AIMS/HYPOTHESIS Screening for islet autoantibodies is an effective method for identifying individuals with pre-symptomatic (stage 1 and 2) type 1 diabetes. This approach offers a valuable opportunity for education and monitoring, which can help to reduce the severity of clinical manifestations at clinical onset (stage 3), including diabetic ketoacidosis. The aim of the study was to evaluate the progression

Aims/hypothesis Insulin resistance in obesity and type 2 diabetes is associated with elevated plasma branched-chain amino acid (BCAA) levels. Here, we examined whether the ability of insulin to clear plasma BCAAs and any influence of acute exercise or exercise training on this response are intact in obesity and type 2 diabetes. Methods In four case–control studies of participants with type 2 diabetes

Aims/hypothesis Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a cornerstone in type 2 diabetes management. In this study we evaluated heterogeneity in body weight and glycaemic responses to the initiation of liraglutide, semaglutide or dulaglutide in real-world clinical practice. Methods Data from 4467 adults with type 2 diabetes in the Diabetes Patient Follow-up (DPV) registry were analysed

Aims/hypothesis Previous studies reporting lower skeletal muscle mitochondrial function in type 1 diabetes did not account for cardiorespiratory fitness, a key confounder when assessing mitochondrial function. We hypothesised that, compared with healthy individuals, muscle mitochondrial phenotypic differences would be abolished in individuals with type 1 diabetes when matched for age, sex, BMI and

Aims/hypothesis Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common feature of obesity and type 2 diabetes. Under lipotoxic stress, hepatocytes release small extracellular vesicles (sEVs) which act locally and contribute to MASLD progression, but their role in beta cell function and development of type 2 diabetes remains largely unexplored. We aimed to examine whether hepatocyte-derived

Aims/hypothesis In type 1 diabetes, the counterregulatory glucagon response to low plasma glucose is impaired. The resulting increased risk of hypoglycaemia necessitates novel strategies to ameliorate alpha cell impairment. Here, we aimed to establish an in vitro type 1 diabetes-like model of alpha cell impairment using standardised reaggregated human islet microtissues (MTs) exposed to proinflammatory

Aims/hypothesis Efficient prediction of clinical type 1 diabetes is important for risk stratification and monitoring of autoantibody-positive individuals. In this study, we compared type 1 diabetes predictive models for predictive performance, cost and participant time needed for testing. Methods We developed 1943 predictive models using a Cox model based on a type 1 diabetes genetic risk score (GRS2)

Aims/hypothesis This study aimed to compare the ability of time in tight range (TITR) and time in range (TIR) to predict the achievement of typical glucose management indicator (GMI) and HbA1c targets. Methods This cross-sectional analysis included 773 adults with diabetes receiving insulin therapy who visited Samsung Medical Center between June 2019 and December 2023 and wore a Dexcom G6 or FreeStyle

This review describes a prolonged research endeavour to test the twin cycle hypothesis that type 2 diabetes is caused by fat-induced dysfunction of the liver and pancreas, guided by the happenstance of clinical practice. Testing of the personal fat threshold hypothesis, that individuals exhibit different levels of tolerance to intra-organ fat accumulation, is also described. Both hypotheses predict

Aims/hypothesis Findings from RCTs and observational studies indicate a positive association between statin use and risk of type 2 diabetes. Mendelian randomisation studies provide evidence to support that the effect is causal. However, little is known about the long-term effects, and data on different types of statins remain limited. Methods We analysed participants with hypercholesterolaemia from

Aims/hypothesis Our aim was to assess treatment discontinuation, reinitiation and switching between drugs within the same drug class for glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors in individuals with type 2 diabetes. Methods We used data from nationwide registers in Sweden to perform separate analyses for all patients with type 2 diabetes

Aims/hypothesis Soluble receptor for advanced glycation end products (sRAGE) has been inversely linked to obesity, which is defined by excess of total body fat. However, body fat accumulation is also relevant for health. In this study, we investigated associations between sRAGE and obesity in individuals with type 1 diabetes over 6.3 years of follow-up. Methods The study included 3886 adults with type

Aims/hypothesis The endoplasmic reticulum (ER) stress-induced unfolded protein response helps determine beta cell survival rate in diabetes. The alternative eukaryotic translation initiation factor 2A (EIF2A) has been proposed to mediate translation initiation independent of the α subunit of EIF2 (EIF2S1) during cellular stress, but its role in beta cells has not been comprehensively examined. Methods

Aims/hypothesis Individuals with type 1 diabetes are at increased cardiovascular risk, particularly in the presence of insulin resistance. A prothrombotic environment is believed to contribute to this risk but thrombotic pathways in type 1 diabetes are only partially understood and the role of platelets is incompletely studied. We hypothesised that platelets from individuals with type 1 diabetes exhibit

Aims/hypothesis Disrupted energy balance is critical for the onset and development of type 2 diabetes mellitus. Understanding of the exact underlying metabolic mechanisms remains incomplete, but skeletal muscle is thought to play an important pathogenic role. As the super-relaxed state of its most abundant protein, myosin, regulates cellular energetics, we aimed to investigate whether it is altered

Aims/hypothesis Excessive endoplasmic reticulum (ER) stress in beta cells can impair proliferation and contribute to autoimmune responses such as the destruction of beta cells in type 1 diabetes. Exocrine–beta cell interactions affect beta cell growth and function. Notably, exocrine abnormalities are frequently observed alongside overloaded beta cells in different types of diabetes, suggesting that

Aims/hypothesis It has been proposed that severe hypoglycaemia events (SHE) may increase the risk of adverse CVD complications in adults with type 1 diabetes. The aim of this study was to evaluate the risk of CVD complications following SHE in a large cohort of adults with type 1 diabetes, and to compare the risk of post-SHE CVD complications for users of intermittently scanned continuous glucose monitoring

Aims/hypothesis Diabetic peripheral neuropathy (DPN) and neuropathic pain (NP) are common complications of type 1 diabetes that can greatly affect quality of life. Studying DNA methylation (DNAm) may help identify potential therapeutic targets; however, epigenome-wide association studies (EWAS) of DPN and NP are lacking. We thus performed prospective EWAS of 28 year DPN and NP incidence in the Pittsburgh

Aims/hypothesis The role of regulatory factor X 3 (RFX3) in human pancreatic islet development has not been explored. This study aims to investigate the function of RFX3 in human pancreatic islet development using human islet organoids derived from induced pluripotent stem cells (iPSCs), hypothesising that RFX3 regulates human islet cell differentiation. Methods We generated RFX3 knockout (RFX3 KO)

Aims/hypothesis Estimated GFRs utilising creatinine- (eGFRcreat) or cystatin C-based (eGFRcyst) equations can generate discrepant results that are associated with clinical outcomes. A low eGFRcyst/eGFRcreat ratio (<0.60), reflecting a pathological glomerular state termed shrunken pore syndrome (SPS), has been associated with excess mortality in some clinical situations including diabetes. The aim of

Both the global prevalence of diabetes and the frequency of natural and man-made disasters are increasing. Of all chronic diseases, the consequences of sudden loss of medical supplies are most serious for those with diabetes, with people living with type 1 diabetes being at risk of death within a few days without insulin. This review considers how to prepare for and respond to sudden reductions in

Aims/hypothesis Inflammation-driven pancreatic beta cell death is a hallmark of type 1 diabetes progression. We have previously shown that serum obtained from individuals after high-intensity interval training prevents cytokine-induced human beta cell apoptosis, but the mediators of this beneficial effect remain to be characterised. In this study we evaluated the role of exercise-induced meteorin-like

Aims/hypothesis Diabetic ketoacidosis remains a severe complication in type 1 diabetes, arising from insufficient insulin levels and accelerated lipolytic rate, leading to increased β-oxidation of NEFA and ketone body production in the liver. The ketone body 3-hydroxybutyrate (3-OHB) inhibits lipolysis in healthy individuals. The current study aimed to test whether this feedback suppression of lipolysis

Aims/hypothesis Low birthweight infants are at increased risk not only of mortality, but also of type 2 diabetes mellitus and CVD in later life. At the opposite end of the spectrum, high birthweight infants have increased risk of birth complications, such as shoulder dystocia, neonatal hypoglycaemia and obesity, and similarly increased risk of type 2 diabetes mellitus and CVD. However, previous genome-wide

Aims/hypothesis Epidemiological studies indicate that type 2 diabetes increases the risk for Alzheimer’s disease. Alterations in cerebral metabolism have been proposed as a potential mechanism underlying this association. A better understanding of these metabolic changes may elucidate potential pathways linking type 2 diabetes to Alzheimer’s disease. The aim of the current exploratory study was to

Aims/hypothesis Women with prior gestational diabetes mellitus (GDM) have higher incidence of age-associated diseases, including type 2 diabetes, CVD and cognitive impairment. Human studies cannot readily determine whether GDM causes these conditions or the underlying mechanisms. Here we used a well-validated rat model of GDM to address these questions. Methods Rats with beta cell-specific expression

Resulting from a combination of genetic and environmental factors, type 2 diabetes is highly heterogeneous in manifestation and disease progression, with the only common feature being chronic hyperglycaemia. In spite of vigorous efforts to elucidate the pathogenetic origins and natural course of the disease, there is still a lack of biomarkers and tools for prevention, disease stratification and treatment

Aims/hypothesis Physical activity increases the risk of hypoglycaemia in individuals with type 2 diabetes when basal or basal-bolus insulin therapy is administered. Once-weekly basal insulins may elevate the risk of physical activity-attributed hypoglycaemia compared with other basal insulins because the administered levels cannot be reduced in anticipation of increased physical activity. This post

Aims/hypothesis Cardiometabolic traits are heritable, and some display parent-of-origin effects, which indicates preferential inheritance from one parent or parental bias. Most studies of these phenomena have focused on adult populations. We aimed to investigate the heritability and parent-of-origin effects on cardiometabolic traits in a birth cohort with serial measurements to determine whether these

Aims/hypothesis Our aim was to detect early structural and functional changes in the macular capillaries using optical coherence tomography angiography during the course of type 1 or 2 diabetes mellitus. Methods In this cross-sectional study, individuals with type 1 diabetes (n=143) or type 2 diabetes (n=197) from the German Diabetes Study (ClinicalTrials.gov registration no. NCT01055093) underwent

Aims/hypothesis Type 2 diabetes is a chronic metabolic disorder characterised by insulin resistance and sustained hyperglycaemia, and is a major cause of blindness, kidney failure, heart attacks and stroke. Our team has recently identified hexosaminidase A (HEXA) as an endocrine factor secreted by the liver that regulates sphingolipid metabolism in skeletal muscle. Specifically, HEXA converts GM2 to

Aims/hypothesis Diabetes is associated with the dysfunction of glucagon-producing pancreatic islet alpha cells, although the underlying mechanisms regulating glucagon secretion and alpha cell dysfunction remain unclear. While insulin secretion from pancreatic beta cells has long been known to be controlled partly by intracellular phospholipid signalling, very little is known about the role of phospholipids

Aims/hypothesis Diabetic retinopathy features damage to the retinal microvasculature that causes vessels to leak and proliferate and can lead to vision loss and blindness. Inflammation contributes to the development of diabetic retinopathy, but little is known about the role of the adaptive immune system, including the benefits of augmenting the Forkhead box protein P3 (Foxp3) regulatory T cell (Treg)

Aims/hypothesis Diabetes is a global health burden characterised by incremental beta cell loss. Islet transplantation is a recognised treatment for individuals with type 1 diabetes and hypoglycaemia unawareness but broader application is constrained by limited islet survival and function post-transplantation. The underlying molecular mechanisms that induce beta cell dysfunction and demise remain unclear

Aims/hypothesis Weight loss can improve glycaemic management in individuals with type 2 diabetes, but its long-term effects on remission, cardiovascular risk factors and complications remain unclear. We investigated clinical outcomes following non-interventional ≥10% body weight loss in people with newly diagnosed type 2 diabetes in a routine care setting. Methods We retrospectively analysed two cohorts

Aims/hypothesis MiRNAs regulate gene expression, influencing beta cell function and pathways. Isoforms of miRNA (isomiRs), sequence variants of miRNAs with post-transcriptional modifications, exhibit cell-type-specific expression and functions. Despite their biological significance, a comprehensive isomiR profile in human pancreatic islets and beta cells remains unexplored. This study aims to profile

Early detection of type 1 diabetes, in its presymptomatic stage, offers significant clinical advantages, including treatment that can delay disease onset. Current screening focuses on identifying islet autoantibody positivity, with proposed optimal testing at ages 2, 6 and 10 years potentially achieving up to 80% sensitivity. However, challenges arise from participation rates and costs associated with

Aims/hypothesis Earlier studies of pancreases from donors with type 1 diabetes demonstrated enteroviral capsid protein VP1 in beta cells. In the context of a multidisciplinary approach undertaken by the nPOD-Virus group, we assessed VP1 positivity in pancreas and other tissues (spleen, duodenum and pancreatic lymph nodes) from 188 organ donors, including donors with type 1 diabetes and donors expressing

Aims/hypothesis Previous pathology studies have associated enterovirus infections with type 1 diabetes by examining the enterovirus capsid protein 1 (VP1) in autopsy pancreases obtained near diabetes diagnosis. The Network for Pancreatic Organ Donors with Diabetes (nPOD) has since obtained pancreases from organ donors with type 1 diabetes (with broad age and disease duration) and donors with disease-associated

Aims/hypothesis The nPOD-Virus group collaboratively applied innovative technologies to detect and sequence viral RNA in pancreas and other tissues from organ donors with type 1 diabetes. These analyses involved the largest number of pancreas samples collected to date. The aim of the current work was to examine the presence of enterovirus RNA in pancreas and lymphoid tissues of organ donors with and

Diabetes is a rapidly growing global health concern projected to affect one in eight adults by 2045, which translates to roughly 783 million people. The profound metabolic alterations often present in dysglycaemia significantly increase the risk of cardiovascular complications. While genetic susceptibility plays a crucial role in diabetes and its vascular complications, identifying genes and molecular

Aims/hypothesis Signalling pathways that regulate endothelial cell (EC) dysfunction, ischaemia and inflammation play a crucial role in retinal microangiopathy such as diabetic retinopathy. MAP4K4 is highly expressed in ECs. However, the involvement of MAP4K4 in retinal vasculopathy of diabetic retinopathy remains unclear. Methods We analysed publicly available single-cell RNA sequencing (scRNA-seq)

Aims/hypothesis Biennial, as opposed to annual, screening for diabetic retinopathy was recently introduced within England for those considered to be at ‘low risk’. This study aims to examine the impact that annual vs biennial screening has on equitable risk of diagnosis of sight-threatening diabetic retinopathy (STDR) among people at ‘low risk’ and to develop an amelioration protocol. Methods In the

Aims/hypothesis Fat deposition in the pancreas is implicated in beta cell dysfunction and the progress of type 2 diabetes. However, there is limited evidence to confirm the correlation and explore how pancreatic fat links with beta cell dysfunction in human type 2 diabetes. This study aimed to examine the spatial relationship between pancreatic fat and islets in human pancreases. Methods Histological

Aims/hypothesis Components of the insulin processing and secretion pathways remain incompletely understood. Here, we examined a genome-wide association study (GWAS) signal for plasma proinsulin levels. Lead GWAS variant rs150781447-T encodes an Arg279Cys substitution in TBC1 domain family member 30 (TBC1D30), but no role for this protein in insulin processing or secretion has been established previously

The accumulation of acquired somatic mutations is a natural consequence of ageing, but the pathophysiological implications of these mutations beyond cancer are only beginning to be understood. Most somatic mutations are functionally neutral, but a few may confer a competitive advantage to a stem cell, driving its clonal expansion. When such a mutation arises in haematopoietic stem cells, it leads to

Aims/hypothesis An intronic variant (rs10830963) in MTNR1B (encoding the melatonin receptor type 2 [MT2]) has been shown to strongly associate with impaired glucose regulation and elevated type 2 diabetes prevalence. However, MTNR1B missense variants have shown conflicting results on type 2 diabetes. Thus, we aimed to gain further insights into the impact of MTNR1B coding variants on type 2 diabetes

Aims/hypothesis Diabetic peripheral neuropathy is a debilitating microvascular complication of diabetes mellitus, with limited disease-modifying therapies to date. This study aimed to assess the effect of metformin on the corneal sub-basal nerve plexus as a peripheral neuropathy outcome measure in people with type 2 diabetes. Methods A cohort of 36 participants with type 2 diabetes receiving metformin

Aims/hypothesis Glycaemic traits such as high fasting glucose levels and insulin resistance are positively associated with the risk of type 2 diabetes and other cardiometabolic diseases. Genetic association studies have identified hundreds of associations for each glycaemic trait, yet very few studies have involved continental African populations. We report the results of genome-wide association studies