetes in the Danish Registry of Diabetic Retinopathy, who attended the national screening programme in the period 2013–2018. According to the worse eye at first screening, DR was classified (levels 0–4) and linked with various national health registries to retrieve information on diabetes duration, systemic comorbidity, and medication. Results: At first screening, median age and duration of diabetes were 45.0 and 16.7 years, and 57.5% were males. The prevalence and five‐year incidences for DR and progression to proliferative DR (PDR) were 44.2%, 8.9% and 2.0%, respectively. In multivariable Cox models, the incidence endpoints were associated with duration of diabetes (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.63–1.89, and HR 2.04, 95% CI 1.73–2.40 per 10 years), moderately low Charlson Comorbidity Index score (HR 1.27, 95% CI 1.10–1.47, and HR 2.80, 95% CI 2.23–3.51), and use of blood pressure lowering medication (HR 1.20, 95% CI 1.05–1.36, and HR 1.98, 95% CI 1.53–2.57). Conclusion: In a study of all patients with type 1 diabetes from the Danish DR‐screening programme, we identified duration of diabetes, systemic disease and use of anti‐hypertensive treatment as consistent risk markers for incident and progressive DR. [ABSTRACT FROM AUTHOR]

Copyright of Retos: Nuevas Perspectivas de Educación Física, Deporte y Recreación is the property of Federacion Espanola de Asociaciones de Docentes de Educacion Fisica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

ABSTRACT Aims/Introduction Materials and Methods Results Conclusions This study evaluated the usability, satisfaction, and accuracy of a real‐time continuous glucose monitoring (rt‐CGM) in children and adolescents with type 1 diabetes (T1D) attending a summer camp.Seven children and adolescents with T1D (camper) and 31 of healthcare providers (HCPs) participating in a 2‐day summer camp in Kumamoto, Japan were enrolled. The usability and satisfaction were evaluated by tailored questionnaire. The accuracy of rt‐CGM was evaluated using self‐monitoring of blood glucose (BG) and sensor glucose (SG) values before or after (off camp) and during (on camp) the camp.The score of the usefulness of rt‐CGM showed 3.29 ± 0.90 in campers and 4.23 ± 0.87 in HCPs (P = 0.017). The degree of recommendation score for rt‐CGM was 3.29 ± 1.11 in campers and 4.23 ± 0.79 in HCPs (P = 0.013). Time in range (TIR) off camp was 45.9% and that on camp was 57.0%. Time above range (TAR) off camp was 53.4% and that on camp was 42.4%. The mean absolute relative difference (MARD) off camp was 19.7% ± 25.2%, whereas that on camp was 16.0% ± 14.8% (P = 0.367). Clinically acceptable zones of the error grid analyses were approximately 96% in total.Rt‐CGM exhibited higher usability and recommendation scores in HCPs than those in campers. This may be related to relatively lower accuracy in rt‐CGM. Overall usability and recommendation are clinically satisfactory, but due to relatively low accuracy, no decision should be made based on a single, non‐verified SG value alone. [ABSTRACT FROM AUTHOR]

Objective: To investigate the prevalence of elevated arterial stiffness and associations to known and potentially novel risk factors in a modern European technology‐based cohort of children and adolescents with type 1 diabetes. Research Design and Methods: Cross‐sectional study, including 127 children recruited from Pediatric Diabetes Departments across Eastern Denmark between May 2022 and January 2024. Arterial stiffness was assessed as carotid–femoral pulse‐wave‐velocity (cfPWV) using the Sphygmocor XCEL system. Unadjusted and adjusted linear regression models explored associations between cfPWV and other risk factors. Adjustments included age, sex, diabetes duration, time‐in‐range, hemoglobin A1c (HbA1c), body mass index (BMI) z‐score, low‐density lipoprotein (LDL)‐cholesterol, and mean arterial pressure (MAP). Results: Median (interquartile range [IQR]) age was 14.2 years (12.0, 16.4), diabetes duration was 4.7 years (2.7, 8.4), HbA1c level was 7.0% (6.5, 7.9), (53 mmol/l: 48–63), time‐in‐range was 63% (53–75), and 52% were male. The majority were treated with continuous‐subcutaneous‐insulin‐infusion (82%), and all (except two) used continuous‐glucose‐monitors. The prevalence of elevated arterial stiffness (cfPWV z‐score over the 90th percentile) was 16%. Unadjusted analyses demonstrated higher cfPWV was associated with longer diabetes duration, higher age, HbA1c, MAP, and liver stiffness, and lower time‐in‐range and insulin sensitivity. Higher cfPWV remained associated with higher age (standardized β (confidence interval (CI) 95%): 0.38 (0.27, 0.48); p < 0.001) and lower time‐in‐range (−0.15 ((−0.26), (−0.03)); p < 0.011) after adjustment. Conclusions: Despite modern treatment technology and better overall metabolic control, children and adolescents with type 1 diabetes present with a high prevalence of elevated arterial stiffness. Higher arterial stiffness was associated with higher age and lower time‐in‐range, independent of other risk factors, including HbA1c. [ABSTRACT FROM AUTHOR]

Introduction: Increasing evidence from human and animal model studies indicates the significant role of microRNAs (miRNAs) in pancreatic beta cell function, insulin signaling, immune responses, and pathogenesis of type 1 diabetes (T1D). Methods: We aimed, using next-generation sequencing, to screen miRNAs from peripheral blood mononuclear cells of eight independent Kuwaiti-Arab families with T1D affected siblings, consisting of 18 T1D patients and 18 unaffected members, characterized by no parent-to-child inheritance pattern. Results: Our analysis revealed 20 miRNAs that are differentially expressed in T1D patients compared with healthy controls. Module-based weighted gene co-expression network analysis prioritized key consensus miRNAs in T1D pathogenesis. These included hsa-miR-320a-3p, hsa-miR-139-3p, hsa-miR-200-3p, hsa-miR-99b-5p and hsa-miR-6808-3p. Functional enrichment analysis of differentially expressed miRNAs indicated that PI3K-AKT is one of the key pathways perturbed in T1D. Gene ontology analysis of hub miRNAs also implicated PI3K-AKT, along with mTOR, MAPK, and interleukin signaling pathways, in T1D. Using quantitative RT-PCR, we validated one of the key predicted miRNA-target gene-transcription factor networks in an extended cohort of children with new-onset T1D positive for islet autoantibodies. Our analysis revealed that hsa-miR-320a-3p and its key targets, including PTEN, AKT1, BCL2, FOXO1 and MYC, are dysregulated in T1D, along with their interacting partners namely BLIMP3, GSK3B, CAV1, CXCL3, TGFB, and IL10. Receiver Operating Characteristic analysis highlighted the diagnostic potential of hsa-miR-320a-3p, CAV1, GSK3B and MYC for T1D. Discussion: Our study presents a novel link between hsa-miR-320a-3p and T1D, and highlights its key regulatory role in the network of mRNA markers and transcription factors involved in T1D pathogenesis. [ABSTRACT FROM AUTHOR]

Hamman's syndrome, a rare complication of diabetic ketoacidosis (DKA), is characterized by subcutaneous emphysema and spontaneous pneumomediastinum. This case report discusses the occurrence of Hamman's syndrome in an 11‐year‐old adolescent male newly diagnosed with type 1 diabetes mellitus (T1DM) and presenting with severe DKA. The patient exhibited symptoms typical of DKA, including polydipsia, polyuria, abdominal pain, and fatigue, alongside signs such as dehydration, Kussmaul breathing, and tachycardia. Following initial management with intravenous fluids and insulin infusion, he was transferred to a tertiary children's hospital for further care. Subsequently, on routine examination, he exhibited bilateral neck crepitus and a mediastinal crunching sound on auscultation, indicative of Hamman's syndrome. Conservative management led to symptom resolution, and the patient was discharged with follow‐up arranged. This case highlights the importance of recognizing Hamman's syndrome as a potential complication of DKA in pediatric patients. Prompt diagnosis and management, along with differentiation from more severe conditions like Boerhaave's syndrome, are crucial for ensuring favorable outcomes. Further awareness and understanding of this rare syndrome are essential for optimal patient care and management. [ABSTRACT FROM AUTHOR]

Background: Islet transplantation is a recommended treatment for type 1 diabetes but is limited by donor organ shortage. This study introduces an innovative approach for improving the differentiation and functionality of insulin-producing cells (IPCs) from iPSCs using 3D spheroid formation and hydrogel matrix as an alternative pancreatic islet source. The extracellular matrix (ECM) is crucial for pancreatic islet functionality, but finding the ideal matrix for β-cell differentiation has been challenging. We aimed to advance IPC differentiation and maturation through an esterified collagen hydrogel, comparing its effectiveness with conventional basement membrane extract (BME) hydrogels. Methods: iPSCs were differentiated into IPCs using a small molecule-based sequential protocol, followed by spheroid formation in concave microwells. Rheological analysis, scanning electron microscopy, and proteomic profiling were used to characterize the chemical and physical properties of each matrix. IPCs, both in single-cell form and as spheroids, were embedded in either ionized collagen or BME hydrogels, which was followed by assessments of morphological changes, pancreatic islet-related gene expression, insulin secretion, and pathway activation using comprehensive analytical techniques. Results: Esterified collagen hydrogels markedly improved the structural integrity, insulin expression, and cell-cell interactions in IPC spheroids, forming densely packed insulin-expressing clusters, in contrast to the dispersed cells observed in BME cultures. Collagen hydrogel significantly enhanced the mRNA expression of crucial endocrine markers and maturation factors, with IPC spheroids showing accelerated differentiation from day 5, suggesting a faster differentiation compared to single cells in hydrogel encapsulation. Insulin secretion in response to glucose in collagen environments, with a GSIS index of 2.46 ± 0.05, exceeded those in 2D and BME, demonstrating superior pancreatic islet functionality. Pathway analysis highlighted enhanced insulin secretion capabilities, evidenced by the upregulation of genes like Secretogranin III and Chromogranin A in collagen cultures. In vivo transplantation results showed that collagen hydrogel enhanced cluster integrity, tissue integration, and insulin secretion compared to non-embedded IPCs and BME groups. Conclusion: Esterified collagen hydrogels demonstrated superior efficacy over 2D and BME in promoting IPC differentiation and maturation, possibly through upregulation of the expression of key secretion pathway genes. Our findings suggest that using collagen hydrogels presents a promising approach to enhance insulin secretion efficiency in differentiating pancreatic β-cells, advancing cell therapy in diabetes cell therapy. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Phage display method is a crucial tool to find novel clinically valuable diabetes‐associated autoantigens and identify known autoantigen epitopes that are associated with diabetes and could provide scientific support and guidance for the artificial construction and synthesis of Type I diabetes mellitus (T1DM) novel biomarkers. Materials and Methods: The phage display system was used for the "biopanning" of T1DM serum. Following the sequencing of the phage DNAs, the homologous sequences of the above fusion heptapeptide were further investigated by BLAST to track the origin of the polypeptide sequences. The antibody spectrum revealed new T1DM‐associated epitopes and antibodies. Results: A total of 1200 phage DNA were sequenced and 9 conserved polypeptide sequences were collected. It was confirmed that the zinc transporter and islet amyloid protease were among them. The conserved polypeptide sequence 8 and another three distinctive polypeptide sequences derived from Proteus were discovered. Furthermore, we expressed recombinant proteins with homologous polypeptide sequences for the human islet amyloid polypeptide (IAPP) and polypeptide precursor human zinc transporter 8 (ZNT8). Through clinical sample detection for the serum from T1DM (n = 100) and T2DM (n = 200) patients, results demonstrate the importance and relevance of these polypeptides in the recognition and classification of various forms of diabetes. Conclusion: Human pancreatic and concurrent bacterial‐derived protein antigens and their epitopes were identified in this research by the phage display system, which is crucial for distinguishing different types of diabetes. [ABSTRACT FROM AUTHOR]

Introduction: Genetic studies may provide valuable information about patients who are at high risk of developing diabetes nephropathy. Before the appearance of albuminuria, there are genetic mutations that can predispose the development of kidney disease. Material and methods: The study included 130 adolescents with type 1 diabetes. Patients were divided into two groups according to the presence of microalbuminuria. This study was performed to examine clinical and laboratory differences between adolescents with type 1 diabetes with and without microalbuminuria and the distribution of the ACE, AGTR1, and MTHFR gene polymorphisms. Results: The mean microalbuminuria in the first group 6.41±7.35 significantly differs from the second group 0.82±0.48 (p<0.001). HbA1c, 24-hour proteinuria, and day-time systolic blood pressure were significantly higher in the MA group (p<0.05). Smaller systolic blood pressure percentage nocturnal decline was observed in the microalbuminuric group (p 0.030). The frequencies of the ACE DD, ID, and II genotypes were 12.5%, 50.0%, and 37.5%, respectively, among T1D patients with MA, and 19.3%, 56.1%, 24.6%, in the control group without MA (P =.510). The frequencies of the AGTR1 AA, AC, and CC genotypes were 62.5%, 25.0%, and 12.5% among TID patients with MA, and 49.1%, 43.9%, 8.0%, in the group without MA (p 0.326). The frequencies of the MTHFR CC, CT and TT genotypes were 37.5%, 50.0%, 12.5% among TID patients with MA, and 37.7%, 45.6%, 16.7% in the group without MA (p 0.901). Conclusion: Our data suggest that common variants in the AGTR1, ACE, and MTHFR genes are not strongly associated with diabetic nephropathy in our patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objectives: Regular retrospective review of glucose data is an important aspect of type 1 diabetes (T1D) management. Continuous glucose monitors (CGMs) facilitate retrospective review by capturing glucose data and generating standardized reports. However, only a minority of adults with T1D retrospectively review their glucose data, and adolescents are understudied. The objectives of this study were to determine the prevalence of self‐reported retrospective glucose data review by adolescents with T1D, determine factors associated with self‐reported retrospective glucose data review, and assess whether self‐reported retrospective glucose data review was associated with improved glycemia. Methods: We conducted a cross‐sectional survey of adolescents aged 12–18 years with T1D in conjunction with review of the associated electronic medical record, which included age, sex, date of diagnosis, clinic hemoglobin A1c (HbA1c), type of insurance, and CGM data. The survey included the Hypoglycemia Fear Survey (HFS) and questions regarding habits and attitudes associated with retrospective review. Results: 112 out of 218 eligible individuals completed the survey (51%). Fifty‐three percent of adolescents who completed the survey reported that they had engaged in retrospective glucose data review. Of these, 88% of individuals reported that they reviewed data regularly. Age, sex, race, type of insurance, and CGM use were not associated with retrospective review status. Self‐report of retrospective glucose data review was associated with improved glycemia as measured by HbA1c and time in range (TIR) compared to adolescents who indicated they do not review glucose data (p = 0.006 and p = 0.04, respectively). There was no difference in HFS scores between reviewers and nonreviewers including the behavioral subscale, worry subscale, and total score. Conclusions: Self‐report of retrospective glucose data review was associated with improved glycemia as measured by HbA1c and TIR. Adolescent‐initiated glucose data self‐review does not appear to be driven by fear of hypoglycemia (FoH). [ABSTRACT FROM AUTHOR]

Aims: According to the gut–kidney axis theory, gut microbiota (GM) has bidirectional crosstalk with the development of diabetic kidney disease (DKD). However, empirical results have been inconsistent, and the causal associations remain unclear. This study was aimed at exploring the causal relationship between GM and DKD as well as the glomerular filtration rate (GFR) and urinary albumin‐to‐creatinine ratio (UACR). Materials and Methods: Two‐sample Mendelian randomisation (MR) analysis was performed with inverse‐variance weighting as the primary method, together with four additional modes (MR–Egger regression, simple mode, weighted mode, and weighted median). We utilised summary‐level genome‐wide association study statistics from public databases for this MR analysis. Genetic associations with DKD were downloaded from the IEU Open GWAS project or CKDGen consortium, and associations with GM (196 taxa from five levels) were downloaded from the MiBioGen repository. Results: In forward MR analysis, we identified 13 taxa associated with DKD, most of which were duplicated in Type 2 diabetes with renal complications but not in Type 1 diabetes. We observed a causal association between genetic signature contributing to the relative abundance of Erysipelotrichaceae UCG003 and that for both DKD and GFR. Similarly, host genetic signature defining the abundance of Ruminococcaceae UCG014 was found to be simultaneously associated with DKD and UACR. In reverse MR analysis, the abundance of 14 other GM taxa was affected by DKD, including the phylum Proteobacteria, which remained significant after false discovery rate correction. Sensitivity analyses revealed no evidence of outliers, heterogeneity, or horizontal pleiotropy. Conclusion: Our findings provide compelling causal genetic evidence for the bidirectional crosstalk between specific GM taxa and DKD development, contributing valuable insights for a comprehensive understanding of the pathological mechanisms of DKD and highlighting the possibility of prevention and management of DKD by targeting GM. [ABSTRACT FROM AUTHOR]

Carney Complex (CNC) is a rare syndrome characterized by spotty skin pigmentation and multiple neoplasms, notably cardiac myxomas, schwannomas, and endocrine tumours. It is often inherited in an autosomal dominant manner with PRKAR1A gene mutations found in the majority of cases. Male infertility is established as part of the CNC phenotype and is largely associated with Large cell calcifying Sertoli cell tumours (LCCSCT). We describe a case of a 30-year-old male patient with Carney Complex, presenting with severe oligoasthenozoospermia and primary pigmented nodular adrenocortical disease (PPNAD). During follow-up consults, the severe oligozoospermia and impaired semen motility persisted and the patient was also diagnosed with a recurring cardiac myxoma and LCCSCT. Molecular testing identified a novel PRKAR1A mutation involving a deletion of exons 4 to 7. Our findings suggest this mutation causes PRKAR1A haploinsufficiency, which may be directly linked to male infertility, irrespective of the presence of testicular tumours. Accordingly, in male patients with CNC, detection of a PRKAR1A gene mutation may serve as a predictive marker for infertility. This case report illustrates the importance of early consideration and management of infertility in male patients diagnosed with CNC. Plain Language Summary: Male infertility associated with a novel PRKAR1A mutation in carney complex Carney Complex (CNC) is a rare genetic disorder that leads to the development of various tumours, including in the heart and endocrine glands. Most cases are linked to mutations in a gene called PRKAR1A and are inherited in an autosomal dominant manner. This case report presents a detailed examination of a patient diagnosed with Carney Complex (CNC), followed over nearly 10 years. The patient initially consulted due to infertility, which led to extensive investigations and diagnosis of several type of tumours: Primary pigmented nodular adrenocortical disease (PPNAD) in the adrenal glands, a cardiac myxoma, and Large cell calcifying Sertoli cell tumours (LCCSCT) in the testes - all tumours are characteristic features of CNC. Notably, genetic testing revealed a novel mutation in the PRKAR1A gene. Through this case, we highlight how this genetic mutation might cause PRKAR1A haploinsufficiency and be solely responsible for infertility in CNC irrespective of testicular tumours, providing valuable insights into a condition where male infertility is rarely documented. This report contributes important new information to the limited existing research on the connection between CNC and male infertility. [ABSTRACT FROM AUTHOR]

Background: The Steno Type 1 Risk Engine (ST1RE) was developed to aid clinical decisions in primary prevention for individuals with type 1 diabetes (T1D), as existing cardiovascular (CV) risk models for the general population and type 2 diabetes tend to underestimate CV risk in T1D. However, the applicability of ST1RE in different populations remains uncertain, as prediction models developed for one population may not accurately estimate risk in another. This study aimed to evaluate the performance of the ST1RE in predicting CV events among ethnically mixed T1D individuals and its association with the progression of microangiopathy complications. Methods: A retrospective survey of 435 adults with T1D who were free of CV events at baseline was assessed by ST1RE and chronic diabetes complications at 5 and 10 years of follow-up. The estimated CV risk rates were compared with the observed rates at 5 and 10 years using statistical analyses, including Receiver Operating Characteristic (ROC) curve analysis, Hosmer-Lemeshow test, Kaplan-Meier curves analysis and Cox-regression models. Results: Among 435 patients (aged 25 years; interquartile range [IQR]: 21–32) with a median T1D duration of 13 years (IQR: 9–18), only 5% were categorized into the high ST1RE group. Within a median follow-up of 9.2 years (IQR 6.0-10.7), 5.5% of patients experienced a CV event (1.6%, 14.9%, and 50% from the low, moderate, and high-risk groups, respectively). The hazard ratios (HRs) for CV events were greater in the high-risk group (HR 52.02; 95% CI 18.60–145.51, p < 0.001) and in the moderate-risk group (HR 8.66; 95% CI 2.90–25.80, p < 0.001) compared to the low-risk group. The ST1RE estimated CV events were similar to the observed at 5 years (3.4% vs. 3.5%; χ2 = 10.12, p = 0.899) and 10 years (6.8% vs. 9.9%; χ2 = 14.80, p = 0.676) of follow-up. The progression of microangiopathies was greater in the high vs. low for retinopathy (p = 0.008), diabetic kidney disease (p < 0.001), peripheral neuropathy (p = 0.021), and autonomic neuropathy (p = 0.008). Conclusions: ST1RE performed well in predicting CV events at 5 and 10 years of follow-up. Moreover, higher ST1RE scores were associated with the progression of microangiopathy complications in this genetically heterogeneous T1D population. [ABSTRACT FROM AUTHOR]

Microorganisms have long been suspected to influence the outcome of immune-related syndromes, particularly autoimmune diseases. Type 1 diabetes (T1D) results from the autoimmune destruction of the insulin-producing beta cells of pancreatic islets, causing high glycemia levels. Genetics is part of its aetiology, but environmental factors, particularly infectious microorganisms, also play a role. Bacteria, viruses, and parasites influence the outcome of T1D in mice and humans. We used nonobese diabetic (NOD) mice, which spontaneously develop T1D, to investigate the influence of a parasitic infection, leishmaniasis. Leishmania amazonensis is an intracellular eukaryotic parasite that replicates predominantly in macrophages and is responsible for cutaneous leishmaniasis. The implication of Th1 immune responses in T1D and leishmaniasis led us to study this parasite in the NOD mouse model. We previously constructed osteopontin knockout mice with a NOD genetic background and demonstrated that this protein plays a role in the T1D phenotype. In addition, osteopontin (OPN) has been found to play a role in the immune response to various infectious microorganisms and to be implicated in other autoimmune conditions, such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in mice. We present herein data demonstrating the role of OPN in the response to Leishmania in NOD mice and the influence of this parasitic infection on T1D. This exploratory study aimed to investigate the environmental infectious component of the autoimmune response, including Th1 immunity, which is common to both T1D and leishmaniasis. [ABSTRACT FROM AUTHOR]

Objective: To assess the feasibility and acceptability of a virtual food skills program for children with type 1 diabetes. Methods: Forty‐three patients, aged 6–14 years with type 1 diabetes, participated in an 8‐week online programme, summerlunch+ At Home, that included weekly live cooking classes, asynchronous learning modules, and quizzes accessed through Google Classroom. Grocery delivery or gift cards were provided to all participants to support equitable access to participation. Descriptive results were summarized, and thematic analysis was performed on answers to a post‐intervention questionnaire, parent/caregivers interview transcripts, and facilitators' field notes. Results: Participants reported having a positive experience and would recommend the programme to others. Acceptable elements included the online format, the cooking class demonstrations, and the well‐organized content. Families enjoyed the recipes, expressed an improvement in the families' cooking skills and nutrition knowledge, and noted the program as a way to improve family bonding and reduce participants' sense of social isolation given the opportunity of meeting peers with diabetes. The intervention also appears to increase participants' independence, confidence, and self‐esteem. While grocery cards were easier to coordinate compared with meal kits, both were deemed acceptable by caregivers. Barriers to participation include a distracting home environment and not feeling comfortable on camera. Factors that negatively impacted satisfaction were the large age range of participants and the class timing and duration. Caregivers noted a desire for more diabetes education, enhanced peer‐to‐peer interaction, and incorporation of animal‐based protein recipes in future programmes. Conclusion: The current study demonstrates the feasibility and acceptability of the virtual summerlunch+ At Home cooking and nutrition program that was adapted for children with diabetes. Similar food skills programmes may support the development of food skills imperative to diabetes self‐management long‐term. Further research can continue to assess food literacy skills, glycemic management, and the social benefits of such interventions. [ABSTRACT FROM AUTHOR]

Age-related cataracts is a highly prevalent eye disorder that results in the clouding of the crystalline lens and is one of the leading causes of visual impairment and blindness. The disease is influenced by multiple factors including genetics, prolonged exposure to ultraviolet radiation, and a history of diabetes. However, the extent to which each of these factors contributes to the development of cataracts remains unclear. Our study identified 101 independent genome-wide significant loci, 57 of which are novel. We identified multiple genes and biological pathways associated with the cataracts, including four drug-gene interactions. Our results suggest a causal association between type 1 diabetes and cataracts. Also, we highlighted a surrogate measure of UV light exposure as a marker of cataract risk in adults. Here, the authors expand knowledge of the genetic architecture of age-related cataracts, exploring associated pathways and drug-gene interactions, and clarify the roles of type 1 diabetes and UV exposure in cataract etiology. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have radically altered cancer treatment, but immune toxicities called immune-related adverse events (irAEs), particularly endocrine toxicities, such as acute-onset diabetes and thyroid dysfunction, pose challenges. Although most irAEs have mild-to-moderate severity, failure to diagnose and treat them promptly can result in life-threatening complications. This report presents the case of a 50-year-old woman who developed ICIinduced diabetes mellitus (ICI-DM) during sintilimab treatment for advanced cervical carcinoma. The patient experienced repeated episodes of diabetic ketoacidosis (DKA) and subclinical hypothyroidism. Unlike the case of patients with typical type 1 diabetes mellitus (T1DM), our patient tested negative for b cell autoantibodies and progressed rapidly. Prompt recognition and insulin treatment are crucial for helping patients overcome such crises. Eventually, sintilimab was discontinued, and chemotherapy was initiated. This case report contributes to our understanding of ICI-DM. The significance of monitoring thyroid function and blood glucose levels before initiating ICI treatment to identify irAEs early and effectively manage them are important considerations. [ABSTRACT FROM AUTHOR]

Background: Asparaginase-associated pancreatitis (AAP) is a major challenge for continuing asparaginase therapy. We aimed to investigate the acute and longterm complications and survival rates related to first and second AAP episodes in Chinese children with haematological malignancies. Methods: We retrospectively analysed clinical data of children with pancreatitis who received asparaginase chemotherapy for acute lymphoblastic leukaemia (ALL), acute mixed cell leukaemia, and non-Hodgkin's lymphoma at Shanghai Children's Medical Center from November 2013 to November 2023. Results: Of the 76 children included in the study, 12 had local complications (15.79%), with no deaths recorded. Systemic complications manifested in 28 patients (36.84%), resulting in 3 deaths (3.95%). Four patients (5.26%) developed long-term complications (chronic pancreatitis or insulin-dependent diabetes mellitus). No significant differences in local or long-term complications were recorded between children in the asparaginase re-exposed (n=39) and non-reexposed (n=45) groups. Among the re-exposed patients, eight (25.81%) experienced a second attack without fatalities or complications. Survival analysis of intermediate-to high-risk patients revealed a significantly higher event-free survival (EFS) rate for the re-exposed group than for the non-reexposed group. The second AAP episode's occurrence and severity had no relation to the first AAP episode's severity, and the second AAP episode was significantly less severe than the first (p<0.001). Conclusions: The second AAP episode's occurrence is unrelated to the first AAP episode's severity, and the second AAP episode's severity is significantly lower than that of the first. Further, asparaginase therapy could improve EFS in children with intermediate and high-risk ALL. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD), particularly ischemic heart disease, remains the leading cause of death and morbidity in patients with type 1 diabetes. Detecting subclinical atherosclerosis could enhance cardiovascular risk stratification and enable individualised therapies. The aim of this study is to investigate the prevalence and predictors of subclinical atherosclerosis in patients with type 1 diabetes without overt cardiovascular disease (CVD) and to assess its impact on patient survival over a follow-up period of at least 5 years. Methods: This observational study included 507 patients treated at the Diabetes Unit of the Hospital of Girona Doctor Josep Trueta between 2015 and 2023. The inclusion criteria for patients were as follows: those aged 18 and older with diabetes for a minimum of 10 years or those aged 40 and older with a diabetes for at least 5 years. Subclinical atherosclerosis was identified via ultrasound imaging of the carotid and femoral arteries. Clinical and biochemical evaluations were also conducted. Major cardiovascular events (MACE) and deaths from other causes were monitored, and survival analysis was performed using Kaplan‒Meier methods. Results: Subclinical atherosclerosis was detected in 218 patients (43%). Multivariate analysis revealed that the male sex, diabetic nephropathy, tobacco exposure, higher HbA1c levels, older age, and longer diabetes duration were significant predictors. During a mean follow-up of 70.64 ± 27.08 months, 19 patients experienced MACE, and 13 died from any cause. The probability of MACE or death was greater in patients with subclinical atherosclerosis, with a hazard ratio (HR) of 25.1 (95% CI 5.81–108, p < 0.001) for MACE and an odds ratio (OR) of 7.57 (95% CI 1.97–53.9, p = 0.004) for death. Conclusion: Subclinical atherosclerosis is independently associated with increased overall mortality and MACE in patients with type 1 diabetes. Identifying clinical predictors can improve risk stratification and personalised therapeutic strategies to prevent MACEs in this high-risk population. [ABSTRACT FROM AUTHOR]

Objective: We sought to evaluate the risk of preterm labor and hypertensive disorders in adolescent pregnancies with and without diabetes. Methods: We evaluated 1,843,139 adolescents (≤20 years old) with labor and delivery admissions in the national Kids' Inpatient Database (KID) in years 2006, 2009, 2012, 2016, and 2019. International classification of disease codes was used to identify diabetes and medical factors affecting pregnancy. Weighted logistic regression was used to evaluate the association between diabetes and complications. Results: Among admissions, 0.2% had type 1 diabetes (T1D), 0.2% had type 2 diabetes (T2D), and 0.7% had gestational diabetes (GDM); 10.1% of admissions were complicated by hypertensive disorders and 5.8% by preterm labor. Compared to adolescents without diabetes, those with diabetes had a higher prevalence of hypertensive disorders (T1D: 35.4%, T2D: 37.8%, GDM: 24.9%, None: 9.9%; p < 0.001) and preterm labor (T1D: 21.5%, T2D: 16.8%, GDM: 6.8%, none: 5.7%; p < 0.001). In adjusted models, odds of hypertensive disorders were higher in later study years (2019 vs. 2006 OR 1.85, 95% CI 1.77–1.94), among those with T1D (OR 4.32, 95% CI 3.94–4.74), with T2D (OR 4.18, 95% CI 3.79–4.61), and with GDM (OR 1.99, 95% CI 1.89–2.10). Adjusted odds of preterm labor were higher among those with T1D (OR 4.53, 95% CI 4.09–5.02), with T2D (OR 3.35, 95% CI 2.96–3.78), and with GDM (OR 1.18, 95% CI 1.08–1.28); disparities were seen by race/ethnicity, insurance, and income. Conclusions: Diabetes, which is increasing among adolescents, is a significant risk factor for preterm labor and hypertensive disorders. Though the absolute number of adolescent pregnancies is decreasing, rates of hypertensive disorders have increased. Appropriate interventions are needed to ensure healthy outcomes for adolescents who are pregnant. [ABSTRACT FROM AUTHOR]

Background: People with diabetes are at an increased risk of contracting the hepatitis B virus (HBV). However, hepatitis B (HepB) vaccination rates among adults with diabetes are low. Factors influencing HepB vaccination have not been adequately explored. Aims: The study aims to identify and understand the barriers adults with diabetes have in receiving the recommended HepB vaccine from the physicians' perspective. Methods: This study used semi-structured interviews to ascertain the perspective of 11 primary care physicians (PCPs) in a large academic medical group about HepB vaccination among their patients with Type 1 and 2 diabetes. Thematic analysis yielded descriptions of barriers and strategies that could potentially impact HepB vaccination among adults with diabetes. Results: Physician responses related to four themes: (1) Conflicting perceptions about HBV risk and the CDC recommendation for adults with diabetes; (2) PCPs don't perceive HepB vaccination as important as other adult vaccines and prioritize vaccination based on risk exposure; (3) PCPs' perceived barriers to HepB vaccination among adults with diabetes; and (4) Physician recommended strategies to increase HepB vaccination among adults with diabetes. Conclusion: Our findings indicate that physicians are generally aware of the existence of the CDC guidelines, but not all physicians recommend the HepB vaccine to adults with diabetes. This is because of a wide variation in treatment concerning glucose monitoring or insulin injection due to varying opinions about actual risk. We also identified barriers adults with diabetes have in receiving the HepB vaccine and strategies to increase HepB vaccination. [ABSTRACT FROM AUTHOR]

Diabetes treatment options have improved dramatically over the last 100 years, however, close to 2 million individuals in the U.S. alone live with type 1 diabetes (T1D) and are still dependent on multiple daily insulin injections and/or continuous insulin infusion with a pump to stay alive and no oral medications are available. After decades of focusing on immunosuppressive/immunomodulatory approaches for T1D, it has now become apparent that at least after disease onset, this by itself may not be sufficient, and in order to be effective, therapies need to also address beta cell health. This Perspective article discusses the emergence of such a beta cell-targeting, novel class of oral T1D drugs targeting thioredoxin-interacting protein (TXNIP) and some very recent advances in this field that start to address this unmet medical need. It thereby focuses on repurposing of the antihypertensive drug, verapamil found to nonspecifically inhibit TXNIP and on TIX100, a new chemical entity specifically developed as an oral anti-diabetic drug to inhibit TXNIP. Both have shown striking anti-diabetic effects in preclinical studies. Verapamil has also proven to be beneficial in adults and children with recent onset T1D, while TIX100 has just been cleared by the U.S. Food and Drug Administration (FDA) to proceed to clinical trials. Taken together, we propose that such non-immunosuppressive, adjunctive therapies to insulin, alone or in combination with immune modulatory approaches, are critical in order to achieve effective and durable diseasemodifying treatments for T1D. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF protein superfamily and was initially identified as a protein capable of inducing apoptosis in cancer cells. In addition, TRAIL can promote pro-survival and proliferation signaling in various cell types. Subsequent studies have demonstrated that TRAIL plays several important roles in immunoregulation, immunosuppression, and immune effector functions. Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia due to the loss of insulin-producing β-cells, primarily driven by T-cell-mediated pancreatic islet inflammation. Various genetic, epigenetic, and environmental factors, in conjunction with the immune system, contribute to the initiation, development, and progression of T1D. Recent reports have highlighted TRAIL as an important immunomodulatory molecule with protective effects on pancreatic islets. Experimental data suggest that TRAIL protects against T1D by reducing the proliferation of diabetogenic T cells and pancreatic islet inflammation and restoring normoglycemia in animal models. In this review, we aimed to summarize the consequences of TRAIL action in T1D, focusing on and discussing its signaling mechanisms, role in the immune system, and protective effects in T1D. [ABSTRACT FROM AUTHOR]

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 β-cell function. [ABSTRACT FROM AUTHOR]

Neonatal diabetes mellitus (NDM) is a rare, insulin-dependent diabetes that manifests within the first month of life and requires insulin therapy for management. NDM is categorized into two primary types: transient NDM (TNDM), which typically resolves during infancy or early childhood, and permanent NDM (PNDM), necessitating lifelong insulin treatment. TNDM has an incidence of approximately 1 in 90,000 to 160,000 live births and is characterized by insulin-dependent hyperglycemia that usually resolves within 12 weeks but may relapse in later adolescence or early adulthood. Congenital manifestations often include intrauterine growth restriction (IUGR), macroglossia, and umbilical hernia, with its etiology linked to epigenetic alterations on chromosome 6q24 that affect the transcription factor PLAGL1. In contrast, PNDM occurs with an incidence ranging from 1 in 108,999 to 1 in 1,029,999 live births and presents with persistent hyperglycemia requiring lifelong insulin therapy. It is primarily associated with mutations in over 49 genes, particularly KCNJ11 and ABCC8, which disrupt ATP-sensitive potassium channels, while some cases involve mutations in the insulin gene that affect β-cell function. Treatment mainly consists of insulin therapy, although some patients may transition to oral sulfonylureas. Long-term follow-up by a multidisciplinary pediatric team is crucial, as individuals with NDM may experience recurrent diabetes and neurological or neuropsychological issues. Insulin therapy is an effective approach for managing NDM, necessitating meticulous monitoring of blood glucose levels to reduce the risk of long-term complications. Genetic testing is essential for diagnosing both types of NDM and informing treatment strategies, including the potential use of oral sulfonylureas for PNDM. Ongoing research into the genetic mechanisms and long-term management approaches is vital for enhancing clinical outcomes and monitoring complications in affected individuals. [ABSTRACT FROM AUTHOR]

The prevalence of T2DM has been increasing dramatically over recent decades, about 537 million people in 2021. LADA type diabetes, a subtype of diabetes that exhibits characteristics of both T2DM and autoimmune beta‐cell destruction similar to T1DM, but with a later onset. The aim of this study is to analyze the main research field on LADA type, including analysis of countries, institutions, journals, authors, and keywords. This research utilized a descriptive bibliometric design. We collected and analyzed data from 672 publications indexed in the Web of Science and Scopus databases, covering the period from 1994 to January 2024. The bibliometric analysis included English‐language research articles that involved studies on patients with LADA type diabetes, aged 18 years or older. RStudio and the Bibliometrix R package were used for data merging and for performing statistical and visual analyses. The annual publication shows an upward trend over the period, with the highest number of publications per year in 2021. The study showed that China leads in the number of articles, with 101 papers published. The United Kingdom demonstrates significant international collaborations, particularly with Germany. The top institutions in terms of the number of published articles are the Norwegian University of Science and Technology in the Kingdom of Norway, followed by the Central South University in China. Tuomi has shown significant long‐term publication impact, while Zhou ranks among the most frequently cited authors. Diabetes Care is one of the most important scientific journals in diabetology with the highest impact factor of 16.2. This abstract summarizes a comprehensive bibliometric analysis that provides insights into the global research field of LADA type, underscoring the importance of international collaboration and the significant contributions of leading countries and institutions in shaping our understanding of this complex subtype of diabetes. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) in children and adolescents with type 1 diabetes mellitus (T1DM) is a growing issue, with controversial data in the terms of prevalence and evaluation timelines. Currently, there are no clear standards for its early detection. Therefore, our aim was to assess the contribution of the Michigan neuropathy screening instrument (MNSI), lipid profile, serum neuron specific enolase (NSE), and serum heat shock protein 27 (HSP 27) to the prediction of DPN in children and adolescents with T1DM. Methods: In this case-control study, fifty children diagnosed with T1DM for at least five years were enrolled and evaluated through complete neurological examination, MNSI, and nerve conduction study (NCS). Additionally, HbA1c, lipid profile, serum NSE, and serum HSP 27 levels were measured for patients and controls. Results: The prevalence of DPN in our study was 24% by NCS, and electrophysiological changes showed a statistically significant lower conduction velocity for the posterior tibial and sural nerves, as well as a prolonged latency period for the common peroneal and sural nerves in neuropathic patients. In these patients, older age, earlier age of diabetes onset, longer disease duration, higher total cholesterol, triglycerides, low density lipoprotein cholesterol, HbA1c, serum NSE, and HSP27 levels were observed. The MNSI examination score ≥ 1.5 cutoff point had an area under the curve (AUC) of 0.955, with 75% sensitivity and 94.74% specificity, according to receiver operating characteristic curve analysis. However, the questionnaire's cutoff point of ≥ 5 had an AUC of 0.720, 75% sensitivity, and 63% specificity, with improved overall instrument performance when combining both scores. Regarding blood biomarkers, serum NSE had greater sensitivity and specificity in discriminating neuropathic patients than HSP27 (92% and 74% versus 75% and 71%, respectively). Regression analysis revealed a substantial dependency for MNSI and serum NSE in predicting DPN in patients. Conclusions: Despite limited research in pediatrics, MNSI and serum NSE are promising predictive tools for DPN in children and adolescents with T1DM, even when they are asymptomatic. Poor glycemic control and lipid profile changes may play a critical role in the development of DPN in these patients, despite conflicting results in various studies. [ABSTRACT FROM AUTHOR]

The intricate etiology of type 1 diabetes mellitus (T1D), characterized by harmful interactions between the immune system and insulin-producing beta cells, has hindered the development of effective therapies including human islet transplantation, which requires strong immunosuppressants that impair beta cell survival and function. As such alternative immunomodulating therapies are required for successful transplantation. The discovery that pharmacological activation of the nuclear receptor LRH-1/NR5A2 can reverse hyperglycemia inmousemodels of T1D by altering, and not suppressing the autoimmune attack, prompted us to investigate whether LRH-1/NR5A2 activation could improve human islet function/survival after xenotransplantation in immunocompetent mice. Human islets were transplanted under the kidney capsule of streptozotocin (STZ)-induced diabetic mice, and treatment with BL001 (LRH-1/NR5A2 agonist) or vehicle was administered one week post-transplant. Our study, encompassing 3 independent experiments with 3 different islet donors, revealed that mice treated for 8 weeks with BL001 exhibited lower blood glucose levels correlating with improved mouse survival rates as compared to vehicle-treated controls. Human C-peptide was detectable in BL001-treated mice at both 4 and 8 weeks indicating functional islet beta cells. Accordingly, in mice treated with BL001 for 8 weeks, the beta cell mass was preserved, while a significant decrease in alpha cells was observed compared to mice treatedwith BL001 for only 4 weeks. In contrast, vehicle-treated mice exhibited a reduction in insulin-expressing cells at 8 weeks compared to those at 4 weeks. These results suggest that BL001 significantly enhances the survival, engraftment, and functionality of human islets in a STZ-induced diabetic mouse model. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing b-cells in the pancreas. This destruction leads to chronic hyperglycemia, necessitating lifelong insulin therapy to manage blood glucose levels. Typically diagnosed in children and young adults, T1D can, however, occur at any age. Ongoing research aims to uncover the precise mechanisms underlying T1D and to develop potential interventions. These include efforts to modulate the immune system, regenerate b-cells, and create advanced insulin delivery systems. Emerging therapies, such as closed-loop insulin pumps, stem cell-derived b-cell replacement and disease-modifying therapies (DMTs), offer hope for improving the quality of life for individuals with T1D and potentially moving towards a cure. Currently, there are no disease-modifying therapies approved for stage 3 T1D. Preserving b-cell function in stage 3 T1D is associated with better clinical outcomes, including lower HbA1c and decreased risk of hypoglycemia, neuropathy, and retinopathy. Tumor Necrosis Factor alpha (TNFa) inhibitors have demonstrated efficacy at preserving b-cell function by measurement of C-peptide in two clinical trials in people with stage 3 T1D. However, TNF-a inhibitors have yet to be evaluated in a pivotal trial for T1D. To address the promising clinical findings of TNF-a inhibitors in T1D, Breakthrough T1D convened a panel of key opinion leaders (KOLs) in the field. The workshop aimed to outline an optimal clinical path for moving TNF-a inhibitors to a pivotal clinical trial in T1D. Here, we summarize the evidence for the beneficial use of TNF-a inhibitors in T1D and considerations for strategies collectively identified to advance TNF-a inhibitors beyond phase 2 clinical studies for stage 3 T1D. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the admission indicators and characteristics of individuals diagnosed with type 1 diabetes (T1D) to ascertain potential impact on the choice of glucose control therapy after discharge. Methods: A total of 398 eligible T1D patients were selected. We conducted multivariable logistic regression analysis to determine the independent influence of predictors on the selection of glucose control therapy after discharge. To explore the influencing factors of different subgroups, we additionally performed subgroup analyses based on gender and age. Results: Our study revealed that body mass index (BMI) was noteworthy influence factor for prescription of insulin and non-insulin antidiabetic drug (NIAD prescription) in T1D patients of general population [OR = 1.109 (1.033-1.195), p = 0.006], male [OR = 1.166 (1.040-1.318), p = 0.011] and individuals below the age of 30 years [OR = 1.146 (1.020-1.301), p = 0.028]. Diastolic blood pressure (DBP) was a protective factor for NIAD prescription in the general population [OR = 0.971 (0.949-0.992), p = 0.008] and women [OR = 0.955 (0.923-0.988), p = 0.008]. The other risk factor of NIAD prescription in men was dyslipidemia [OR = 4.824 (1.442-22.246), p = 0.020]. Pulse pressure [OR = 1.036 (1.007-1.068), p = 0.016] constituted an additional risk factor of NIAD prescription among individuals below the age of 30 years. The risk factors of NIAD prescription for people aged 30 to 50 years were length of stay [OR = 1.097 (1.014-1.196), p = 0.026] and initial blood glucose [OR = 1.078 (1.007-1.168), p = 0.047]. In the case of individuals aged above 50 years, physicians exhibited a higher tendency to prescribe supplementary non-insulin medications to men [OR = 9.385 (1.501-87.789), p = 0.029]. Conclusions: We identified notable factors that influence discharge prescriptions in patients with T1D. In order to enhance the treatment outcome for the patient, clinicians ought to have a special focus on these indicators or factors. [ABSTRACT FROM AUTHOR]

Background: This study employed a bidirectional Mendelian Randomization (MR) approach to explore the causal relationships between Oral Lichen Planus (OLP), diabetes mellitus (DM), and glycemic control. It also aims to identify potential pharmacological and herbal treatments that effectively address both OLP and the metabolic dysfunctions associated with DM. Methods: This study employs a two-way MR approach to investigate the potential causal relationships between diabetes type and glycated hemoglobin (HbA1c) levels, and the risk of OLP. We analyzed differentially expressed genes from the OLP dataset in the Genomics Expression Omnibus (GEO) database, cross-referencing these with HbA1c-related genes for enrichment analysis. Additionally, the Drug-Gene Interaction Database (DGIdb) and Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) were utilized to assess the effectiveness of specific drugs, herbs, and ingredients in treating OLP while managing blood glucose levels. Results: The MR analysis revealed a significant association between Type 1 Diabetes mellitus (T1DM) and an increased risk of OLP, unlike Type 2 Diabetes mellitus (T2DM). This finding indicates a unique immunological interaction in T1DM that may predispose individuals to OLP. The drug prediction analysis focused on core targets linked to OLP and HbA1c, evaluating the therapeutic potential of retinoic acid, prednisone, and thalidomide for treating OLP and regulating blood glucose levels. Additionally, herbal medicines such as Ecliptae herbaand Amygdalus communis vas, along with herbal ingredients like quercetin, luteolin, and 17-beta-estradiol, were identified for their anti-inflammatory properties and potential to mitigate metabolic dysfunction in diabetes. Conclusion: The study highlighted a complex interplay between diabetes and OLP, underscoring the efficacy of integrated therapeutic strategies that target both conditions. The findings suggest that both pharmaceutical and herbal treatments can effectively manage the clinical manifestations of OLP and associated metabolic challenges. This holistic approach to treatment could significantly enhance patient outcomes by addressing the interconnected aspects of these chronic conditions. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by hyperglycemia resulting from the destruction of insulin-producing β-cells that is traditionally deemed irreversible, but partial remission (PR) with temporary reversal of hyperglycemia is sometimes observed. Here we use single-cell RNA sequencing to delineate the immune cell landscape across patients in different T1D stages. Together with cohort validation and functional assays, we observe dynamic changes in TIGIT+CCR7− Tregs and CD226+CCR7−CD8+ cytotoxic T cells during the peri-remission phase. Machine learning algorithms further identify TIGIT+CCR7− Tregs and CD226+CD8+ T cells as biomarkers for β-cell function decline in a predictive model, while cell communication analysis and in vitro assays suggest that TIGIT+CCR7− Tregs may inhibit CD226+CCR7−CD8+ T cells via TGF-β signaling. Lastly, in both cyclophosphamide-induced and streptozotocin (STZ)-induced mouse diabetes models, CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity. Our results thus identify two interrelated immune cell subsets that may serve as biomarkers for monitoring disease progression and targets for therapeutic intervention of T1D. Type 1 diabetes (T1D) manifests as hyperglycemia, with spontaneous remission occasionally observed, but the underneath mechanisms are unclear. Here the authors analyses patients at different stages to find two populations of immune cells correlating with disease progression or remission, while results from mouse diabetes models validate these observations. [ABSTRACT FROM AUTHOR]

Background: Health-related stigma and its internalization among individuals with chronic health conditions contribute to impaired mental and physical health and quality of life. Research on health-related stigma has been siloed, with disease-specific measures that may not capture the experiences of individuals with multiple health conditions and that prevent comparisons across health conditions. The current study aimed to develop and test a transdiagnostic measure of internalized health-related stigma for use among adults with different physical health conditions. Methods: An existing measure of internalized mental health stigma was adapted to assess stigma due to chronic physical health conditions following COSMIN procedures, with input from advisory boards of community members living with a range of stigmatized health conditions (obesity, type 1 and type 2 diabetes, skin diseases, HIV, chronic pain, and cancers) and of health professionals who specialized in these conditions. The new Internalized Health-Related Stigma (I-HEARTS) Scale was tested in an online sample of 300 adults with these health conditions, recruited from ResearchMatch. Additional psychosocial measures of mental health and quality of life were administered, and participants provided information about their health conditions and demographic characteristics. Exploratory factor analysis and tests of reliability and validity were conducted to determine the psychometric properties of the I-HEARTS Scale, and k-means clustering and receiver of characteristic curve analysis were used to determine a clinically meaningful cutoff score indicating high levels of internalized stigma. Results: Factor analysis results yielded a 25-item scale with a 3-factor solution, with subscales of Perceived and Anticipated Stigma, Stereotype Application and Self-Devaluation, and Stigma Resistance. Psychometric properties for internal consistency, inter-item and item-total correlations, and test-retest reliability were strong. Certain demographics (e.g., younger age) and characteristics related to health conditions (e.g., greater symptom severity) were associated with higher levels of internalized stigma. I-HEARTS Scale scores correlated moderately to strongly with related but distinct psychosocial measures, and a cutoff score of 3.40 or higher on the 1–7 rating scale was determined to indicate clinically meaningful levels of internalized stigma. Conclusions: The I-HEARTS Scale is a reliable and valid measure for the assessment of internalized health-related stigma among adults with varied stigmatized chronic health conditions. Study pre-registration: https://osf.io/84c5d/?view_only=87238512f6d6475c87f8f64280a8a15f. [ABSTRACT FROM AUTHOR]

Latent Autoimmune Diabetes in Adults (LADA) is a type of diabetes mellitus often overlooked in clinical practice for its dual resemblance to Type 1 Diabetes Mellitus (T1DM) in pathogenesis and to Type 2 Diabetes Mellitus (T2DM) in clinical presentation. To better understand LADA's distinctiveness from T1DM and T2DM, we conducted a comprehensive review encompassing etiology, pathology, clinical features, treatment modalities, and prognostic outcomes. With this comparative lens, we propose that LADA defies simple classification as either T1DM or T2DM. The specific treatments for the disease are limited and should be based on the therapies of T1DM or T2DM that address specific clinical issues at different stages of the disease. It is crucial to identify LADA cases potentially misdiagnosed as T2DM, warranting prompt screening for poor blood sugar control, short-term blood sugar deterioration, and other conditions. If the prognosis for LADA is similar to T2DM, it can be managed as T2DM. However, if the prognosis fundamentally differs, early LADA screening is crucial to optimize patient outcomes and enhance research on tailored treatments. The pathogenesis of LADA is clear, so the prognosis may be the key to determining whether it can be classified as T2DM, which is also the direction of future research. On the one hand, this paper aims to provide suggestions for the clinical screening and treatment of LADA based on the latest progress and provide worthy directions for future research on LADA. [ABSTRACT FROM AUTHOR]

Background: The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels. Present study was aimed to study associated comorbidities and microvascular/macrovascular complications in diabetic patients attending a tertiary care center. Material and Methods: Present study was Cross sectional study, conducted in Type 1 and Type 2 Diabetes mellitus or newly diagnosed diabetes mellitus patients. Results: In present study regarding the eGFR maximum patients 47 (46.54%) were in stage III-B (G3a) followed by 37 (36.63%) were in stage IV (G4), 9 (8.91%) were in stage 5 (G5) and 8 (7.92%) in stage III-A (G3b) of chronic kidney disease. Data revealed that majority of patient's eGFR was moderately decreased. Majority of patients 93 (92.08%) lies in very high risk as per KDIGO classification and remaining 8 (7.92%) were at high risk. In present study out of 101 patients 48 (47.52%) had retinopathy. Among the 48 cases of retinopathy maximum patients 43 (89.58%) were having non-proliferative diabetic retinopathy (NDRP) followed by 4 (8.33%) were having mixed NDRP/PDR and single case was having proliferative retinopathy. Majority 81 (80.20%) not having neuropathy and 20 (19.80%) had neuropathy. Regarding macrovascular complication majority of patients 30 (29.70%) had unstable angina followed by myocardial infarction in 25 (24.75%), Heart failure in 18 (17.82%) and 15 (14.85%) had stroke. In present study maximum patients 97 (96.04%) were discharged and 4 (3.96%) were died during the study period. Further data reveals significant correlation between stages of CKD with outcome as p<0.05. Maximum mortality was seen in progressive stage of CKD. Conclusion: Among diabetic population, advancing age, gender, concomitant hypertension, increasing duration of diabetes and the presence of macrovascular complication were found to be important risk factors. [ABSTRACT FROM AUTHOR]

Background: In people with type 1 diabetes mellitus, free radical activity is a major contributor to vascular problems. However, there is a dearth of information on vascular consequences in type 2 diabetes mellitus. Objectives: This research evaluated the free radical activity of individuals with type 2 diabetes who had hypertension to those who did not. Supplies and Procedures: Fifty type 2 diabetes outpatients had their blood levels of the lipid peroxidation product MDA (malondialdehyde), the free radical scavenger SOD (superoxide dismutase), and NO (nitric oxide) measured. The diabetic outpatients without hypertension were considered the controls. Result: Among 50 patients thus studied 18 were hypertensive. The concentration (median (range)) of both SOD (20.31(5.33-26.64) vs. 16.65(6.66-22.64) U/dl; p< 0.05) and NO (19.54 (11.40-37.07) vs.20.40 (15.69-35.65) U/dl; p< 0.05) were reduced in the hypertensive group. Similarly, concentration (median (range) of MDA (354(231-718) vs. 390(256-666)lmoles/dl; p< 0.01 were increased in thehypertensive group.. Conclusion: In comparison to healthy controls, we concluded that our study shows a considerable increase in free radical activity in Type II diabetes patients. [ABSTRACT FROM AUTHOR]

Background: Intense exercise leads to neutrophil extracellular traps (NETs) formation, which triggers cell disintegration. NET, as well as other processes of apoptosis, necrosis, and spontaneous secretion, result in increased levels of cell-free DNA (cf-DNA) in the circulation. An increment of cf-DNA is also observed in autoimmune diseases, such as type 1 diabetes mellitus (T1DM). Repeated exhaustive exercises are an impulse for physiological adaptation; therefore, in this case–control study, we compared the exercise-induced increase in cf-DNA in men with T1DM and healthy controls to determine the development of the tolerance to exercise. Methods: Volunteers performed a treadmill run to exhaustion at a speed matching 70% of their personal VO2 max at three consecutive visits, separated by a 72 h resting period. Blood was collected before and after exercise for the determination of plasma cell-free nuclear and mitochondrial DNA (cf n-DNA, cf mt-DNA) by real-time PCR, blood cell count and metabolic markers. Results: Each bout of exhaustive exercise induced a great elevation of cf n-DNA levels. An increase in cf mt-DNA was observed after each run. However, the significance of the increase was noted only after the second bout in T1DM participants (p < 0.02). Changes in cf-DNA concentration were transient and returned to baseline values during 72 h of resting. The exercise-induced increment in circulating cf n-DNA and cf mt-DNA was not significantly different between the studied groups (p > 0.05). Conclusions: Cf-DNA appears to be a sensitive marker of inflammation, with a lower post-exercise increase in individuals with T1DM than in healthy men. [ABSTRACT FROM AUTHOR]

Background: Adolescence is a particularly crucial period of physical, emotional, and social development and adaptation, rendering these formative years rather challenging for individuals with chronic conditions like type 1 diabetes (T1D). Despite rapid improvement in diabetes therapies, adolescents with T1D are characterized by poorer adherence to treatment regimens compared with other pediatric age groups. Insufficient adherence is strongly related to low diabetes control, increasing morbidity, and risk for premature mortality. This study aimed to provide a comprehensive overview of adolescents' most common barriers to T1D adherence, stressing the need for a deep and comprehensive understanding of these barriers. The complexity of these barriers is underscored by the diverse factors contributing to poor T1D adherence in adolescents. Methods: A narrative review was conducted, surveying four databases (PubMed, Scopus, EMBASE, and Web of Science) for full-text articles in the English language published up to June 2024. All studies related to barriers to T1D adherence in adolescents were considered. The literature was selected using selection and exclusion criteria and extracted and organized using Mendeley. Exclusion criteria included studies with insufficient data and non-peer-reviewed articles. This review revealed that adolescents face numerous obstacles to T1D adherence related to psychological factors, flux in family dynamics, perceived social pressures, therapy-related factors, transitioning responsibility, risk-taking behaviors, and pubertal changes. Conclusions: Navigating the adaptations to the different aspects of T1D, from treatment to complications and adolescents' personal growth, effectively requires a thorough understanding of the barriers of a treatment regimen that patients at this critical age face. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy (DN) is a common complication of long-lasting type 1 and type 2 diabetes, with no curative treatment available. Here, we tested the effect of the incretin mimetic liraglutide in DN in mice with early-stage type 1 diabetes bred in a standard laboratory or enriched environment. With a single i.p. injection of streptozotocin 150 mg/kg, we induced murine diabetes. Liraglutide (0.4 mg/kg once daily, i.p. for ten days since the eighth post-streptozotocin day) failed to decrease the glycemia in the diabetic mice; however, it alleviated their antinociceptive behavior, as tested with formalin. The second phase of the formalin test had significantly lower results in liraglutide-treated mice reared in the enriched environment vs. liraglutide-treated mice under standard conditions [2.00 (0.00–11.00) vs. 29.00 (2.25–41.50) s, p = 0.016]. Liraglutide treatment, however, decreased the threshold of reactivity in the von Fray test. A significantly higher neopterin level was demonstrated in the diabetic control group compared to treatment-naïve controls and the liraglutide-treated diabetic mice (p < 0.001). The glutamine/glutamate ratio in both liraglutide-treated groups, either reared under standard conditions (p = 0.003) or an enriched environment (p = 0.002), was significantly higher than in the diabetic controls. This study demonstrates an early liraglutide effect on pain sensation in two streptozotocin-induced diabetes mouse models by reducing some inflammatory and oxidative stress parameters. [ABSTRACT FROM AUTHOR]

Type 1 Diabetes Mellitus (T1DM) is a chronic autoimmune disease that results in the destruction of pancreatic β cells, leading to hyperglycaemia and the need for lifelong insulin therapy. Although genetic predisposition and environmental factors are considered key contributors to T1DM, the exact causes of the disease remain partially unclear. Recent evidence has focused on the relationship between the gut, the oral cavity, immune regulation, and systemic inflammation. In individuals with T1DM, changes in the gut and oral microbial composition are commonly observed, indicating that dysbiosis may contribute to immune dysregulation. Gut dysbiosis can influence the immune system through increased intestinal permeability, altered production of short chain fatty acids (SCFAs), and interactions with the mucosal immune system, potentially triggering the autoimmune response. Similarly, oral dysbiosis may contribute to the development of systemic inflammation and thus influence the progression of T1DM. A comprehensive understanding of these relationships is essential for the identification of biomarkers for early diagnosis and monitoring, as well as for the development of therapies aimed at restoring microbial balance. This review presents a synthesis of current research on the connection between T1DM and microbiome dysbiosis, with a focus on the gut and oral microbiomes in pediatric populations. It explores potential mechanisms by which microbial dysbiosis contributes to the pathogenesis of T1DM and examines the potential of microbiome-based therapies, including probiotics, prebiotics, synbiotics, and faecal microbiota transplantation (FMT). This complex relationship highlights the need for longitudinal studies to monitor microbiome changes over time, investigate causal relationships between specific microbial species and T1DM, and develop personalised medicine approaches. [ABSTRACT FROM AUTHOR]

Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis. [ABSTRACT FROM AUTHOR]

Pro-inflammatory cytokines play a role in the failure of β cells in type 1 and type 2 diabetes. While existing data from 'omics' experiments allow for some understanding of the molecular mechanisms behind cytokine-induced dysfunction in β cells, no report thus far has provided information on the direct imaging of the β cell landscape with nanoscale resolution following cytokine exposure. In this study, we use Airyscan-based optical super-resolution microscopy of Insulinoma 1E (INS-1E) cells to investigate the structural properties of two subcellular membranous compartments involved in the production, maturation and secretion of insulin-containing granules, the endoplasmic reticulum (ER) and the Golgi apparatus (GA). Our findings reveal that exposure of INS-1E cells to IL-1β and IFN-γ for 24 h leads to significant structural alterations of both compartments. In more detail, both the ER and the GA fragment and give rise to vesicle-like structures with markedly reduced characteristic area and perimeter and increased circularity with respect to the original structures. These findings complement the molecular data collected thus far on these compartments and their role in β cell dysfunction and lay the groundwork for future optical microscopy-based ex vivo and in vivo investigations. [ABSTRACT FROM AUTHOR]

Background: The TrialNet Oral Insulin (OI) prevention trial showed no overall treatment effect, using the diagnosis of type 1 diabetes as an endpoint. A significant delay in onset was only found in a high‐risk stratum (termed secondary stratum 1) of participants with low first‐phase insulin release (FPIR). Methods: Since trials with an endpoint of type 1 diabetes take years to complete, in this post hoc analysis, we assessed whether a novel combination of glucose and C‐peptide markers could identify a therapeutic benefit after 1 year of follow‐up (trial participants followed for a median 2.7 years). Results: Participants were relatives with multiple islet autoantibodies and low FPIR (n = 40). Glucose rose, and C‐peptide declined in the placebo group, whereas glucose rose minimally, and C‐peptide increased in the OI group. When glucose and C‐peptide were plotted on two‐dimensional grids using 30–120‐min oral glucose tolerance test (OGTT) time points, changes in ratios of their central points (centroid ratio) differed between groups (p = 0.037 adjusted for age, BMI, and baseline C‐peptide and glucose). Conclusions: These findings support a favorable early effect of OI on combined glucose and C‐peptide endpoints in high‐risk individuals, indicating metabolic benefit. With further study, these measures may allow for shorter trials compared to the standard endpoint of type 1 diabetes diagnosis. [ABSTRACT FROM AUTHOR]

Maternal glucose is the principal macronutrient that sustains fetal growth. Prolonged exposure of the fetus to hyperglycemia from the early stages of pregnancy accelerates the maturation of the stimulus–secretion coupling mechanism in β cell autoimmunity, which leads to early hyperinsulinemia in type 1 diabetes mellitus (T1DM). Nowadays, diabetes mellitus (DM) is the most common medical complication of pregnancy, and among young women, the prevalence of overt diabetes and undiagnosed hyperglycemia is rising. Even though conventional medication is effective in treating DM, it is expensive and has harmful side effects. Herbal medicine will thus incorporate alternative therapy and be more effective and less toxic. Due to their bioactive components, olive leaves (Olea europaea) are frequently used medicinally; however, little is known about how this plant affects the immune system when it comes to diabetes. The current study used a pregnant mother rat model of alloxan-induced T1DM to examine the antidiabetic properties and embryonic safety of olive leaves. Forty adult female Sprague Dawley rats were split up into four groups as follows: nondiabetic, diabetic, olive, and diabetic-olive groups. All the mother rats were sacrificed on the 20th day of pregnancy, and fetuses were collected for further investigations. In diabetic pregnant mothers, fetuses had systemic modulation-negative effects. These effects were significantly reversed when the diabetic groups were supplemented with extracts from olive leaves. The findings showed that the olive leaf extract inhibits the diabetogenic effect mediated by alloxan with effective and protective systemic immunomodulation during embryonic development. [ABSTRACT FROM AUTHOR]