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PubMed2026

Research progress and application prospects of multi-omics integration strategies in precision risk stratification of type 1 diabetes mellitus.

Type 1 diabetes (T1D) is a chronic metabolic disease mediated by autoimmunity. Its pathogenesis involves complex interactions between genetic susceptibility and environmental factors. Conventional T1D risk stratification primarily relies on genetic markers, islet autoantibodies, and glycemic indicators. Although these biomarkers remain indispensable in current clinical practice, they are often insufficient when used alone to accurately identify ultra-early high-risk individuals, predict disease progression rates, or support individualized preventive strategies. Consequently, more comprehensive molecular approaches are needed to improve precision risk stratification. In recent years, the rapid development of multi-omics technologies has provided new strategies for precise risk stratification of T1D. This narrative review critically evaluates how multi-omics integration strategies can improve precision risk stratification throughout the T1D disease continuum by integrating complementary molecular information from genomics, transcriptomics, proteomics, metabolomics, epigenomics, and the microbiome. Particular emphasis is placed on stage-specific biomarker discovery, multi-omics data integration frameworks, artificial intelligence-assisted prediction models, biomarker validation, and the opportunities and challenges associated with clinical translation. Current evidence suggests that integrated multi-omics approaches have the potential to improve risk prediction accuracy, distinguish heterogeneous disease trajectories, identify individuals at imminent risk of progression, and provide biologically informed targets for precision intervention. However, important challenges remain, including data harmonization, external validation, model interpretability, cost-effectiveness, and integration into routine clinical screening programs. Future research should prioritize prospective multicenter cohorts, standardized analytical pipelines, externally validated prediction models, and clinically interpretable multi-omics frameworks to facilitate the translation of precision risk stratification into routine T1D prevention and management.

Humans↗

PubMed2025

Exploring proteomic immunoprofiles: common neurological and immunological pathways in multiple sclerosis and type 1 diabetes mellitus.

BACKGROUND: Interest in the study of type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS) has increased because of their significant negative impact on the patient quality of life and the profound implications for the health care system. Although the clinical symptoms of T1DM differ from those of MS, such as pancreatic β-cell failure in T1DM and demyelination in the central nervous system (CNS) in MS, both pathologies are considered as autoimmune-related diseases with shared pathogenic pathways, which include autophagy, inflammation and degeneration, among others. Considering the challenges in obtaining pancreatic β-cells and CNS tissue from patients with T1DM and MS, respectively, it is fundamental to explore alternative methods for evaluating disease status. Proteomic analysis of peripheral blood mononuclear cells (PBMCs) is an ideal approach for identifying novel and potential biomarkers for both autoimmune diseases. METHODS: We conducted a proteomic analysis of PBMCs from patients with T1DM and relapsing remitting Multiple Sclerosis (herein forth MS) patients (n = 9 per condition), using a label-free quantitative proteomics approach. The patients were diagnosed following the American Diabetes Association (ADA) criteria for T1DM and McDonald criteria for MS respectively, and were aged over 18 years and more than 2 years from the onset respectively. RESULTS: A total of 2476 proteins were differentially expressed in PBMCs from patients with T1DM and MS patients compared with those form healthy controls (H). Predictive analysis highlighted 15 common proteins, up- or downregulated in PBMCs from patients with T1DM and MS patients vs. healthy controls, involved in the immune system activity (BTF3, TTR, CD59, CSTB), diseases of the neuronal system (TTR), signal transduction (STMN1, LAMTOR5), metabolism of nucleotides (RPS21), proteins (TTR, ENAM, CD59, RPS21, SRP9) and RNA (SRSF10, RPS21). In addition, this study revealed both shared and distinct molecular patterns between the two conditions. CONCLUSIONS: Compared with H, patients with T1DM and MS presented a specific expression pattern of common proteins has been identified. This pattern underscores the shared mechanisms involved in their immune responses and neurological complications, alongside dysregulation of the autophagy pathway. Notably, CSTB has emerged as a differential biomarker, distinguishing between these two autoimmune diseases.

Humans↗

PubMed2026

ZBTB16-associated NK cell alterations reveal shared immunometabolic signatures linking primary Sjögren's syndrome and type 1 diabetes mellitus.

BACKGROUND: Primary Sjögren's syndrome (pSS) and type 1 diabetes mellitus (T1DM) share immune-inflammatory features, yet conserved pathogenic signatures linking these autoimmune disorders remain incompletely understood. The present research sought to uncover common molecular markers and dissect the underlying immune-metabolic cross-talk underlying pSS and T1DM. METHODS: Gene expression profiles of patients with pSS and T1DM were retrieved from the Gene Expression Omnibus database, normalized, and corrected for batch effects prior to downstream analyses. Overlapping potential biomarkers were screened by integrating differential expression analysis, weighted gene co-expression network analysis and least absolute shrinkage and selection operator regression. Functional enrichment based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases was implemented to interpret gene biological properties, and a protein-protein interaction network was further established afterwards. Diagnostic performance was evaluated using receiver operating characteristic analysis. Experimental validation was conducted in non-obese diabetic (NOD) mice using quantitative PCR, immunohistochemistry, and flow cytometry. The CIBERSORT algorithm was adopted to quantify immune cell infiltration levels. RESULTS: ZBTB16 was identified as a shared hub biomarker in both pSS and T1DM and exhibited favorable diagnostic performance. Experimental validation confirmed significantly reduced ZBTB16 expression in peripheral blood mononuclear cells, salivary gland tissues, and pancreatic tissues of NOD mice. Gene Set Enrichment Analysis indicated that ZBTB16-associated signatures were enriched in mitochondrial-related processes, neuroactive ligand-receptor interactions, and ribosome-related pathways. Immune infiltration analysis revealed that resting natural killer (NK) cells were positively correlated with ZBTB16 expression in both diseases. Flow cytometric analysis further confirmed a reduced proportion of resting NK cells in peripheral blood of NOD mice, consistent with the CIBERSORT-based prediction. CONCLUSION: This study identifies ZBTB16 as a shared biomarker linking pSS and T1DM. Reduced resting NK-cell abundance was consistently observed in both computational and experimental analyses, and bioinformatic correlation analysis suggested a positive association with ZBTB16 expression. These findings provide evidence for shared molecular and immunological signatures underlying the two autoimmune disorders and support further investigation of the biological role and diagnostic value of ZBTB16 in pSS and T1DM.

Sjogren's Syndrome↗

PubMed2025

Expression of long noncoding RNAs in peripheral blood mononuclear cells of patients with type 1 diabetes mellitus: potential biomarkers for disease onset.

OBJECTIVE: Long non-coding RNAs (lncRNAs) do not encode proteins and are transcripts longer than 200 nucleotides. The precise involvement of lncRNAs in type 1 diabetes mellitus (T1DM) pathogenesis remains unclear. Therefore, this study aimed to analyze the expressions of five lncRNAs in peripheral blood mononuclear cells of individuals with T1DM and without DM. MATERIALS AND METHODS: This study comprised 27 patients with T1DM (cases) and 13 individuals without DM (controls). The case group was divided into two subgroups based on T1DM duration: < 5 years of diagnosis group and long-term diabetes group (≥5 years). LncRNA expression was evaluated by qPCR. RESULTS: MALAT1 and TUG1 were upregulated in patients within the first five years of diagnosis of T1DM compared to the other groups. MEG3 was upregulated in the case group of < 5 years of diagnosis compared to controls. TUG1 and MALAT1 levels were negatively correlated with the duration of T1DM, while TUG1 and MEG3 were positively correlated with glycated hemoglobin levels. Bioinformatics analysis revealed that MALAT1, MEG3, and TUG1 regulate and interact with protein-codifying genes and microRNAs involved in T1DM-related pathways. CONCLUSION: Our study revealed MALAT1, MEG3, and TUG1 upregulation in patients within the first five years of diagnosis of T1DM.

Humans↗

PubMed2025

Diabetes mellitus polygenic risk scores: heterogeneity and clinical translation.

Diabetes mellitus encompasses several disorders, each with differing clinical presentation, prognoses and pathophysiology. Distinct polygenic architectures underlie type 1 diabetes mellitus and type 2 diabetes mellitus, and govern numerous pathophysiological pathways that converge on dysglycaemia. Over the previous decade, polygenic risk scores (PRS) derived from large genome-wide association studies have become broadly recognized for their potential in precision medicine. PRS, and now partitioned polygenic scores generated by clustering of risk variants, can quantify individual genetic predisposition to diabetes mellitus and reveal molecular heterogeneity responsible for variation in clinical presentation and prognoses. In this Review, we examine and contrast progress in the development of type 1 diabetes mellitus PRS and type 2 diabetes mellitus PRS, and discuss paths to further methodological advances. We examine how studies in the past 10 years have harnessed PRS and novel partitioned polygenic scores to reveal insights into diabetes mellitus aetiology and characterize changes in cellular and tissue-specific disease-modifying molecular pathways. Additionally, we discuss advances and opportunities in areas of clinical translation, including improved classification of diabetes mellitus type, screening of those at risk and personalized interventions informed by PRS. Finally, we emphasize the urgent need to overcome ancestry-related challenges and highlight current progress and gaps in ensuring the equitable translation of PRS for diabetes mellitus precision medicine.

Humans↗

PubMed2017

Genome-wide analysis suggests a differential microRNA signature associated with normal and diabetic human corneal limbus.

Small non-coding RNAs, in particular microRNAs (miRNAs), regulate fine-tuning of gene expression and can impact a wide range of biological processes. However, their roles in normal and diseased limbal epithelial stem cells (LESC) remain unknown. Using deep sequencing analysis, we investigated miRNA expression profiles in central and limbal regions of normal and diabetic human corneas. We identified differentially expressed miRNAs in limbus vs. central cornea in normal and diabetic (DM) corneas including both type 1 (T1DM/IDDM) and type 2 (T2DM/NIDDM) diabetes. Some miRNAs such as miR-10b that was upregulated in limbus vs. central cornea and in diabetic vs. normal limbus also showed significant increase in T1DM vs. T2DM limbus. Overexpression of miR-10b increased Ki-67 staining in human organ-cultured corneas and proliferation rate in cultured corneal epithelial cells. MiR-10b transfected human organ-cultured corneas showed downregulation of PAX6 and DKK1 and upregulation of keratin 17 protein expression levels. In summary, we report for the first time differential miRNA signatures of T1DM and T2DM corneal limbus harboring LESC and show that miR-10b could be involved in the LESC maintenance and/or their early differentiation. Furthermore, miR-10b upregulation may be an important mechanism of corneal diabetic alterations especially in the T1DM patients.

Adult↗

PubMed2026

Overcoming Immunological Barriers in MSC-Derived Insulin-Producing Cells through CRISPR-Based Hypoimmunogenic Engineering and Translational Perspectives for Type 1 Diabetes.

Mesenchymal stromal cell (MSC)-derived insulin-producing cells (IPCs) represent an emerging strategy for β-cell replacement in type 1 diabetes mellitus (T1DM) owing to their differentiation potential, intrinsic immunomodulatory properties, and lower tumorigenic risk compared with pluripotent stem cell-derived platforms. However, accumulating evidence indicates that differentiation-associated immunogenicity, context-dependent immune recognition, and recurrent autoimmune responses may substantially limit long-term graft survival and therapeutic durability following transplantation. This review critically examines the immunological barriers associated with MSC-derived IPCs, including altered MHC expression, susceptibility to alloimmune and autoimmune-mediated rejection, and potential reactivation of autoreactive immune memory. We discuss the application of CRISPR-based hypoimmunogenic engineering strategies targeting antigen presentation pathways, NK-cell activation, and immune checkpoint modulation to generate more immune-evasive MSC-derived IPCs while preserving β-cell functionality. By integrating insights from T1DM immunopathogenesis, MSC biology, genome editing, and translational immunology, we propose a framework linking immune engineering with controlled differentiation, functional maturation, and long-term safety evaluation. In parallel, we comparatively position MSC-derived IPCs alongside clinically advancing iPSC-derived β-cell platforms to highlight their distinct translational niche, including potential advantages related to safety, immunomodulatory capacity, manufacturing accessibility, and scalability, while acknowledging the superior functional maturity and clinical progression currently demonstrated by iPSC-derived systems. Finally, we discuss key translational challenges, including genomic stability, immune-evasion durability, GMP-compliant manufacturing, and the need for rigorous functional and immunological benchmarking prior to clinical application of hypoimmunogenic MSC-derived IPC therapies in T1DM.

Humans↗

PubMed2026

Immunoproteomic Profiling of Autoantibodies and Antibodies against Infectious Agents in Autoimmune Diseases.

Prior research investigated limited antibody sets within individual autoimmune diseases. Using the Nucleic-Acid Programmable Protein Array platform, we measured antibodies against 280 human, 40 viral, and 15 bacterial antigens in serum from 237 patients with 8 autoimmune diseases, including autoimmune gastritis (AG), autoimmune thyroiditis (AT), celiac disease (CD), idiopathic inflammatory myopathies (IIM), type 1 diabetes mellitus (T1D), rheumatoid arthritis (RA), Sjögren's disease (SjD), and systemic lupus erythematosus (SLE), and 112 controls. Candidate antibodies were identified by combining Firth logistic regression and machine learning. We identified disease-specific antibodies, ranging from 3 in IIM to 13 in SLE for IgG and 1 in CD to 13 in AG for IgA. Additionally, 63 IgG and 44 IgA antibodies were shared across two or more diseases. Notably, two IgG autoantibodies overlapped in up to five diseases: directed against STNM4 (SLE, SjD, T1D, CD, and RA) and TRIM21 (SLE, SjD, IIM, CD, and RA); and three IgA antibodies in up to seven diseases: directed against H1N1 Influenza A virus NP (IIM, SjD, AG, T1D, CD, RA, and AT) and Coxsackievirus B3MK012537 and Enterovirus C PVgp1 (IIM, SjD, AG, T1D, CD, SLE, and RA). These findings underscore the potential of antibody profiling in autoimmune disease characterization and biomarker discovery.

Humans↗

PubMed2025

Dual-approach analysis of gut microbiome in patients with type 1 diabetes and diabetic kidney disease.

BACKGROUND: Type 1 diabetes (T1D) is a multifactorial autoimmune disease mediated by genetic, epigenetic, and environmental factors. Diabetic kidney disease (DKD) is a major complication of diabetes mellitus which affects 30-40% of T1D patients. Increasing evidence suggests the significant role of the microbiome in the progression of both T1D and DKD. MATERIALS AND METHODS: Here we recruited 76 T1D patients and 22 healthy controls and combined data from sigmoid colon biopsy samples analysed with V3-V4 region amplification of 16S rRNA gene and shotgun metagenomics data obtained from faecal samples. Additionally, we compared T1D patients with and without progression of DKD. RESULTS: We observed significant differences within both sample types at various taxonomic and functional levels. T1D patient microbiota detected using biopsy samples had a lower abundance of the Bacteroides genus when compared to healthy controls. Significantly, despite only a few taxonomic differences patients with and without DKD progression were vastly different at the functional pathway level within the faecal samples - we observed 2 and 61 enriched pathways in these groups. respectively, with several of these pathways linked to the mediation of renal function. CONCLUSION: Altogether, we present novel data about microbial signatures relevant to T1D and DKD progression, which partly supports previous data and also presents possible tissue type or population-specific elements. DKD progression is characterized with significant differences within the functional level of the gut microbiome.

Humans↗

PubMed2026

Genetic Risk Factors for Kidney Function in Individuals with Type 1 Diabetes.

KEY POINTS: Previous research has identified polygenic risk scores that are associated with low eGFR and albuminuria in the general population. We observed that these eGFR and albuminuria polygenic risk scores were associated with eGFR and albuminuria, respectively, in type 1 diabetes. Associations were independent of glycemic control and suggest shared genetic kidney risk factors between type 1 diabetes and the general population. BACKGROUND: Genetic risk factors underlying kidney disease in type 1 diabetes (T1D) remain poorly understood. We examined whether previously established polygenic risk scores (PRS) for eGFR and albuminuria are associated with these measures in adults with T1D in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications study. METHODS: We applied eGFR and albuminuria PRS derived in general population cohorts to 1304 DCCT/Epidemiology of Diabetes Interventions and Complications participants with genome-wide genotyping. We tested PRS associations with eGFR and urine albumin excretion rate (AER) as well as incident eGFR <60 ml/min per 1.73 m 2 , AER ≥30 mg/24 h, and AER ≥300 mg/24 h. For consistency, PRS values were linearly transformed so higher scores corresponded to higher eGFR and AER. We also examined associations of kidney outcomes with rs55703767 in COL4A3 , which has previously been associated with CKD in T1D. RESULTS: At DCCT baseline, participants had a mean age of 27 years; 53% were male. 49% of participants were randomized to intensive versus conventional glucose-lowering therapy. Participants were followed for median of (first-third quartiles) 35 (33-37) years. The eGFR PRS was significantly associated with continuous eGFR (per one SD higher PRS 2.72 ml/min per 1.73 m 2 higher [95% confidence interval (CI), 2.05 to 3.40]) and incident eGFR <60 ml/min per 1.73 m 2 (hazard ratio [HR]=0.82 [95% CI, 0.73 to 0.92]), but not consistently with albuminuria. There was no association with quantitative AER (2.42 mg/24 h [95% CI, -1.86 to 6.89]) or sustained AER ≥30 mg/24 h (HR=1.03; [95% CI, 0.94 to 1.14]). The albuminuria PRS was significantly associated with incident AER ≥30 mg/24 h (HR=1.12 [95% CI, 1.02 to 1.22]) but not continuous eGFR (0.49 ml/min per 1.73 m 2 higher [95% CI, -0.23 to 1.21]) or incident eGFR <60 ml/min per 1.73 m 2 (HR=0.96 [95% CI, 0.85 to 1.08]). Associations were similar in analyses stratified by DCCT treatment group assignment. rs55703767 was associated with lower incident macroalbuminuria in the overall cohort (HR=0.77 per minor allele [95% CI, 0.59 to 0.99]), and upon stratification by DCCT treatment group assignment, only within the conventional and not intensive glucose-lowering therapy group. CONCLUSIONS: PRS associated with eGFR and albuminuria in the general population were associated with corresponding measures in adults with T1D. The results suggest shared genetic risk factors for kidney disease between T1D and the general population but different genetic risk factors for albuminuria and eGFR in T1D. CLINICAL TRIALS REGISTRATION NUMBERS: NCT00360893 , NCT00360815 .

Adult↗

PubMed2026

Early Worsening of Diabetic Retinopathy Following Initiation of Hybrid Closed-Loop/Automated Insulin Delivery Systems in Type 1 Diabetes: A Systematic Review and Structured Study-Level Synthesis.

BACKGROUND: Hybrid closed-loop (HCL) systems achieve rapid, algorithm-driven improvements in glycaemia in type 1 diabetes (T1D). Paradoxically, rapid improvement in glycaemic control is associated with early worsening of diabetic retinopathy (EWDR), a phenomenon established in the intensive insulin therapy era. Whether HCL initiation carries a clinically meaningful EWDR risk is unknown. No systematic review has previously addressed this question. METHODS: A systematic review and structured quantitative synthesis was performed using study-level estimates only (PROSPERO CRD:420261391951). MEDLINE, SCOPUS and Web of Science were searched to 14th May 2026. Studies reporting retinal outcomes in people with T1D initiating any HCL system were eligible. Two reviewers independently screened studies and extracted data. Risk of bias was assessed using ROBINS-I and certainty of evidence using the GRADE framework. EWDR incidence was summarised using study-level proportions, and comparative studies were summarised using study-specific risk ratios for HCL versus control therapy. Given substantial heterogeneity in EWDR definitions, retinal assessment timing, follow-up duration, and comparator groups, no pooled or meta-analytic estimates were derived. RESULTS: Eight studies (n = 1487 participants; 860 HCL users) were included; all were observational and six were retrospective. EWDR varied markedly with the timing of retinal assessment. In studies assessing the retina within ≤ 12 months of HCL initiation, EWDR rates ranged from 8.9% to 26.5%. Studies with longer follow-up reported lower rates of retinal worsening or incident DR, 6.7% at 24 months and 6.1% over a mean follow-up of 4.9 years, suggesting that these studies may capture background DR progression rather than true early worsening. Three comparative studies included 177 HCL users and 315 controls; EWDR study-specific risk ratios were directionally inconsistent, ranging from 0.32 to 1.51, and were therefore not pooled. The most consistently identified risk factors were higher baseline HbA1c and older age. The magnitude of HbA1c reduction was not a consistent predictor of EWDR in the HCL context, in contrast to pre-HCL era evidence. Risk of bias ranged from moderate to critical and certainty of evidence was very low for all outcomes. CONCLUSIONS: Study-defined retinal worsening was reported in a minority of participants. The current evidence base is dominated by retrospective studies, variable retinal assessment timing, and inconsistent EWDR definitions. Well-designed prospective studies with protocol-specified retinal surveillance anchored to HCL initiation are required to generate reliable incidence estimates, identify risk factors, determine visual consequences, and inform standardised screening guidance.

Humans↗

PubMed2026

Emphysematous pyelonephritis in children: Lessons from a case report and systematic review.

BACKGROUND: Emphysematous pyelonephritis (EPN) is a rare, life-threatening gas-producing renal infection. Literature on pediatric EPN remains scarce. OBJECTIVE: To describe a case of pediatric EPN and systematically review the data on clinical presentations, diagnostic modalities, management strategies, and prognosis in pediatric emphysematous pyelonephritis. METHODS: A comprehensive search in PubMed, Embase and Web of Science using defined search terms was done, along with the Joanna Briggs Institute (JBI) critical appraisal checklist for quality assessment. RESULTS: Of 100 records, 20 studies (n = 21) were included in the review. The median (IQR) age of presentation was 48 (8-138) months. The major risk factor was reflux/obstructive nephropathy (52.3 %), and E. coli was the common organism. Management included antibiotics (47.6 %), minimally invasive procedures (33.3 %), or nephrectomy (19 %). We additionally report an adolescent girl with Type 1 diabetes mellitus and class 3A right-sided EPN. She improved with antibiotics and percutaneous nephrostomy (PCN) insertion. CONCLUSION: Obstructive or reflux nephropathy is a major risk factor for pediatric EPN. Antibiotics are the mainstay for treatment with supportive management. Refractory cases may require percutaneous drainage or partial/total nephrectomy.

Humans↗

PubMed2026

Case Report: Persistent isolated hyperhomocysteinemia in an adolescent with celiac disease and homozygous MTHFR c.665C>T polymorphism: a multifactorial disturbance of one-carbon metabolism.

UNLABELLED: Hyperhomocysteinemia in adolescence typically prompts investigation for classical inborn errors of sulfur amino acid metabolism, including cystathionine β-synthase deficiency and cobalamin-dependent remethylation disorders. However, persistent elevations may also arise from interactions between common genetic polymorphisms and acquired nutritional conditions that alter one-carbon metabolism. CASE PRESENTATION: We report an 18-year-old male with type 1 diabetes mellitus, celiac disease on a strict gluten-free diet, congenital unilateral sensorineural hearing loss, and persistent isolated hyperhomocysteinemia. At age 16, he presented with an acute visual field disturbance and right occipital cortical MRI changes suggestive of ischemia. Plasma homocysteine was persistently between 50 and 65 μmol/L.Extensive metabolic and genetic investigations, including targeted gene panels, whole-exome and research whole-genome sequencing, mitochondrial DNA sequencing, mitochondrial complex activities in fibroblasts, and fibroblast complementation, excluded classical homocystinuria and remethylation defects. Sequential trials of pyridoxine, hydroxocobalamin, and high-dose betaine produced modest or transient improvement. Re-analysis of exome data showed homozygosity for the common MTHFR c.665C>T (p.Ala222Val) variant. Family testing revealed that his father (TT) and mother (CT) had normal homocysteine (10.9 and 10.4 μmol/L), indicating that MTHFR TT alone is insufficient to cause a biochemical phenotype and functions as a susceptibility factor. Combined oral methylfolate (1,000 µg daily) and vitamin B12 (cyanocobalamin 1,000 µg daily) reduced homocysteine from 66 to 24.6 μmol/L in 8 weeks. CONCLUSION: This case illustrates multifactorial hyperhomocysteinemia arising from interactions between celiac disease-related micronutrient vulnerability and reduced MTHFR activity. Recognition of gene-nutrient interactions is important when classical metabolic disorders are excluded and may guide targeted therapy.

MTHFR polymorphism↗

PubMed2026

Gold and Clarke Questionnaires Identify Different People With Insulin-Treated Diabetes and Impaired Awareness of Hypoglycaemia in Almost 60% of Cases: A Post Hoc Analysis From the Hypo-METRICS Study.

AIMS: Gold and Clarke questionnaires are used to identify impaired awareness of hypoglycaemia (IAH) and severe hypoglycaemic event (SHE) risk in people with diabetes (pwD). We explored their overlap, including Clarke's Hypoglycaemia Awareness Status (Clarke-HAS) subfactor, and subsection differences in SHE incidence (Gold, Clarke, overlap). MATERIALS AND METHODS: This post hoc analysis of the Hypo-METRICS study recruited pwD on insulin (type 1: T1D; type 2: T2D) with ≥ 1 hypoglycaemic event in the previous 3 months. IAH was defined as Gold ≥ 4, Clarke ≥ 4, Clarke-HAS ≥ 2. RESULTS: Gold and Clarke were completed by 232 pwT1D and 285 pwT2D (age: 47 vs. 62 years, p < 0.001; HbA1c: 56 mmol/mol (7.3%) vs. 57 mmol/mol (7.4%), p = 0.03). IAH prevalence in T1D vs. T2D was 21% vs. 26% (p = 0.1), 14% vs. 18% (p = 0.2), and 41% vs. 48% (p = 0.2) according to Gold, Clarke and Clarke-HAS. The overlap between Gold ≥ 4, Clarke ≥ 4 was 40% (T1D: 45%; T2D: 37%); between Gold ≥ 4, Clarke-HAS ≥ 2 it was 45% (T1D: 43%; T2D: 47%). The overlap between Gold ≥ 4, Clarke ≥ 4 was 41% vs. 39% in CGM vs. non-CGM users (T1D: 50% vs. 35%; T2D: 32% vs. 40%); between Gold ≥ 4, Clarke-HAS ≥ 2 it was 39% vs. 53% (T1D: 38% vs. 54%; T2D: 40% vs. 53%). In the IAH sample, SHE rate was lower in people found with IAH by Gold vs. Clarke, 9% vs. 53%, and in those assessed by Gold-Clarke overlap vs. Clarke, 20% vs. 53% (all p < 0.001). CONCLUSIONS: Gold and Clarke show moderate consistency (37%-54%) in identifying IAH in insulin-treated diabetes, with/without CGM use, each associated with different SHE rates, indicating the two questionnaires measure different, independent aspects of IAH.

Humans↗

PubMed2026

Impact of Albuminuria-Lowering Treatments on Cardiovascular Predictive Ceramides in Diabetes: Post Hoc Analysis of the ROTATE Trials.

AIM: Cardiovascular disease (CVD) is the leading cause of mortality in individuals with diabetes. Diabetic kidney disease, closely related to CVD risk, is prevalent in up to 40% of this population. Emerging evidence suggests ceramide lipids as accurate biomarkers for CVD. We assessed the effect of four albuminuria-lowering drugs on CVD-related ceramides in diabetes by post hoc analysis of the ROTATE trials. MATERIALS AND METHODS: Twenty six adults with type 1 (T1D) as well as 37 with type 2 diabetes (T2D) with a urine albumin-creatinine ratio (UACR) of 30-500 mg/g participated in a 4-week 4-time randomized crossover study with periods of telmisartan, empagliflozin, linagliptin and baricitinib treatment, each separated by a 4-week washout period. Blood samples were collected at the beginning and end of each period and ceramide lipids (Cer16, Cer18, Cer20, Cer22, Cer24 and Cer24:1) were measured. The effect of each treatment was evaluated using linear mixed-effect models. RESULTS: At baseline, individuals with T2D had greater levels of Cer22 and Cer24 compared to the individuals with T1D. Among the treatments, linagliptin was the only drug that demonstrated a reduction of Cer22, Cer24 and Cer24:1 from baseline by 22.6% (95% CI: -33.58; -9.79, p = 0.001), 25.7% (95% CI: -38.94; -9.69, p = 0.003) and 19.6% (95% CI: -31.34; -5.95, p = 0.007), respectively. No changes in the ceramides were observed for the other drugs. CONCLUSION: Our exploratory findings suggest that certain albuminuria-lowering drugs may affect ceramide levels as a secondary effect. However, further mechanistic investigations are needed.

Humans↗

PubMed2026

Large-scale multiethnic electronic health record resource for diabetes complications research: the North West London Diabetes Cohort (NWLDC) - cohort profile.

PURPOSE: The North West London Diabetes Cohort is established to provide systematic characterisation of a large diabetes population as a foundation for complications research and prognostic modelling. Many predictive modelling studies neglect the essential descriptive characterisation of underlying cohorts, focusing narrowly on model accuracy. This cohort profile addresses this gap by comprehensively describing the demographic composition, clinical characteristics and complication incidence patterns. The notably diverse, multiethnic population enables examination of ethnic disparities and supports future development of reliable prognostic models and evidence-based prevention strategies for diabetes complications. PARTICIPANTS: At baseline, 337 271 patients with diabetes were identified. It includes 279 067 patients with type 2 diabetes, 17 638 with type 1 diabetes, 33 590 with gestational diabetes and 6916 with unspecified diabetes. The earliest diabetes diagnosis dates to January 1932, with data updated to 27 May 2025. FINDINGS TO DATE: This cohort profile describes baseline characteristics of patients with comprehensive data collected on demographics (age, sex, Deprivation Index, ethnicity), clinical measures (glycated haemoglobin, body mass index, blood pressure, lipids and estimated glomerular filtration rate) and 14 major diabetes complications tracked longitudinally. Key findings for patients with type 2 diabetes reveal diabetic retinopathy as the most common complication (74.6 per 1000 person-years), followed by hypertension (51.0) and kidney disease (31.4). Cumulative incidence analyses using the Aalen-Johansen estimator, which accounts for mortality as a competing risk, demonstrated significant ethnic disparities, with black, Asian, mixed and other ethnic groups showing elevated risk compared with white patients. Time-varying Cox models identified strong clustering between cardiovascular and renal complications, confirming a cardiometabolic-renal syndrome. Mental health conditions (depression and anxiety) were prevalent throughout the disease timeline, occurring both before and after diabetes diagnosis. FUTURE PLANS: This cohort will be used as a platform for developing and validating prognostic models for diabetes complications, enabling risk stratification and targeted interventions. Future work will incorporate medication data to refine diabetes type classification, examine the effectiveness of antidiabetic medications in preventing different complications and address demographic differences in prognostic model performance and prediction accuracy. To better characterise lifestyle, further interrogation of electronic health record data will examine recording of advice given, including dietary advice, referral to weight management schemes and presence of alcohol consumption codes.

Humans↗

PubMed2026

Maternal Intake of Vitamins A, C, D, and E During Pregnancy and Risk of Type 1 Diabetes in the Child: The Norwegian Mother, Father, and Child Cohort Study.

BACKGROUND: Dietary vitamins play a role in antioxidant defense and immunoregulation. However, prospective studies exploring the association between vitamin intakes during pregnancy and the child's risk of type 1 diabetes are limited. OBJECTIVES: This population-based prospective cohort study aimed to investigate the association between maternal intake of vitamins A, C, D, and E during pregnancy and risk of type 1 diabetes in children. METHODS: We included 85,244 children born between 2002 and 2009 in the Norwegian Mother and Child Cohort Study, with follow-up until 31 December, 2021. Maternal intake of vitamins from food and dietary supplements from conception to the 22nd week of pregnancy was assessed with a validated food frequency questionnaire. Cox proportional hazards regression was used to estimate hazard ratios (HRs), adjusting for background factors. RESULTS: During follow-up, 529 (0.6%) children were diagnosed with type 1 diabetes at a mean age of 9.4 y (standard deviation: 4.1 y) No associations were observed between maternal pregnancy intake of vitamin A [HR: 0.993; 95% confidence interval (CI): 0.983, 1.003/100 μg], vitamin C (HR: 1.000; 95% CI: 0.993, 1.007/10 mg), vitamin D (HR: 0.991; 95% CI: 0.978, 1.003/1 μg), or vitamin E (HR: 0.999; 95% CI: 0.996, 1.004/10 mg) and risk of type 1 diabetes in the child when adjusted for potential confounders. The results were similar when intakes were assessed separately from food and dietary supplements and after restriction to children with human leukocyte antigen DQ2 and/or DQ8 risk haplotypes. CONCLUSIONS: This prospective cohort study does not support the hypothesis that higher maternal intake of vitamins A, C, D, and E during pregnancy would decrease risk of type 1 diabetes in the child. Corroborated with previous evidence, our findings support a general pattern of null associations.

Humans↗

PubMed2022

A Distinctive γδ T Cell Repertoire in NOD Mice Weakens Immune Regulation and Favors Diabetic Disease.

Previous studies in mice and humans suggesting that γδ T cells play a role in the development of type 1 diabetes have been inconsistent and contradictory. We attempted to resolve this for the type 1 diabetes-prone NOD mice by characterizing their γδ T cell populations, and by investigating the functional contributions of particular γδ T cells subsets, using Vγ-gene targeted NOD mice. We found evidence that NOD Vγ4+ γδ T cells inhibit the development of diabetes, and that the process by which they do so involves IL-17 production and/or promotion of regulatory CD4+ αβ T cells (Tregs) in the pancreatic lymph nodes. In contrast, the NOD Vγ1+ cells promote diabetes development. Enhanced Vγ1+ cell numbers in NOD mice, in particular those biased to produce IFNγ, appear to favor diabetic disease. Within NOD mice deficient in particular γδ T cell subsets, we noted that changes in the abundance of non-targeted T cell types also occurred, which varied depending upon the γδ T cells that were missing. Our results indicate that while certain γδ T cell subsets inhibit the development of spontaneous type 1 diabetes, others exacerbate it, and they may do so via mechanisms that include altering the levels of other T cells.

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