The aim of the study was to evaluate the ability of the FreeStyle Libre Pro iQ continuous glucose monitoring (CGM) system to discriminate between presymptomatic stages of type 1 diabetes and stratify progression to stage 3 type 1 diabetes. The study also aimed to compare the performance of the FreeStyle Libre Pro iQ with that of the Dexcom G6. From December 2023 to December 2025, 50 children and adolescents without islet autoantibodies (control participants) and 89 with early-stage (stage 1 or 2) type 1 diabetes underwent CGM with the FreeStyle Libre Pro iQ. Participants with early-stage type 1 diabetes were followed up for the development of stage 3 clinical type 1 diabetes. CGM data were unavailable or incomplete for 13 participants (9
Type 2 diabetes exhibits remarkable clinical heterogeneity, represented by distinct pathological subtypes. However, the precise molecular alterations underlying these subgroups at single-cell resolution remain poorly understood. In this study, we integrated clinical metadata from both healthy control groups and individuals with type 2 diabetes with pancreatic islet single-cell transcriptomes to explore subtype-associated molecular alterations across mild age-related diabetes (MARD), mild obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD) and severe insulin-resistant diabetes (SIRD). We applied the established type 2 diabetes clustering framework with independent validation against external centroids to evaluate subtype assignment accuracy across 43 pancreatic islet donors with type 2 diabetes. High-throughput single-cell RNA sequencing data comprising 131,083 cells from 32 pancreatic islet donors were subsequently analysed to systematically compare cellular composition and subtype-associated molecular perturbation patterns across these subgroups. Four type 2 diabetes subgroups were identified, and validation against external centroids confirmed high assignment concordance, with subtype mapping sensitivities ranging from 85.0
There are substantial differences in the clinical presentation of type 1 diabetes depending on the first-developing autoantibody, although the underlying mechanisms are poorly understood. The DR3-DQ2 (DR3) and DR4-DQ8 (DR4) haplotypes at the MHC locus associate with GADA and IAA as the first-developing autoantibodies, respectively, and can therefore be used as proxies for first autoantibody development in large cohort studies of type 1 diabetes cases and control individuals. We performed the first genome-wide association study of type 1 diabetes stratified by DR3 and DR4 status using 9091 type 1 diabetes cases and 14,157 control individuals from multiple cohorts. We estimated heritability and genetic correlation between type 1 diabetes with DR3 and DR4 (DR3-T1D and DR4-T1D, respectively), and with other immune and glycaemic phenotypes. We assessed heterogeneity in effects on type 1 diabetes between DR3 and DR4 individuals at known type 1 diabetes loci. We determined enrichment of type 1 diabetes heritability in DR3 and DR4 among variants in cell-type-specific cis-regulatory elements (cREs) and biological pathways, and annotated risk variants in cREs. We observed only moderate genetic correlation between DR4-T1D and DR3-T1D (rg=0.6), which was lower compared with stratifications based on age of onset and sex, and distinct patterns of genetic correlations with other autoimmune diseases. Among type 1 diabetes-associated loci, the IL2 locus had significantly larger effect on type 1 diabetes in DR4 while several other loci (TAGAP, KLRG1) had more nominal heterogeneity. There was stronger enrichment of DR4-T1D-associated variants in T cell cREs and T cell-related pathways, while DR3-T1D-associated variants were specifically enriched in mast cell cREs and secretion-related pathways. We finally prioritised specific loci annotated in mast cells with stronger effects on type 1 diabetes in DR3 individuals. We performed the first GWAS of type 1 diabetes stratified by DR3 and DR4 status, which revealed heterogeneity in genetic risk and biological mechanisms dependent on high-risk HLA background.
Simultaneous pancreas–kidney transplantation (SPKTx) and kidney transplantation alone (KTx) are common treatment modalities for individuals with type 1 diabetes with end-stage kidney disease. This study compared metabolic and macrovascular disease outcomes between SPKTx and KTx in recipients with type 1 diabetes. We conducted a systematic search of the Embase, MEDLINE and Scopus databases (last searched 23 February 2025). We included retrospective and case–control studies, owing to a lack of randomised controlled trials in English, with adult patients. We excluded studies reporting on a return to dialysis post transplant, islet–kidney transplantation or separate pancreas–kidney transplants. Bias and study quality were assessed via the Newcastle–Ottawa scale for cohort studies. Demographic and outcome data were synthesised as both categorical and continuous data, with pooled means and summary statistics computed where applicable. Meta-analysis was performed on post-transplant outcomes in studies evaluating total cholesterol (TC), triglyceride (TG) level, HDL, LDL, blood pressure, HbA1c and renal function. Macrovascular outcomes included the frequency of new or adverse events associated with coronary artery disease (CAD), cerebrovascular disease (CeVD) and peripheral vascular disease (PVD). A total of 15 studies (n=564 SPKTx, 419 KTx) were included. Meta-analysis demonstrated lower post-transplant TC (mean difference −0.41 mmol/l [95
Environmental factors, including infections, have been suspected to influence the risk of type 1 diabetes. Studies of rotavirus vaccine and risk of type 1 diabetes have shown conflicting results. We took advantage of the rapid and high uptake of the rotavirus vaccine among infants in Norway as a natural experiment to study the potential association between rotavirus vaccination and type 1 diabetes incidence in Norway. In this cohort study, we followed all children born in Norway during 2007–2019 from 6 months to 5 years of age for type 1 diabetes. In an interrupted time series analysis, we compared type 1 diabetes incidence in children born before compared with after introduction of the rotavirus vaccination programme in September 2014. Of 740,744 included children, 846 were diagnosed with type 1 diabetes between 6 months and 5 years of age. Our primary interrupted time series analysis showed an increasing trend after implementation of the rotavirus vaccination programme (relative HR 1.11 [95
Chronic iron overload represents a significant morbidity in transfusion-dependent β-thalassaemia (TDT), leading to various complications, including diabetes and CVDs. The glucagon-like peptide-1 receptor agonist dulaglutide has been approved for the treatment of type 2 diabetes in paediatrics. In addition, it was recently approved for the treatment of CVDs. Hence, this study aimed to assess the effect of dulaglutide compared with conventional insulin therapy on glycaemic metrics, pancreatic reserve, iron load and dyslipidaemia among adolescents with TDT-induced diabetes. The open-label, parallel-group, randomised-controlled DIADEMA trial took place at the Paediatric Haematology Unit and the Paediatric and Adolescent Diabetes Unit, Paediatrics Hospital, Ain Shams University, Cairo, Egypt. Eligibility criteria were adolescents with TDT-induced diabetes aged 10–18 years, uncontrolled on metformin. The 80 participants were randomly assigned based on a computer-generated randomisation sequence to receive either subcutaneous dulaglutide (0.75 mg weekly) or conventional basal-bolus insulin therapy. Participants were followed up for 24 weeks with assessment of fasting blood glucose, HbA1c, fructosamine, fasting C-peptide, continuous glucose monitoring (CGM)-derived metrics, haemolysis markers, serum ferritin and lipid profile. The primary efficacy endpoint was the change in the CV as an index for glycaemic variability from baseline to week 24. People assessing the outcomes were masked (blind) to group assignment. Both groups were similar as regards baseline clinico-laboratory characteristics (p>0.05). After 24 weeks, dulaglutide resulted in a significant decrease in CV (from 39.45 ± 3.97
Islet transplantation is an appropriate treatment for selected individuals with type 1 diabetes mellitus and hypoglycaemia unawareness. The gold standard of maintenance immunosuppression to prevent allograft rejection is calcineurin inhibitor-based therapy; however, side effects warrant exploration of alternative immunosuppression. The co-stimulatory blocker belatacept and the mammalian target of rapamycin inhibitor sirolimus have demonstrated clinical benefit in solid organ transplantation, but efficacy in human islet transplantation is unknown. We conducted a non-randomised, phase 2, multi-centre, open-label clinical study. Participants with type 1 diabetes receiving at least one islet transplant were treated with belatacept/sirolimus (bela/siro) and compared with a contemporaneous cohort treated with tacrolimus/mycophenolate mofetil (tac/MMF). The primary outcome was freedom from hypoglycaemia, with positive C-peptide and HbA1c <53 mmol/mol (7.0
Diabetes mellitus is strongly associated with metabolic dysfunction-associated steatotic liver disease (MASLD). For many years, MASLD has not been recognised as either a common pathophysiological feature of type 2 diabetes or a diabetes-related complication. This special issue of Diabetologia puts the liver in focus in the context of diabetes. This review discusses current challenges in, and emerging opportunities for, the diagnosis and management of MASLD and fibrosis in type 2 diabetes. Up to 95
Individuals with A−β+ ketosis-prone diabetes (KPD) resemble those with type 2 diabetes but are prone to developing unprovoked diabetic ketoacidosis (DKA). We previously noted decreased plasma arginine concentrations in clinically stable individuals with KPD. We hypothesised that defective arginine metabolism could distinguish individuals with KPD from those with type 2 diabetes during hyperglycaemia and contribute to their proclivity to develop DKA. Hence, we quantified arginine production and catabolism, bioavailability and relation to insulin secretion under euglycaemic and hyperglycaemic conditions in participants with KPD compared with type 2 diabetes. Non-diabetic control participants were also studied to establish normative ranges. In Protocol 1, participants with KPD and type 2 diabetes and non-diabetic control participants were studied under euglycaemic and hyperglycaemic conditions. Kinetics of arginine, citrulline, ornithine and phenylalanine were measured using stable isotope tracer infusions with mass spectrometric analyses, together with quantification of insulin secretion in response to glucose and arginine. In Protocol 2, ten participants with KPD (adults diagnosed after an episode of unprovoked DKA, lacking islet autoantibodies, with substantial beta cell functional reserve and HbA1c <58.5 mmol/mol [7.5
Type 1 diabetes is highly influenced by genetic risk factors, especially variation in the HLA genes. Polygenic scores can strongly predict type 1 diabetes risk by integrating variants across the genome. Most polygenic scores perform best in European-ancestry populations, due to low representation of other ancestry groups in existing studies, as well as substantial variation in HLA alleles across the globe. However, recent multi-ancestry genome-wide association studies have broadened our understanding of type 1 diabetes genetic risk, and advanced computational techniques can accurately capture HLA alleles at high resolution. This article will review novel approaches to develop type 1 diabetes polygenic scores that demonstrate high predictive power across diverse populations.
Leukocyte cell-derived chemotaxin 2 (LECT2), a newly discovered hepatokine involved in immunomodulation and inflammatory processes, has recently been implicated in diabetic retinopathy pathogenesis. However, the specific role and mechanism of LECT2 in diabetic retinopathy remain largely unclear. A publicly available liquid biopsy proteomics dataset was reanalysed and validated using retinal samples from individuals with diabetic retinopathy. A LECT2-knockdown (Lect2+/−) mouse model of diabetic retinopathy was established to evaluate the role of LECT2 in vivo. Retinal pathology was assessed by Periodic Acid–Schiff staining and H E staining, and LECT2 expression was assessed by western blotting. In parallel, a high glucose (HG)-induced human Müller cell model was used to investigate the subcellular localisation and functional effects of LECT2. LECT2 expression and inflammatory signalling were analysed following LECT2 knockdown or overexpression, and its nucleus–cytoplasm distribution was examined by fractionation assays. The interaction between LECT2 and ribosomal protein S27a (RPS27A) was characterised by immunoprecipitation-MS, co-immunoprecipitation, molecular docking and split-GFP assays, followed by RPS27A silencing to assess its effects on inflammatory protein expression. Proteomic reanalysis of proliferative diabetic retinopathy liquid biopsy data identified 1479 upregulated proteins, with chemotaxis among the most significantly enriched Gene Ontology terms (false discovery rate <0.001). Among 17 chemotaxis-related candidate proteins, LECT2 emerged as a potential regulator of diabetes-associated inflammation, a finding further supported by its elevated expression in the retinas of individuals with diabetic retinopathy. In diabetic Lect2+/− mice, LECT2 deficiency aggravated retinal microvascular injury and inflammatory responses. LECT2 was predominantly expressed in retinal Müller cells, implicating it in glia-associated retinal inflammation. In HG-treated human retinal Müller cells, RPS27A was identified as a downstream target of LECT2 and was upregulated under hyperglycaemic conditions. Mechanistically, HG stimulation increased the expression and nuclear accumulation of both LECT2 and RPS27A. LECT2 interacted with RPS27A at the Lys48 site, promoting its nuclear retention and limiting its cytoplasmic translocation. This, in turn, inhibited IκBα ubiquitination and degradation, thereby suppressing NF-κB-driven inflammatory signalling. Taken together, our studies indicated the protective role of LECT2 in diabetes-induced dysfunction of retinal Müller cells, supporting the feasibility of targeting LECT2 in the management of diabetic inflammation and microvasculopathy.
Although exocrine pancreatic insufficiency (EPI) is thought to be common in type 1 diabetes, little is known about the relationship of EPI with type 1 diabetes parameters or food intake and abdominal complaints. Characterising individuals with EPI could help prevent EPI-related complications such as malabsorption and osteoporosis. In a cross-sectional cohort of 443 individuals with type 1 diabetes (62
Impaired regulation of islet microvascular blood flow has been implicated in beta cell dysfunction in diabetes; this dysregulation is linked to endothelial dysfunction with reduced nitric oxide bioavailability. However, dynamic regulation of islet microvascular flow has not been directly examined in vivo. We hypothesised that acute pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) rapidly enhances islet microvascular flow through NO-dependent mechanisms under diabetic conditions. Islet microvascular dynamics were visualised in vivo using intravital two-photon microscopy in mice with hyperglycaemia induced by multiple low doses of streptozocin (STZ), which represents a model of beta cell dysfunction, and in normoglycaemic controls. Acute vascular responses to the GLP-1R agonist liraglutide were quantified by measuring peri-islet vascular volume fraction and erythrocyte velocity, with or without inhibition of nitric oxide synthase using Nω-nitro-l-arginine methyl ester (l-NAME). To assess the physiological relevance of the results, a subset of diabetic mice received chronic liraglutide treatment, followed by analyses of islet hypoxia and beta cell function. Acute liraglutide administration in the diabetic mice rapidly increased peri-islet vascular volume fraction (p=0.010) and erythrocyte velocity (p=0.003). These vascular responses were completely abolished by treatment with l-NAME, and were absent in normoglycaemic mice, indicating a diabetes-specific, NO-dependent microvascular response. Chronic liraglutide treatment was associated with reduced islet hypoxia and improved glucose-stimulated insulin secretion (p=0.042), supporting the physiological relevance of acute microvascular enhancement. Acute pharmacological activation of the GLP-1R rapidly enhances NO-dependent islet microvascular flow specifically under diabetic conditions. This previously unrecognised in vivo vascular response indicates dynamic regulation of the islet microenvironment by GLP-1R signalling, and suggests that rapid microvascular adaptation may contribute to preservation of beta cell function during metabolic stress.
Most people with type 2 diabetes have metabolic dysfunction-associated steatotic liver disease (MASLD), yet fewer than 2
Endometriosis is a heterogeneous inflammatory condition that may influence long-term metabolic health. Prior studies have reported largely null associations with type 2 diabetes, potentially missing subtype-specific and subgroup heterogeneity. We investigated the association between endometriosis, including clinically relevant subtypes, and incident type 2 diabetes, and assessed effect modification by menopausal status, BMI and history of gestational diabetes mellitus. We assembled a dynamic population-based cohort of 2,939,364 individuals assigned as female at birth from the Utah Population Database (1996–2021). Endometriosis and subtypes were identified using validated ICD-9/10 codes and modelled as time-varying exposures. Incident type 2 diabetes was ascertained using ICD codes. Cox proportional hazards models with calendar time as the time scale were used to estimate HRs and 95
This study aimed to investigate whether concurrent training, when added to a palaeolithic-type diet-induced weight loss intervention, is associated with altered physiological responses and circulating lipid dynamics during exercise and recovery in individuals with type 2 diabetes. In a previously reported clinical trial, individuals with overweight or obesity who had type 2 diabetes (n=27) were randomised to either 12 weeks of palaeolithic-type diet (PD) or PD and supervised concurrent exercise training three times weekly (PD+E). Physiological and glycaemic responses to exercise and recovery were monitored during an exercise test at baseline and following the intervention. This secondary analysis focuses on a subgroup (n=21), in which plasma samples were collected before and after exercise, and after 30 min of recovery, and lipid profiles were analysed using mass spectrometry-based lipidomics. Glycaemic management during and after the exercise test improved similarly in both groups, whereas only the PD+E group showed improvements in cardiometabolic fitness. In plasma samples obtained at rest before exercise, the intervention reduced levels of triacylglycerols in both groups, with additional reductions of very-long-chain ceramides (>C22 acyl chains) in the PD+E group. During the exercise test, sphingomyelins and ceramides increased in both groups, but only PD+E resulted in improved clearance of these bioactive lipids from circulation during recovery. The specific lipid response during recovery from exercise was associated with improvements in fat oxidation during exercise. Concurrent training during PD-induced weight loss improves cardiometabolic fitness and is associated with an enhanced ability to clear bioactive sphingomyelins and ceramides from the circulation in the recovery phase after an exercise test. The improved lipid response during recovery and its association with the capacity for fat oxidation suggest that concurrent training during PD-induced weight loss may augment lipid handling beyond diet-induced changes, although causal mechanisms cannot be established.
