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.

Long-term TNF-alpha therapy for preserving beta cell function in new onset type 1 diabetes: a case report.

BACKGROUND: Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by destruction of pancreatic islet beta-cells. There is significant residual beta-cell function, measured through circulating C-peptide, present at the time of T1D diagnosis but this subsequently decreases with time. Higher residual beta-cell function at diagnosis associates with better glycaemic control and less glucose variability, and later in the disease course with less hypoglycaemia, lower glucose variability and fewer microvascular complications. There is therefore value in preserving residual beta cell function in new onset T1D Immunotherapeutic agents can protect residual beta-cell function in type 1 diabetes. However, clinical trials of such agents, whilst demonstrating C-peptide preservation in short term studies, have yet to be taken forward into routine clinical care due to concerns around safety and long-term efficacy. Here we report the case of a gentleman with newly diagnosed T1D whose glycaemic control and insulin requirement improved whilst on a five year infusion programme of infliximab, a monoclonal antibody against TNF-alpha, for colitis. CASE PRESENTATION: A 52-year-old White Caucasian man was diagnosed with T1D in August 2018. Glucose was 25.6 mmol/L, HbA1c was 98mmol/mol and GAD antibodies were strongly positive. HbA1c marginally improved to 91mmol/mol following initiation of insulin detemir 5 units at night and 1:10 g of insulin aspart (November 2018). In June 2019, he developed rectal bleeding and abdominal pain. Following colonoscopy, he was diagnosed with "indeterminate colitis" and commenced on 6-weekly infusions of 400-450 mg infliximab. Thus far, he has received 32 doses and achieved colitis remission. Following infliximab initiation there was increased frequency of mild-moderate hypoglycaemia and he was gradually weaned off and discontinued detemir in June 2020. Since then, HbA1c improved from 57mmol/mol in August 2019 to 52mmol/mol in April 2022, remaining stable at 51mmol/mol. His most recent HbA1c is 54mmol/mol in February 2024. His c-peptide was 550pmol/L in October 2022 and 442pmol/L in February 2024, suggesting well-preserved beta-cell function almost 6 years post-diagnosis. CONCLUSIONS: Our patient's improvement in glycaemic control can be explained by immunomodulation and C peptide preservation from infliximab. With the growing focus on type 1 diabetes disease modulation and working towards an 'insulin free T1D', our findings strengthen the evidence base for the repurposing of and long-term treatment with anti-TNF-α agents to preserve beta-cell function in new onset T1D.

Potential contribution of gut microbiota in the development of autoantibodies in T1D children carrying HLA-DRB1/DQB1 risk alleles: an experimental and in silico analysis.

This study aimed to investigate the prevalence of insulin autoantibody (IAA), glutamic acid decarboxylase antibody (GADA), and insulinoma-associated antigen-2 antibody (IA-2A) in type 1 diabetes (T1D) children based on the presence of predisposing HLA-II alleles. Additionally, to assess the sequence homology between autoantigens of islet cells and selected proteins derived from gut bacteria in terms of their binding capacities to HLA risk alleles, HLA-DRB1/DQB1 alleles were determined by PCR-SSOP in 111 T1D children (probands) along with 222 parents and 133 siblings. Autoantibodies were measured by ELISA, and in silico analysis was run as follows: protein extraction, homology and epitope prediction, peptide alignment, and HLA-peptide docking. Higher significant frequencies of DRB1*03:01, DQB1*02:01, and DQB1*03:02 alleles and DRB1*03:01 ~ DQB1*02:01 haplotype and lower frequencies of DRB1*11:01, DRB1*14:01, and DQB1*03:01 alleles were found in probands compared to parents and siblings. DRB1*11:01 ~ DQB1*03:01, DRB1*14:01 ~ DQB1*05:03, and DRB1*15:01-DQB1*06:02 haplotypes were significantly less frequent in the probands compared to parents. Out of 111 probands, 21 were seronegative, 90 tested positive for one autoantibody, and 15 showed the concurrent presence of three autoantibodies. Logistic regression analysis revealed that DRB1*04 ~ DQB1*03:02 haplotype was associated with the induction of GADA and IA-2A, while DRB1*11:01 ~ DQB1*03:01 was associated with seronegativity. Epitopes derived from GAD and gut bacteria showed strong binding capacities to HLA risk alleles. Due to the sequence similarities between gut bacteria-derived proteins and islet cell autoantigens and their potential for binding to HLA risk alleles, dysbiosis of gut microbiota can be considered another risk factor for the development of T1D, especially in genetically susceptible individuals.

Reversing Immune Checkpoint Inhibitor-Associated Cardiotoxicity via Bioorthogonal Metabolic Engineering-Driven Extracellular Vesicle Redirecting.

The cardiotoxicity induced by immune checkpoint inhibitors (ICIs) is associated with high mortality rates. T cells play an important role in ICI-induced cardiac injury. The inhibition of local T-cell activity is considered an effective strategy for alleviating ICI-related cardiotoxicity. Tumor-derived extracellular vesicles (EVs) contribute to immunosuppression via PD-L1 overexpression. In this study, a bioorthogonal metabolic engineering-driven EV redirecting (Biomeder) strategy for in situ engineered EVs with myocardial-targeting peptides is developed. Accumulated tumor-derived EV (TuEVs) reverses the immune environment in the heart by increasing PD-L1 levels in cardiomyocytes and/or by directly inhibiting T-cell activity. More importantly, it is found that the redirection of TuEVs further disrupts immunosuppression in tumors, which facilitates anti-tumor activity. Thus, redirecting TuEVs to the heart simultaneously enhances the antitumor efficacy and safety of ICI-based therapy. Furthermore, the Biomeder strategy is successfully expanded to prevent ICI-induced type 1 diabetes. This Biomeder technique is a universal method for the treatment of various ICI-related adverse events.

Epidemiology of Periodontal Diseases in Individuals With Diabetes in Saudi Arabia: A Systematic Review.

Diabetes mellitus (DM) is one of the most common and prevalent metabolic disorders worldwide. It affects men, women, and children and can cause severe organ damage, including kidney damage. The two most common types of DM are Type 1 DM and Type 2 DM. Similarly, periodontal disease (PD) affects a significant portion of the population and involves the tissues supporting the teeth. The bidirectional relationship between diabetes and PD is a well-established phenomenon. However, no comprehensive study on the prevalence of PD among diabetic patients has been conducted on the Saudi population. This systematic review aims to examine the current literature on the impact of these conditions on the Saudi population. A literature search was conducted from January 2001 through June 2024 using Scopus, PubMed, and Google Scholar. An extensive search was performed, duplicates were removed, and inclusion and exclusion criteria were applied. Nine studies were selected for review, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The retrieved studies confirm the relationship between DM and PDs in regional studies. The review highlights the need for integrated healthcare approaches to manage both conditions effectively. Further research is recommended to understand the causal mechanisms and develop comprehensive treatment strategies.

Importance of Studying Non-Coding RNA in Children and Adolescents with Type 1 Diabetes.

Type 1 diabetes (T1D) mellitus is a chronic illness in children and teens, with rising global incidence rates. It stems from an autoimmune attack on pancreatic ß cells, leading to insufficient insulin production. Genetic susceptibility and environmental triggers initiate this process. Early detection is possible by identifying multiple autoantibodies, which aids in predicting future T1D development. A new staging system highlights T1D's onset with islet autoimmunity rather than symptoms. Family members of T1D patients face a significantly increased risk of T1D. Italy recently passed a law mandating national T1D screening for pediatric populations. Measurements of ß cell function continue to be essential in assessing efficacy, and different models have been proposed, but more appropriate biomarkers are mandatory for both progression studies before the onset of diabetes and during therapeutic monitoring. Biomarkers like microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) play key roles in T1D pathogenesis by regulating gene expression. Understanding their roles offers insights into T1D mechanisms and potential therapeutic targets. In this review, we summarized recent progress in the roles of some non-coding RNAs (ncRNAs) in the pathogenesis of T1D, with particular attention to miRNAs, lncRNAs, and circRNAs.

Mycobacterium paratuberculosis: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of autoimmunity, neurodegenerative disease and cancer. What infections trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases, Crohn's disease, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA) and autoimmune thyroiditis. MAP is also associated with Alzheimer's disease (AD) and Parkinson's disease (PD). Autoimmune diabetes, MS and RA are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation, including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via the un-silencing of HERV. We examine the link between the ever-increasing number of MAP-associated diseases and the MAP/HERV intersection with these diverse medical conditions, and propose treatment opportunities based upon this association.

Invariant VD and DJ Motifs Define a Novel Class of Human Antibodies and TCRs Prototyped by antigen receptors of Dual-Expresser Lymphocytes.

INTRODUCTION: Dual-expressing lymphocytes (DEs) are unique immune cells that express both B cell receptors (BCRs, surface antibody) and T cell receptors (TCRs). In type 1 diabetes, DE antibodies are predominated by one antibody (x-mAb), an IgM monoclonal antibody with a germline-encoded CDR3 that recognizes self-reactive TCRs. We explored if x-mAb and its interacting TCRs have distinct structural features. METHODS: Using bioinformatics, we compared x-mAb and its most common interacting TCRαß to billions of antigen receptor sequences to determine if they were unique or randomly generated. RESULTS: X-mAb represents a unique class of human antibodies with a conserved CDR3 sequence (CARx1-4DTAMVYYFYDW), consisting of a fixed DJH motif (DTAMVYYFDYW) paired with various VH genes. A public TCRß clonotype (CASSPGTEAFF) associated with x-mAb on DEs features two invariant segments, VßD (CASSPGT) and DJß (PGTEAFF), key to two large families of public TCRß clonotypes-CASSPGT-Jßx and CASSPGT-Jßx-formed by recombining the VßD motif with Jß genes and the DJß motif with Vß genes. B cells also use CASSPGT as a VHD motif for public IGH clonotypes (CASSPGT-Jßx). DISCUSSION: DEs, unlike conventional T and B cells, use invariant motifs to create public antibodies and TCRs, a trait previously seen only in cartilaginous fish.

Exploring the molecular mechanisms of macrophages in islet transplantation using single-cell analysis.

Background: Islet transplantation is a promising treatment for type 1 diabetes that aims to restore insulin production and improve glucose control, but long-term graft survival remains a challenge due to immune rejection. Methods: ScRNA-seq data from syngeneic and allogeneic islet transplantation grafts were obtained from GSE198865. Seurat was used for filtering and clustering, and UMAP was used for dimension reduction. Differentially expressed genes were analyzed between syngeneic and allogeneic islet transplantation grafts. Gene set variation analysis (GSVA) was performed on the HALLMARK gene sets from MSigDB. Monocle 2 was used to reconstruct differentiation trajectories, and cytokine signature enrichment analysis was used to compare cytokine responses between syngeneic and allogeneic grafts. Results: Three distinct macrophage clusters (Mø-C1, Mø-C2, and Mø-C3) were identified, revealing complex interactions and regulatory mechanisms within macrophage populations. The significant activation of macrophages in allogeneic transplants was marked by the upregulation of allograft rejection-related genes and pathways involved in inflammatory and interferon responses. GSVA revealed eight pathways significantly upregulated in the Mø-C2 cluster. Trajectory analysis revealed that Mø-C3 serves as a common progenitor, branching into Mø-C1 and Mø-C2. Cytokine signature enrichment analysis revealed significant differences in cytokine responses, highlighting the distinct immunological environments created by syngeneic and allogeneic grafts. Conclusion: This study significantly advances the understanding of macrophage roles within the context of islet transplantation by revealing the interactions between immune pathways and cellular fate processes. The findings highlight potential therapeutic targets for enhancing graft survival and function, emphasizing the importance of understanding the immunological aspects of transplant acceptance and longevity.

A functional variant rs912304 for late-onset T1D risk contributes to islet dysfunction by regulating proinflammatory cytokine-responsive gene STXBP6 expression.

BACKGROUND: Our previous genome­wide association studies (GWAS) have suggested rs912304 in 14q12 as a suggestive risk variant for type 1 diabetes (T1D). However, the association between this risk region and T1D subgroups and related clinical risk features, the underlying causal functional variant(s), putative candidate gene(s), and related mechanisms are yet to be elucidated. METHODS: We assessed the association between variant rs912304 and T1D, as well as islet autoimmunity and islet function, stratified by the diagnosed age of 12. We used epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to prioritize the most likely functional variant and potential causal gene. We also performed functional experiments to evaluate the role of the causal gene on islet function and its related mechanisms. RESULTS: We identified rs912304 as a risk variant for T1D subgroups with diagnosed age ≥ 12 but not < 12. This variant is associated with residual islet function but not islet-specific autoantibody positivity in T1D individuals. Bioinformatics analysis indicated that rs912304 is a functional variant exhibiting spatial overlaps with enhancer active histone marks (H3K27ac and H3K4me1) and open chromatin status (ATAC-seq) in the human pancreas and islet tissues. Luciferase reporter gene assays and eQTL analyses demonstrated that the biallelic sites of rs912304 had differential allele-specific enhancer activity in beta cell lines and regulated STXBP6 expression, which was defined as the most putative causal gene based on Open Targets Genetics, GTEx v8 and Tiger database. Moreover, Stxbp6 was upregulated by T1D-related proinflammatory cytokines but not high glucose/fat. Notably, Stxbp6 over-expressed INS-1E cells exhibited decreasing insulin secretion and increasing cell apoptosis through Glut1 and Gadd45ß, respectively. CONCLUSIONS: This study expanded the genomic landscape regarding late-onset T1D risk and supported islet function mechanistically connected to T1D pathogenesis.

Novel AHR ligand AGT-5 ameliorates type 1 diabetes in mice through regulatory cell activation in the early phase of the disease.

Type 1 diabetes (T1D) is an autoimmune disease with a strong chronic inflammatory component. One possible strategy for the treatment of T1D is to stimulate the regulatory arm of the immune response, i.e. to promote the function of tolerogenic dendritic cells (tolDC) and regulatory T cells (Treg). Since both cell types have been shown to be responsive to the aryl hydrocarbon receptor (AHR) activation, we used a recently characterized member of a new class of fluorescent AHR ligands, AGT-5, to modulate streptozotocin-induced T1D in C57BL/6 mice. Prophylactic oral administration of AGT-5 reduced hyperglycemia and insulitis in these mice. Phenotypic and functional analysis of cells in the pancreatic infiltrates of AGT-5-treated mice (at the early phase of T1D) revealed a predominantly anti-inflammatory environment, as evidenced by the upregulation of tolDC and Treg frequency, while CD8+ cell, Th1 and Th17 cells were significantly reduced. Similarly, AGT-5 enhanced the proportion of Treg and tolDC in small intestine lamina propria and suppressed the activation status of antigen-presenting cells through down-regulation of co-stimulatory molecules CD40, CD80 and CD86. The expression levels of Cyp1a1, controlled by the AHR, were increased in CD4+, CD8+ and Treg, confirming the AHR-mediated effect of AGT-5 in these cells. Finally, AGT-5 stimulated the function of regulatory cells in the pancreatic islets and lamina propria by upregulating indoleamine 2,3-dioxigenase 1 (IDO1) in tolDC. These findings were supported by the abrogation of AGT-5-mediated in vitro effects on DC in the presence of IDO1 inhibitor. AGT-5 also increased the expression of CD39 or CD73 ATP-degrading ectoenzymes by Treg. The increase in Treg is further supported by the upregulated frequency of IL-2-producing type 3 innate lymphoid cells (ILC3) in the lamina propria. Anti-inflammatory effects of AGT-5 were also validated on human tonsil cells, where in vitro exposure to AGT-5 increased the proportion of immunosuppressive dendritic cells and ILC3. These results suggest that AGT-5, by stimulating AHR, may promote a general immunosuppressive environment in the pancreas and small intestine lamina propria at the early phase of disease, and thereby inhibit the severity of T1D in mice.

An investigation of functionalized chitosan and alginate multilayer conformal nanocoating on mouse beta cell spheroids as a model for pancreatic islet transplantation.

Multilayer conformal coatings have been shown to provide a nanoscale barrier between cells and their environment with adequate stability, while regulating the diffusion of nutrition and waste across the cell membrane. The coating method aims to minimize capsule thickness and implant volume while reducing the need for immunosuppressive drugs, making it a promising approach for islet cell encapsulation in clinical islet transplantation for the treatment of Type 1 diabetes. This study introduces an immunoprotective nanocoating obtained through electrostatic interaction between quaternized phosphocholine-chitosan (PC-QCH) and tetrahydropyran triazole phenyl-alginate (TZ-AL) onto mouse ß-cell spheroids. First, successful synthesis of the proposed polyelectrolytes was confirmed with physico-chemical characterization. A coating with an average thickness of 540 nm was obtained with self-assembly of 4-bilayers of PC-QCH/TZ-AL onto MIN6 ß-cell spheroids. Surface coating of spheroids did not affect cell viability, metabolic activity, or insulin secretion, when compared to non-coated spheroids. The exposure of the polyelectrolytes to THP-1 monocyte-derived macrophages lead to a reduced level of TNF-α secretion and exposure of coated spheroids to RAW264.7 macrophages showed a decreasing trend in the secretion of TNF-α and IL-6. In addition, coated spheroids were able to establish normoglycemia when implanted into diabetic NOD-SCID mice, demonstrating in vivo biocompatibility and cellular function. These results demonstrate the ability of the PC-QCH/TZ-AL conformal coating to mitigate pro-inflammatory responses from macrophages, and thus can be a promising candidate towards nanoencapsulation for cell-based therapy, particularly in type 1 diabetes, where the insulin secreting ß-cells are subjected to inflammation and immune cell attack.

Impact of Probiotics on the Glycemic Control of Pediatric and Adolescent Individuals with Type 1 Diabetes: A Systematic Review and Meta-Analysis.

AIMS: Human recombinant insulin is currently the only therapy for children and adolescents with type 1 diabetes (T1D), although not always efficient for the glycemic control of these individuals. The interrelation between the gut microbiome and the glycemic control of apparently healthy populations, as well as various populations with diabetes, is undeniable. Probiotics are biotherapeutics that deliver active components to various targets, primarily the gastrointestinal tract. This systematic review and meta-analysis examined the effect of the administration of probiotics on the glycemic control of pediatric and adolescent individuals with T1D. MATERIALS AND METHODS: Randomized controlled trials employing the administration of probiotics in children and adolescents with T1D (with ≥10 individuals per treatment arm), written in English, providing parameters of glycemic control, such as mean glucose concentrations and glycosylated hemoglobin (HbA1c), were deemed eligible. RESULTS: The search strategy resulted in six papers with contradictory findings. Ultimately, five studies of acceptable quality, comprising 388 children and adolescents with T1D, were included in the meta-analysis. Employing a random and fixed effects model revealed statistically significant negative effect sizes of probiotics on the glycemic control of those individuals, i.e., higher concentrations of glucose and HbA1c than controls. CONCLUSIONS: Children and adolescents with T1D who received probiotics demonstrated worse glycemic control than controls after the intervention. Adequately powered studies, with extended follow-up periods, along with monitoring of compliance and employing the proper strains, are required to unravel the mechanisms of action and the relative effects of probiotics, particularly concerning diabetes-related complications and metabolic outcomes.

Small RNA-Seq and real time rt-qPCR reveal islet miRNA released under stress conditions.

Replacement of beta cells through transplantation is a potential therapeutic approach for individuals with pancreas removal or poorly controllable type 1 diabetes. However, stress and death of beta cells pose significant challenges. Circulating miRNA has emerged as potential biomarkers reflecting early beta cell stress and death, allowing for timely intervention. The aim of this study was to identify miRNAs as potential biomarkers for beta cell health. Literature review combined with small RNA sequencing was employed to select islet-enriched miRNA. The release of those miRNA was assessed by RT-qPCR in vivo, using a streptozotocin induced diabetes mouse model and in vitro, through mouse and human islets exposed to varying degrees of hypoxic and cytokine stressors. Utilizing the streptozotocin induced model, we identified 18 miRNAs out of 39 candidate islet-enriched miRNA to be released upon islet stress in vivo. In vitro analysis of culture supernatants from cytokine and/or hypoxia stressed islets identified the release of 45 miRNAs from mouse and 8 miRNAs from human islets. Investigation into the biological pathways targeted by the cytokine- and/or hypoxia-induced miRNA suggested the involvement of MAPK and PI3K-Akt signaling pathways in both mouse and human islets. We have identified miRNAs associated with beta cell health and stress. The findings allowed us to propose a panel of 47 islet-related human miRNA that is potentially valuable for application in clinical contexts of beta cell transplantation and presymptomatic early-stage type 1 diabetes.

Time above range and no coefficient of variation is associated with diabetic retinopathy in individuals with type 1 diabetes and glycated hemoglobin within target.

AIMS: This study aimed to investigate the association between glucose metrics and diabetic retinopathy in type 1 diabetes (T1D) patients using flash continuous glucose monitoring (FGM) systems, including those maintaining glycated hemoglobin (HbA1c) within the target range. METHODS: We conducted a cross-sectional study involving 1070 T1D patients utilizing FGM systems. Data on clinical, anthropometric, and socioeconomic characteristics were collected and retinopathy was classified based on international standards. RESULTS: Patients' mean age was 47.6 ± 15.0 years, with 49.4% of them being females. Within the cohort, 24.8% of patients presented some form of retinopathy. In the analysis involving the entire sample of subjects, male gender (OR = 1.51, p = 0.027), Time Above Range (TAR) > 250 mg/dL (OR = 1.07, p = 0.025), duration of diabetes (OR = 1.09, p < 0.001), smoking (OR = 2.30, p < 0.001), and history of ischemic stroke (OR = 5.59, p = 0.025) were associated with diabetic retinopathy. No association was observed between the coefficient of variation and diabetic retinopathy (p = 0.934). In patients with HbA1c < 7%, the highest quartile of TAR > 250 was independently linked to diabetic retinopathy (OR = 8.32, p = 0.040), in addition to smoking (OR = 2.90, p = 0.031), duration of diabetes (OR = 1.09, p < 0.001), and hypertension (OR = 2.35, p = 0.040). CONCLUSION: TAR > 250 mg/dL significantly emerges as a modifiable factor associated with diabetic retinopathy, even among those patients maintaining recommended HbA1c levels. Understanding glucose metrics is crucial for tailoring treatment strategies for T1D patients.

A Review of Stage 0 Biomarkers in Type 1 Diabetes: The Holy Grail of Early Detection and Prevention?

Type 1 diabetes mellitus (T1D) is an incurable autoimmune disease characterized by the destruction of pancreatic islet cells, resulting in lifelong dependency on insulin treatment. There is an abundance of review articles addressing the prediction of T1D; however, most focus on the presymptomatic phases, specifically stages 1 and 2. These stages occur after seroconversion, where therapeutic interventions primarily aim to delay the onset of T1D rather than prevent it. This raises a critical question: what happens before stage 1 in individuals who will eventually develop T1D? Is there a "stage 0" of the disease, and if so, how can we detect it to increase our chances of truly preventing T1D? In pursuit of answers to these questions, this narrative review aimed to highlight recent research in the field of early detection and prediction of T1D, specifically focusing on biomarkers that can predict T1D before the onset of islet autoimmunity. Here, we have compiled influential research from the fields of epigenetics, omics, and microbiota. These studies have identified candidate biomarkers capable of predicting seroconversion from very early stages to several months prior, suggesting that the prophylactic window begins at birth. As the therapeutic landscape evolves from treatment to delay, and ideally from delay to prevention, it is crucial to both identify and validate such "stage 0" biomarkers predictive of islet autoimmunity. In the era of precision medicine, this knowledge will enable early intervention with the potential for delaying, modifying, or completely preventing autoimmunity and T1D in at-risk children.

Exploring the Diagnostic Complexity of Diabetes Subtypes in Pediatric Obesity: A Case Report of an Adolescent With Prader-Willi Phenotype and Literature Review.

Obesity among adolescents poses a significant global health concern with profound short- and long-term impact on physical and mental well-being. The intricate relationship between obesity and the onset of diabetes remains ambiguous, particularly in cases where the manifestation may differ from that observed in individuals with uncomplicated obesity. Herein, we present the case of a 14-year-old male adolescent with Prader-Willi phenotype and subsequent obesity, exhibiting symptoms of polyuria and polydipsia over a 10-day period, indicative of potential diabetes mellitus (DM). Laboratory assessments revealed a hemoglobin A1c level of 10%, confirming the suspected diagnosis. Notably, despite the absence of ketosis, elevated C-peptide levels and the presence of slightly positive islet-cell antibodies warranted further investigation. While the presence of antibodies typically aligns with a diagnosis of type 1 DM, recent research has highlighted the occurrence of anti-insulin pancreatic cell antibodies in type 2 DM cases. This article aims to delve into the multifaceted issues surrounding adolescent obesity, atypical presentations of DM with positive antibodies, and the long-term management of patients with genetic syndromes.

Diabetic Ketoacidosis Presenting as Abdominal Pain in a Two-Year-Old Female: A Case Report.

Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes and can sometimes be the first indication of undiagnosed type 1 diabetes mellitus (T1DM). Our case presents a unique scenario in which a two-year-old female presented to her pediatrician with persistent abdominal pain, along with fatigue and tachypnea. On physical examination, she was mildly distressed, tachypneic, and utilized accessory muscles during respiration. Subsequent urinalysis indicated elevated glucose levels of 500 milligrams/deciliter (mg/dL). She was promptly referred to the emergency department to be treated for DKA. Upon arrival, the patient's glucose level was elevated at 533 mg/dL, with an anion gap of 25. She was stabilized and admitted to the pediatric intensive care unit (PICU) with a new diagnosis of T1DM with ketoacidosis. Given the emergent nature of DKA and the need for immediate treatment, physicians should consider DKA as a potential diagnosis for any pediatric patient presenting with abdominal pain.

Convergence of Crisis: A Case Report of Diabetic Ketoacidosis Masking an Impending Thyroid Storm and Periodic Paralysis.

Diabetic ketoacidosis (DKA) is an extreme complication of diabetes mellitus characterized by hyperglycemia, metabolic acidosis, and ketonemia. Thyroid storm, a potentially life-threatening manifestation of thyrotoxicosis, presents with a multitude of symptoms, including hyperthermia, tachycardia, and altered mental status. Periodic paralysis can be precipitated by different metabolic disturbances, including thyrotoxicosis, and may lead to extreme episodes of muscle weakness and paralysis. We present a case of a 41-year-old female with a history of type 1 diabetes mellitus and hyperthyroidism, who presented with DKA complicated by an impending thyroid storm and likely periodic paralysis exacerbated due to hypokalemia. Prompt recognition and aggressive management of each component of this triad were essential for a positive patient outcome. This case highlights the importance of a broad and comprehensive approach to managing complex metabolic emergencies, particularly in patients with multiple comorbidities. Our patient presented to the emergency department with symptoms of severe vomiting, shortness of breath, and altered mental status. Laboratory investigations revealed metabolic derangements consistent with DKA, alongside impending thyrotoxicosis and hypokalemia-induced periodic paralysis. Management involved aggressive fluid resuscitation, insulin therapy, anti-thyroid medications, and potassium supplementation, with a multidisciplinary approach to stabilize the patient's condition.

Blood Glucose Prediction from Nutrition Analytics in Type 1 Diabetes: A Review.

INTRODUCTION: Type 1 Diabetes (T1D) affects over 9 million worldwide and necessitates meticulous self-management for blood glucose (BG) control. Utilizing BG prediction technology allows for increased BG control and a reduction in the diabetes burden caused by self-management requirements. This paper reviews BG prediction models in T1D, which include nutritional components. METHOD: A systematic search, utilizing the PRISMA guidelines, identified articles focusing on BG prediction algorithms for T1D that incorporate nutritional variables. Eligible studies were screened and analyzed for model type, inclusion of additional aspects in the model, prediction horizon, patient population, inputs, and accuracy. RESULTS: The study categorizes 138 blood glucose prediction models into data-driven (54%), physiological (14%), and hybrid (33%) types. Prediction horizons of ≤30 min are used in 36% of models, 31-60 min in 34%, 61-90 min in 11%, 91-120 min in 10%, and >120 min in 9%. Neural networks are the most used data-driven technique (47%), and simple carbohydrate intake is commonly included in models (data-driven: 72%, physiological: 52%, hybrid: 67%). Real or free-living data are predominantly used (83%). CONCLUSION: The primary goal of blood glucose prediction in T1D is to enable informed decisions and maintain safe BG levels, considering the impact of all nutrients for meal planning and clinical relevance.