Although scientific societies have made substantial efforts through the implementation of guidelines and by increasing awareness among both expert and non-expert healthcare professionals (HCPs), delayed referral of patients with diabetic foot ulcers (DFUs) to specialized diabetic foot services (DFS) remains a common issue. Early referral to a DFS has been widely documented as the most important intervention for achieving ulcer healing, reducing healing time, and avoiding major amputations. Furthermore, it has been reported that many HCPs working in primary care are not adequately trained in the recognition and management of DFUs. The onset of a DFU may rapidly deteriorate and evolve into a diabetic foot attack (DFA), a dangerous condition characterized by advanced ischaemia, severe infection, and/or acute Charcot neuroarthropathy, potentially leading to limb- and life-threatening consequences. The current document aims to identify the main clinical patterns of DFA, describing their clinical characteristics, appropriate management pathways, and indications for treatment. Accordingly, the authors aimed to develop a practical, fast-track model to define referral timing to specialized diabetic foot centers based on the severity of each clinical presentation. The proposed fast-track approach distinguishes between emergency conditions requiring immediate management within hours and urgent conditions requiring specialist evaluation within 24-48 h to prevent clinical deterioration and poorer outcomes.This document was developed on behalf of the Italian Diabetic Foot Study Group of Società Italiana di Diabetologia (SID) and Associazione Medici Diabetologi (AMD) with the aim of reducing cases of delayed referral and their severe consequences.
This systematic review and meta-analysis aimed to investigate the effects of time-restricted eating (TRE) on glucose metabolism and regulation in individuals with prediabetes (fasting blood glucose of 5.6-6.9 mmol/l or HbA1c of 39-47 mmol/mol [5.7-6.4%]) or type 2 diabetes (fasting blood glucose ≥7 mmol/l or HbA1c ≥48 mmol/mol [6.5%]). A literature search was performed in MEDLINE, Embase and CENTRAL from inception to 5 August 2025. Moreover, forward and backward citation searches were performed. Eligible studies were RCTs in adults with prediabetes or type 2 diabetes, lasting ≥2 weeks, reporting markers of glucose metabolism and regulation, comparing TRE (≤12 h eating window) with a non-time-restricted control diet. Studies involving pregnancy, other fasting regimens, or non-peer-reviewed publications were excluded. Data were pooled as weighted mean differences with 95% CIs using random-effects generic inverse variance models in Cochrane Review Manager Web, and results are presented as forest plots. The certainty of evidence was defined using Grading of Recommendations, Assessment, Development and Evaluations methodology, and risk of bias was estimated by using the Revised Cochrane risk-of-bias tool for randomised trials (RoB 2). Out of 2043 records identified through the database search, as well as 1249 from forward and backward citation searches, ten RCTs including 599 participants were included. The mean length of the studies was 4 months, and the eating windows ranged from 4 to 10 h per day. The pooled meta-analysis showed no overall effect of TRE on HbA1c (-3.33 mmol/mol; 95% CI -6.87, 0.20 (-0.30% points; -0.63, 0.02); p=0.06, moderate certainty). Nevertheless, following stratification by subgroups, TRE resulted in a reduction in HbA1c of 0.93 mmol/mol (-1.70, -0.17 [-0.09% points; -0.16, -0.02]; p=0.02) in individuals with prediabetes but not in individuals with type 2 diabetes (-4.68 mmol/mol; -10.08, 0.72 (-0.43% points; -0.92, 0.07); p=0.09). TRE reduced fasting blood glucose in the pooled analysis (-0.30 mmol/l; -0.53, -0.07; p<0.01, moderate certainty) as well as in the subgroup analyses in individuals with prediabetes (-0.14 mmol/l; -0.27, -0.01; p=0.03) and with type 2 diabetes (-0.48 mmol/l; -0.78, -0.17; p<0.01). Moreover, TRE lowered body weight by 1.6 kg (-2.2, -1.0; p<0.001) in the pooled analysis. The evidence was limited by imprecision arising from wide confidence intervals in some of the included studies, which may be due to small sample sizes. Lastly, the effects of TRE on markers of insulin sensitivity, beta cell function and continuous glucose monitoring measurements were inconclusive. Moderate-certainty evidence indicates that TRE reduces fasting blood glucose but not HbA1c. The subgroup analyses revealed that TRE improved HbA1c and fasting glucose in individuals with prediabetes and improved fasting glucose in individuals with type 2 diabetes. Future large-scale studies should investigate long-term effects of TRE in prevention and treatment of type 2 diabetes. PROSPERO CRD42024523591 FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Three authors (JS, A-DT, THA) are employed at Steno Diabetes Center Copenhagen, a public hospital and research institution under the Capital Region of Denmark, partly funded by a grant from the Novo Nordisk Foundation.
Youth-onset type 2 diabetes is an aggressive phenotype of metabolic disease, yet tools to identify children with obesity at highest short-term risk are limited. We evaluated whether the paediatric liver fibrosis risk scores (pFIB) pFIB-c and pFIB-6, originally developed for metabolic dysfunction-associated steatotic liver disease (MASLD) fibrosis risk stratification, identify individuals at increased risk of incident type 2 diabetes. A cohort study was conducted using the Swedish Childhood Obesity Treatment Register (BORIS, 2005-2020) linked with national registers, from which type 2 diabetes was ascertained. We included 4856 children with obesity (aged 12.0 years at baseline) and 23,758 general population comparators. The pFIB-c and pFIB-6 scores were calculated as published. Time-to-event analysis yielding HR was performed using Cox regression and flexible parametric survival models. Among children with obesity, 12.4% had a pFIB-6 ≥4. A high pFIB-6 score increased the risk for type 2 diabetes at 9-19 years of age (adjusted HR 3.05 [95% CI 2.17, 4.28]). The incidence rate (95% CI) per 10,000 person-years was 1.02 (0.61, 1.72) in the general population comparators, 45.5 (37.8, 54.7) in individuals with obesity and a pFIB-6 <4, and 161.7 (122.2, 213.9) when the pFIB-6 was ≥4. In contrast, neither score, measured at paediatric age, predicted type 2 diabetes risk at 20-25 years of age. Among individual score components, elevated alanine aminotransferase (ALT) and HOMA-IR were most strongly associated with type 2 diabetes risk. In an independent cohort, higher pFIB-6 scores were associated with greater adipose tissue insulin resistance. A liver-derived composite risk score identifies a subgroup of adolescents with obesity at markedly increased short-term risk of type 2 diabetes. These findings suggest that integrating hepatic and metabolic variables may improve early risk stratification in paediatric obesity and help identify individuals who may benefit from intensified monitoring during adolescence.
People with type 2 diabetes have a 60-70% higher risk of developing dementia than those without diabetes. Given the increasing number of older people living with diabetes, preventing dementia in this population is becoming increasingly important. However, dementia in individuals with type 2 diabetes is not a single entity and no diabetes-specific pathologies contributing to dementia have been identified yet. Here, we suggest that the relation between type 2 diabetes and dementia may be best understood through a probabilistic model that considers the context in which type 2 diabetes develops and the involvement of multiple dementia-related pathologies. Within this model, type 2 diabetes alters both the probability of dementia-related pathologies occurring and their downstream consequences. Opportunities for prevention of dementia evolve across the lifespan and comprise reducing cumulative exposures to dementia risk factors through a holistic approach rather than through targeting a single factor. Accordingly, beyond preventing type 2 diabetes itself, glucose-lowering medications with effects beyond glycaemic management (e.g. multihormone receptor modulators, such as glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors), alongside traditional multi-domain cardiovascular risk management, may be most effective at lowering excess dementia risk in individuals with type 2 diabetes.
Occult lymph node metastases occur in up to 50% of patients with clinically node-negative papillary thyroid carcinoma eligible for thyroid lobectomy. Nevertheless, the 2025-ATA guidelines discourage routine prophylactic ipsilateral central neck dissection in clinically node-negative clinical T1b-T2 low-risk disease. This multicentric retrospective study evaluated the impact of routine ipsilateral central neck dissection on recurrence risk stratification in patients with unifocal clinically node-negative clinical T1b-T2 papillary thyroid carcinoma eligible for thyroid lobectomy. Among 9,028 thyroidectomies performed in four referral centres, 264 patients met the inclusion criteria. Lymph node metastases were found in 135 (51.1%) patients, with extranodal extension in 8.9% of node-positive cases. Median tumour size was 12 mm. Final histopathology showed pT1a disease in 88 (33.3%), pT1b in 165 (62.5%), and pT2 in 11 (4.2%). Extrathyroidal extension, vascular invasion, multifocality, and aggressive histologic variants were observed in 12.1, 60.6, 43.2, and 18.9%, respectively. According to the 2025-ATA risk stratification system, excluding pathologic nodal status, 60 (22.7%) patients were low risk, 31 (11.8%) low-intermediate risk, 170 (64.4%) intermediate-high risk, and 3 (1.1%) high risk. After inclusion of nodal status, 54 (20.4%) were low risk, 24 (9.1%) low-intermediate risk, 171 (64.8%) intermediate-high risk, and 15 (5.7%) high risk (p < 0.001). Overall, 8% of patients experienced risk upgrading, and > 70% were classified in higher-risk categories. Pathologic nodal assessment substantially modifies recurrence risk stratification in clinical node-negative T1b-T2 papillary thyroid carcinoma eligible for thyroid lobectomy, supporting routine ipsilateral central neck dissection for staging and tailored surgical decision-making.
Sexual function during pregnancy is commonly described in terms of overall decline or sexual dysfunction prevalence, potentially overlooking heterogeneity across individual domains. We aimed to identify distinct sexual function phenotypes during pregnancy and to examine whether gestational diabetes mellitus (GDM) is associated with poorer sexual function or specific sexual profiles. In this cross-sectional observational study, 83 pregnant women undergoing routine GDM screening between weeks 24 and 28 of gestation completed the Female Sexual Function Index (FSFI). Clinical and obstetric data were collected. K-means cluster analysis on standardized FSFI domain scores identified multidomain phenotypes. Group comparisons and multivariable regression models were performed. Sexual dysfunction was present in 51 of 83 women (61.4%). Three sexual phenotypes were identified: preserved sexual function (n=49), global sexual impairment (n=25), and desire-satisfaction dissociation (n=9). Pre-pregnancy weight differed across phenotypes (p=0.026). Hypertensive disorders of pregnancy, twin pregnancy, and conception by assisted reproductive technology (ART) were more frequent in the desire-satisfaction dissociation phenotype (p=0.024, p=0.042, and p=0.048, respectively). Older age (OR 1.15, 95% CI 1.01-1.32; p=0.041) and lower pre-pregnancy weight (OR 0.95, 95% CI 0.92-0.99; p=0.019) were independently associated with global sexual impairment. GDM was not associated with total FSFI score, sexual dysfunction prevalence, or phenotype distribution. Female sexual function during pregnancy is heterogeneous and distributed across distinct multidomain phenotypes. Gestational diabetes mellitus did not explain this heterogeneity, whereas phenotype-based profiling identified distinctive sexual patterns. These findings support a more nuanced framework for studying sexuality in pregnancy beyond dichotomous definitions of dysfunction.
The COVID-19 pandemic was a dynamic and often confusing period for clinical and biomedical research. As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread globally, knowledge accumulated rapidly through publications that were frequently based on preliminary or sometimes conflicting evidence, yet these papers played a critical role in shaping evolving medical, research and societal responses. Early in the pandemic, diabetes emerged as one of the strongest predictors of severe COVID-19 outcomes and mortality, placing it at the centre of early risk-stratification and therapeutic frameworks and prompting urgent efforts to understand the biological basis of these associations. As the pandemic progressed, reports of new-onset diabetes following COVID-19 infection raised the possibility of a bidirectional relationship between SARS-CoV-2 infection and diabetes. In this review, we provide a post-pandemic reappraisal of the clinical and experimental literature examining the intersection of COVID-19 and diabetes. We summarise proposed pathophysiological mechanisms, including the effects of SARS-CoV-2 infection in the pancreas and on peripheral insulin-sensitive tissues. We review key meta-analyses assessing the association between COVID-19 and incident type 1 and type 2 diabetes and highlight strengths and weaknesses of the epidemiologic studies underpinning these findings. We highlight the highest-quality evidence from prospective cohorts, as well as relevant clinical trials and registry-based studies that emerged from this collective experience. We discuss emerging relationships between long COVID and diabetes and the effect of vaccination on diabetes risk following SARS-CoV-2 infection. Finally, we identify critical knowledge gaps and outline priorities for ongoing and future studies needed to resolve remaining uncertainties.
G-protein-coupled receptors (GPCRs) play an important role in maintaining systemic glucose homeostasis by regulating insulin secretion, with protein kinase A (PKA) signalling serving as a key downstream effector. Our previous work identified specific expression of type IIB PKA in pancreatic beta cells. Based on these findings, we propose that type IIB PKA is involved in mediating the GPCR signalling in pancreatic beta cells. The glucagon-like peptide-1 (GLP-1) analogue liraglutide was administered to mice 30 min before glucose injection during an IPGTT, whereas the glucose levels and insulin levels were measured in wild-type and RIIβ-knockout mice. The isolated islets were subjected to both perifusion assay and static batch incubations following stimulation with liraglutide, glucagon and follicle-stimulating hormone (FSH). RNA-seq analysis was performed to identify molecular changes in islets with RIIβ ablation. Both western blotting and quantitative PCR were employed to quantify the gene expression. Whole-cell patch-clamp recordings were conducted to measure KATP and Ca2+ currents. Insulin granule morphology and abundance were evaluated by electron microscopy and flow cytometry using EGFP-labelled Syncollin, respectively. RIIβ-knockout mice exhibited impaired glucose tolerance and attenuated insulin secretion in response to liraglutide. Islets isolated from RIIβ-knockout mice showed reduced insulin secretion following liraglutide stimulation. Similarly, RIIβ-ablated islets displayed decreased insulin secretion in response to both glucagon and FSH. Further mechanistic studies revealed that RIIβ deficiency impaired liraglutide-mediated PKA signalling activation. Specifically, RIIβ-ablated beta cells exhibited reduced basal KATP channel activity and lack of liraglutide-mediated channel inhibition. Multiple voltage-gated Ca2+ channel genes were downregulated in RIIβ-ablated islets, leading to a mild reduction in basal Ca2+ current and a significant decrease following liraglutide treatment. RIIβ-knockout beta cells also exhibited reduced insulin granule size, decreased total granule number and fewer granules docked at the plasma membrane. Our results highlight type IIB PKA as a primary mediator of Gs-coupled receptor-potentiated insulin secretion, providing a new molecular framework for metabolic regulation research.
Impairments in peripheral glucose metabolism and reduced brain insulin sensitivity are linked to an increased risk of both metabolic and neurodegenerative diseases. Brain insulin resistance represents a shared pathological mechanism underlying these disorders. Notably, hippocampal insulin responsiveness declines with age and differs between men and women. This study aimed to identify clinically relevant metabolic predictors of hippocampal insulin sensitivity in the context of age and sex. In 260 non-diabetic participants (165 women, mean BMI 29.7 ± 6.2 kg/m2, mean age 44.2 ± 16.6 years), functional MRI was performed before and after intranasal insulin administration to assess hippocampal insulin response. Metabolic phenotyping comprised laboratory assessments including oral glucose tolerance tests, whole-body MRI and 1H-MRS. In addition, participants were assigned to high- and low-risk prediabetes clusters using the Tübingen risk cluster tool. Prediabetes was defined as impaired fasting glucose and/or impaired glucose tolerance and/or elevated HbA1c. We used linear regression models to select the most relevant predictors, including interactions with sex and age. Fasting plasma glucose levels predicted lower hippocampal insulin response with age independently of sex (estimate 0.533, p=0.016). Significant interactions were present between age, sex and body fat distribution (waist-to-hip ratio [WHR]: estimate 0.233, p=0.010; visceral adipose tissue [VAT]: estimate 0.007, p=0.013; intrahepatic lipid content [IHL]: estimate 0.003, p=0.010). In women, higher WHR, VAT and IHL were predictors of lower hippocampal insulin responsiveness with increasing age. These effects remained significant after adjusting for BMI. Postmenopausal women showed lower hippocampal insulin responsiveness with higher WHR and IHL (p<0.05), and women in high-risk Tübingen prediabetes clusters also showed lower hippocampal insulin responsiveness than men (sex × cluster type: estimate 0.39, p=0.02). The hippocampal insulin response did not correlate with hippocampal volume (p>0.05). Unhealthy body fat distribution was a sex-dependent predictor for decreased hippocampal insulin sensitivity with increasing age. Older women with high abdominal fat and/or those assigned to high-risk clusters were most vulnerable to impaired insulin responsiveness in the hippocampus. These findings may contribute to explaining sex differences in the development of type 2 diabetes and neurodegenerative diseases.
Diabetic nephropathy is a leading cause of end-stage renal disease, with podocyte loss being a critical event in its progression. However, the dominant molecular mechanism driving podocyte loss remains elusive, hindering targeted therapy. We aimed to identify the key pathways of podocyte failure in human diabetic nephropathy and investigate metformin's therapeutic potential. We employed an integrative multi-omics approach, including single-nucleus RNA-seq (snRNA-seq) of 156,043 human kidney nuclei from individuals with diabetic nephropathy and healthy control individuals, db/db mouse models of diabetic nephropathy, spatial metabolomics, in vitro podocyte cultures, and targeted urinary metabolomics in individuals with diabetic nephropathy and healthy control individuals. snRNA-seq identified ferroptosis and fatty acid metabolic dysregulation as the most enriched pathways within podocytes, mechanistically linked to the MAPK14-solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) axis. In murine diabetic nephropathy models and in vitro, metformin directly inhibited this MAPK14-SLC7A11-GPX4 axis, suppressed podocyte ferroptosis (including restoration of GPX4 and SLC7A11 expression and reduction of p-p38 and lipid peroxidation) and restored compartment-specific renal lipid accumulation as shown by spatial metabolomics. Clinically, we identified and validated a urinary fatty acid signature, with palmitoylcarnitine as a key biomarker (AUC 0.974, calculated from receiver operating characteristic curves), correlating with disease indices including blood glucose, eGFR, serum creatinine and blood urea nitrogen. Our study reveals podocyte ferroptosis to be a central pathogenic event in human diabetic nephropathy, repositioning metformin as a direct ferroptosis inhibitor that preserves podocyte integrity via the MAPK14-SLC7A11-GPX4 axis. Furthermore, we provide a high-performance urinary biomarker, offering a direct translational link toward targeted anti-ferroptosis therapies and non-invasive diagnostics for diabetic nephropathy.
Growing interest in precision diagnostics has stimulated efforts to classify type 2 diabetes into more granular subtypes. Recent research has focused on four pathophysiology-based subtypes: severe insulin-deficient diabetes (SIDD); severe insulin-resistant diabetes (SIRD); moderate obesity-related diabetes (MOD); and moderate age-related diabetes (MARD). While these subtypes provide an attractive framework for precision medicine, they also come with methodological challenges. This narrative review highlights three key issues: (1) uncertainty about the existence of four discrete subtypes; (2) low certainty in subtype assignment; and (3) limited evidence for prognostic and therapeutic value compared with other approaches. As an alternative to subtyping, we discuss individualised prediction models, which provide personalised treatment recommendations based on routine clinical features. These models avoid some of the limitations of discrete subtyping but they do not provide insights into a person's underlying pathophysiology. Thus, these two approaches can be viewed as complementary, each serving a different purpose in precision medicine.
Cardiometabolic residual risk in type 2 diabetes mellitus (T2D) persists despite major advances in glucose-lowering therapy, lipid management, blood pressure control, weight reduction, and organ-protective strategies. This residual burden should not be interpreted solely as the consequence of incomplete achievement of conventional therapeutic targets, but rather as the clinical expression of persistent molecular activity involving multiple interconnected organs and pathways. Insulin resistance, metaflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, endothelial impairment, hepatic metabolic dysregulation, renal inflammation, fibrotic remodeling, and metabolic memory interact within a dynamic network linking adipose tissue, liver, kidney, immune cells, and vasculature. In this review, we discuss the biochemical and molecular drivers of cardiometabolic residual risk in T2D, with particular emphasis on impaired insulin receptor substrate/PI3K/Akt signaling, stress-kinase activation, NLRP3 inflammasome priming and assembly, MASLD-related lipotoxicity and fibrogenesis, podocyte and tubular injury, endothelial nitric oxide synthase uncoupling, AGE-RAGE signaling, and thrombo-inflammatory vascular injury. These pathways explain why biological vulnerability may persist even when conventional clinical parameters appear adequately controlled. We also examine the role of translational biomarkers and simple clinical indices, including TyG-derived indices, adiposity markers, hepatic steatosis and fibrosis scores, albuminuria, eGFR, and lipid-related markers, as accessible windows into active biological pathways. Finally, we review how contemporary therapeutic strategies may modulate selected components of this residual-risk network. A pathway-centered interpretation of T2D may support more precise residual-risk phenotyping and help move cardiometabolic care beyond isolated target control toward mechanism-based prevention. This review further links these mechanisms to the contemporary cardiovascular-kidney-metabolic (CKM) framework, as defined by the 2026 AHA/ACC/ADA/ASN CKM Guideline, and disaggregates the underlying molecular network into organ-specific pathway cascades that make the causal relationships between metabolic, inflammatory, hepatic, renal, and vascular injury more explicit.
The breastmilk microbiome plays a crucial role in gut microbial colonisation and immune development, but little is known about how it is influenced by type 1 diabetes. We conducted a longitudinal 16S rRNA gene sequencing study of milk from women with type 1 diabetes (n=69 pregnancies; 174 samples) and women who did not have type 1 diabetes (n=49 pregnancies; 123 samples), collected at seven timepoints from birth to 15 months postpartum. Alpha diversity (richness, inverse Simpson evenness) was analysed by generalised linear mixed models, beta diversity was analysed by Bray-Curtis dissimilarities and PERMANOVA, and differential abundance was analysed by limma. Additionally, we examined associations with maternal genetic risk score (GRS), maternal HLA type, glycaemic management (HbA1c) and breastmilk secretory IgA (sIgA), and performed a parallel analysis for the infant stool microbiome. A significant interaction between type 1 diabetes status and timepoint was observed for alpha diversity, both richness (p=0.01) and inverse Simpson diversity (p=0.003), indicating distinct temporal trajectories between women with and without type 1 diabetes. In those without type 1 diabetes, richness increased significantly between birth and 1 week postpartum, but this early increase was delayed in women with type 1 diabetes to between 1 week and 3 months postpartum (p=0.002). Beta diversity analysis revealed earlier and more extensive compositional shifts in women without type 1 diabetes compared to those with type 1 diabetes. These differences persisted after adjusting for Caesarean delivery, BMI, parity and infant sex, and were not attributable to a delay in initiating breastfeeding. Taxa with delayed enrichment in women with type 1 diabetes included Streptococcus spp. and Rothia mucilaginosa, which metabolise human milk oligosaccharides to short-chain fatty acids to promote development of the infant's gut barrier and immune system. Maternal GRS, HLA, HbA1c or sIgA were not associated with milk microbiota diversity trajectories. In infant stool samples, alpha diversity did not differ between exposure groups, and showed no evidence of delayed maturation. Beta diversity revealed an early compositional shift between birth and 1 week postpartum only in infants born to women without type 1 diabetes. Similarly, significant taxonomic changes between birth and 1 week postpartum were detected only in infants born to women without type 1 diabetes, but with some taxa differing between exposure groups at 1 week. Maternal type 1 diabetes is associated with delayed early maturation of the breastmilk microbiome. Early compositional differences in microbiota restructuring were also observed in the infant gut, partially mirroring the pattern in the milk microbiome; however, sustained differences in infant gut microbiota diversity were not detected. Further investigation could determine whether these changes affect development of the infant's gut and immune system.
The temporal evolution of body composition surrounding type 2 diabetes diagnosis is unclear. To clarify this process, we characterised and compared the trajectories of BMI, boplledy roundness index (BRI) and handgrip strength (HGS) in the years preceding and following the diagnosis. We analysed data from participants aged ≥50 years from the Health and Retirement Study (HRS, waves 7-14), the English Longitudinal Study of Ageing (ELSA, waves 2-6), and the Survey of Health, Ageing and Retirement in Europe (SHARE, waves 2-9). Incident diabetes cases were matched 1:4 with control participants based on age, sex and education level, with the timeline centred on the year of diagnosis. Linear mixed-effects models (LMMs) allowing for non-linear trends were employed to estimate the trajectories of BMI, BRI and HGS, and to assess the temporal evolution of differences between cases and controls. The analysis included 74,790 participants for BMI, 19,895 for BRI, and 69,560 for HGS. Over a follow-up period of up to 14 years surrounding diagnosis, BMI trajectories exhibited a distinct inverted U shape, peaking approximately 2-4 years prior to diagnosis. BRI showed an overall upward trend, but its growth in cases was accelerated during weight gain and attenuated during weight loss relative to controls. HGS declined universally; although the rates of decline were similar between groups in HRS and ELSA, cases in the SHARE cohort experienced a significantly accelerated decline compared with controls. When evaluated through multidimensional surrogate indicators, the trajectory of type 2 diabetes involves patterns that are indicative of a rise then a fall in total body mass, persistent visceral accumulation (albeit attenuated during weight loss), and probably accelerated muscle depletion. The dynamic evolution of these proxy metrics provides novel insights for capturing the full picture of body composition remodelling.
The Automated Insulin Delivery among Pregnant women with Type 1 diabetes (AiDAPT) trial demonstrated that using the CamAPS FX automated insulin delivery (AID) was associated with improved glycaemic outcomes. This study aimed to assess the clinical and economic impact of improving third-trimester HbA1c. Using the AiDAPT data, a health economics model was built to estimate clinical outcomes and healthcare resource utilisation associated with third-trimester HbA1c categories (<42 mmol/mol, 42-53 mmol/mol, ≥53 mmol/mol). AiDAPT HbA1c distribution and associated clinical outcomes (obstetric: pre-eclampsia, delivery method; neonatal: length of stay in normal/critical/intensive care) were used to estimate perinatal complications. UK-specific healthcare costs were extracted from the NHS National Schedule and other published sources. Total costs to the UK healthcare system were estimated using an incremental 3.3 mmol/mol (0.3%) HbA1c reduction observed with CamAPS FX AID over Standard Care in AIDAPT. In the model, HbA1c improvement with CamAPS FX AID was associated with projected reductions in pre-eclampsia risk (-13%), high dependency neonatal care days (-16%), neonatal intensive care unit days (-12%) and clinic visits. The model projected cost reduction for the NHS healthcare system of £6,696,636 under conservative modelling assumptions, being cost saving at 96.8% of the simulations. The projected incremental cost difference per woman treated with CamAPS FX AID was -£1016, mainly derived from a modelled shift in the distribution of neonatal care, with reduced length of stay in high dependency neonatal intensive care. CamAPS FX AID improves third-trimester HbA1c with projected cost reductions for the UK healthcare system.
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Hybrid closed-loop insulin delivery systems are increasingly regarded as the preferred therapy for type 1 diabetes, although evidence in older adults remains limited. The aim of this randomised study was to evaluate the effectiveness and safety of the MiniMed 780G system in individuals with type 1 diabetes aged ≥65 years, with HbA1c<86 mmol/mol (10%), who were naive to this technology, with the primary endpoint based on glycaemic management (time in range). Vascular status and other glycaemic metrics were assessed as secondary outcomes. This single-centre, open labelled (outcome assessors were not masked), randomised, controlled, parallel-group trial enrolled 34 participants who were randomly assigned in a 1:1 ratio using a computer-generated randomisation schedule to either advanced hybrid closed-loop (AHCL) therapy or control therapy (multiple daily injections or continuous subcutaneous insulin infusion) and followed for 12 months. Twenty-nine participants completed the study. Baseline characteristics, including glycaemic metrics, were comparable across groups (p>0.05). The AHCL group demonstrated a rapid and sustained improvement in glycaemic management, with time in range increasing from 57.4% at baseline to 79.7% at 12 months (p<0.001), accompanied by reductions in hyperglycaemia as reflected by time above range and time above range 2 (nominal p<0.001; p<0.001), and with no increase in hypoglycaemia across time below range and time below range 2 (nominal p=0.463; p=1). Adjusted between-group differences favoured AHCL for time in range (15.7% [95% CI 8.6, 22.6]) and HbA1c (-5 mmol/mol; [95% CI -9.7, -0.4 mmol/mol] [-0.46%; -0.89%, -0.04%]). No serious adverse events or episodes of diabetic ketoacidosis or severe hypoglycaemia occurred. Post-occlusive reactive hyperaemia showed a shortening of time to maximal flow in the AHCL group, indicating a favourable numerical trend towards improved microvascular function (nominal p>0.05). Retinal vascular status assessed using artificial intelligence remained stable throughout follow-up in both eyes (nominal p=0.710 and p=0.563, respectively). The MiniMed 780G system appears effective for glycaemic management and safe for use in older adults with long-standing type 1 diabetes and a high burden of comorbidities. A non-statistically significant numerical tendency (p>0.05) in the improvement of vascular function that requires further confirmation was also observed. ClinicalTrials.gov NCT06207838.
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.
Metabolic dysfunction-associated steatotic liver disease (MASLD) includes a spectrum of progressive liver conditions ranging from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis and cirrhosis. Currently, MASLD is the leading cause of chronic liver disease worldwide. MASLD is strongly associated with type 2 diabetes, cardiovascular disease, chronic kidney disease and certain extrahepatic cancers. MASLD shares a common pathogenesis with cardiometabolic diseases, especially type 2 diabetes, primarily driven by unhealthy dietary habits, dysfunctional adipose tissue, insulin resistance and low-grade inflammation. Substantial heterogeneity in the pathophysiology of MASLD may influence its rate of progression, its relationship with cardiometabolic diseases and its treatment response. In addition to lifestyle interventions, including a healthy low-energy diet and increased physical activity levels, pharmacological treatment of MASLD/MASH is recommended. For individuals with type 2 diabetes and MASLD/MASH, treatment should preferably include glucagon-like peptide-1 (GLP-1) receptor agonist-based therapies and sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have been shown to improve MASLD/MASH and provide established cardiorenal benefits. In this narrative review, we assess the efficacy of these pharmacotherapies and discuss other treatment approaches for MASLD/MASH, with a focus on their metabolic benefits.
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% CIs, adjusting for birth year, birth state, race/ethnicity, age and BMI at cohort entry. Stratified analyses evaluated effect modification by menopausal status, BMI and history of gestational diabetes mellitus. During a mean follow-up duration of 10.8 years, 99,978 women were diagnosed with endometriosis. Endometriosis was associated with a 46% higher risk of type 2 diabetes compared with no endometriosis (aHR 1.46; 95% CI 1.43, 1.50). Risk varied by subtype, with the strongest associations observed for 'other site' endometriosis (specified site: aHR 2.67; 95% CI 2.51, 2.84; unspecified site: aHR 2.47; 95% CI 2.35, 2.60). Associations were stronger among premenopausal women than postmenopausal women (aHR 1.55; 95% CI 1.50, 1.60) and those with BMI <30 kg/m2 than those in higher BMI categories (aHR 2.39; 95% CI 2.34, 2.44), and were present regardless of history of gestational diabetes mellitus. Endometriosis was associated with increased type 2 diabetes risk, with substantial heterogeneity by subtype and metabolic context. Associations were strongest among individuals who are traditionally considered at lower baseline risk, although these findings should be interpreted cautiously given the potential for residual confounding and detection bias.