Diabetes Care

Background Glycated haemoglobin (HbA1c) underpins type 2 diabetes (T2D) and prediabetes management worldwide and reflects both glycaemia and erythrocyte biology. A missense variant in PIEZO1 (rs563555492T), carried by 1 in 12 South Asians, has been associated with a nonglycaemic reduction in HbA1c. We aimed to further characterise this association and evaluate its clinical consequences. Methods We undertook genetic and linked health data analyses across two cohorts: 19,898 (37.4% female) South Indians from the Madras Diabetes Research Foundation (MDRF) and 43,011 (54.4% female) British Bangladeshis and British Pakistanis in Genes & Health. In MDRF, we tested associations with glycaemic and erythrocytic traits using additive genetic models. In Genes & Health we modelled diagnosis of prediabetes, T2D, and diabetic eye disease using flexible parametric survival models. Ten-year absolute risks were estimated for a population aged 40-50 years. Findings PIEZO1 rs563555492T was associated with erythrocytic traits and lower HbA1c, but not with fasting glucose, postprandial glucose, or C-peptide. This variant reduced risk of prediabetes (HR 0.63, 95% CI 0.58-0.69) and T2D (0.85, 0.78-0.93) diagnosis, and increased risk of diabetic eye disease among individuals with T2D (1.20, 1.01-1.43). Modelling suggested approximately 1,019 missed prediabetes and 303 missed T2D diagnoses per 100,000 adults over 10 years. Interpretation An ancestry-enriched PIEZO1 variant is associated with lower HbA1c independent of glycaemia, reduced prediabetes and T2D diagnosis suggesting delayed detection, and increased complication risk. Reliance on HbA1c may systematically underestimate glycaemic risk in a substantial minority of South Asians. Funding The Wellcome Trust; NIHR

Aims Type 2 diabetes mellitus (T2DM) increases risks of stroke and dementia, yet these risks vary across individuals. We hypothesized that clinically derived diabetes subtypes contribute to this heterogeneity. We aimed to identify data-driven subtypes using routine clinical features and examine their associations with dementia, stroke, mortality, and brain structure. Methods K-means clustering was applied to 14,353 UK Biobank participants with prevalent T2DM using age at diagnosis, body mass index, glycated hemoglobin, insulin resistance (triglyceride/HDL ratio), systolic blood pressure, and C-reactive protein. Cox models assessed associations with incident dementia (all-cause, Alzheimers disease [AD], vascular dementia [VaD]), stroke (all-cause, ischemic [IS], intracerebral hemorrhage [ICH]), and mortality. Brain MRI outcomes were analyzed in 779 participants using inverse probability-weighted linear regression. Results Three subtypes were identified: severe obesity-related inflammatory diabetes (SOID), mild metabolic diabetes (MMD, reference), and mild age-related hypertension-predominant diabetes (MARD-H). Compared with MMD, SOID showed higher risks of dementia (HR 1.24), VaD (HR 1.42), stroke (HR 1.38), IS (HR 1.48), all-cause mortality (HR 1.59), and cardiovascular death (HR 1.88). MRI showed lower gray matter volume and greater white matter hyperintensity burden in SOID. Conclusions Data-driven subtyping revealed heterogeneity in neurological risk in T2DM, with the obesity-inflammation subtype showing elevated vascular and neuroimaging risk.

Background: The glucagon-like peptide-1 receptor (GLP1R) is a key regulator of glucose metabolism and appetite and a major therapeutic target for type 2 diabetes (T2D) and obesity. Genetic studies have implicated the GLP1R locus in both body mass index (BMI) and T2D, but it remains unclear whether their underlying genetic associations are the same. Methods: We analyzed 431,107 participants of genetically inferred European ancestry from the Million Veteran Program. Within 500 kb of GLP1R, we performed locus-wide linear regression models for BMI and logistic regression models for T2D, adjusted for age, sex, and 10 principal components. We identified primary and secondary BMI sentinel variants using conditional analyses and evaluated their associations with T2D. Bayesian fine-mapping was used to construct credible sets of GLP1R locus for BMI and T2D. Results: Conditioning on the primary sentinel variant rs12213929 (upstream of GLP1R, {beta} = 0.11; 95% CI 0.09-0.14; p = 1.94E-17), we identified a secondary variant (rs13216992, intron of GLP1R) independently associated with BMI ({beta} = 0.10; 95% CI 0.07-0.13; p = 7.88E-14). The two sentinel variants showed low linkage disequilibrium (r2 = 0.03). A two-variant allelic burden score (0-4; sum of the rs12213929 G-allele count and rs13216992 C-allele count) showed that participants with 4 risk alleles had 0.47 kg/m2 higher BMI than those with 0 risk alleles (95% CI 0.39-0.55; p < 2E-16). Both variants were associated with higher T2D risk, but with distinct patterns after BMI adjustment: the rs12213929-T2D association persisted after adjustment for BMI (OR = 1.02; 95% CI 1.01-1.03; p = 0.0004), whereas the rs13216992-T2D association was fully attenuated (OR = 1.00; 95% CI 0.99-1.01; p = 0.68). Fine-mapping identified a compact 95% BMI credible set of 17 variants and a broader 95% T2D credible set of 42 variants, with all BMI credible variants contained within the T2D set. Conclusions: The GLP1R locus harbors at least two independent BMI-associated variants that exhibit heterogeneous relationships with T2D: rs12213929 influences T2D risk partly through BMI-independent pathways, whereas rs13216992 appears to act predominantly via adiposity. These findings refine the genetic architecture at this key therapeutic target gene and provide a foundation for functional and pharmacogenomic studies to determine whether GLP1R variation can inform precision prevention and treatment of obesity and T2D.

Importance Women have been under-represented in clinical trials of type 2 diabetes mellitus (T2D), and evidence on sex differences in effectiveness of T2D treatments remains limited. Objective To assess sex differences in comparative effectiveness and safety of four second-line antidiabetic agents: glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), and sulfonylureas (SU). Design Retrospective cohort study using an active-comparator new-user design, following each participant till treatment discontinuation or end of data. Setting Multinational study across ten real-world databases from the Observational Health Data Sciences and Informatics (OHDSI) network in the United States, United Kingdom, Germany, and Spain. Participants 5.15 million adults with T2D who initiated one of the four second-line therapies following metformin during 1992-2021. Exposures GLP-1RA, SGLT2i, DPP4i, or SU. Main Outcomes and Measures Cardiovascular effectiveness as measured through 7 outcomes (major adverse cardiovascular events and glycemic control) and safety through 18 outcomes as highlighted by ADA guideline. Hazard ratios (HRs) are estimated separately for women and men using propensity score-stratified Cox models with empirical calibration. Sex differences were tested using Z-tests on log-HR differences. Results Drug initiation rates differed by sex with 9.28% of women initiating on GLP-1RA, 11.91% SGLT2i, 27.81% DPP4i, and 50.99% SU; the rates among the men were 5.41%, 12.84%, 24.64%, and 57.10%. No significant sex differences were observed for cardiovascular effectiveness outcomes. Several safety outcomes showed significant sex differences that are consistent across drug comparisons. Focusing on GLP-1RA compared to SGLT2i for brevity, GLP-1RA users experienced the following comparative benefits and risks: higher risk of acute pancreatitis among women (HR 1.39 [1.13, 1.70]) while non-differential risk among men (HR 0.91 [0.74, 1.12]) with p = 0.005 for the test of difference; non-differential risk of hypotension among women (HR 1.08 [0.98, 1.19]) while lower risk among men (HR 0.87 [0.78, 0.96]) with p = 0.003. Where no sex differences were found, our findings were consistent with existing evidence. Conclusions and Relevance This large-scale multinational study on antidiabetic agents identified clinically relevant sex differences, which are biologically plausible but previously lacked clinical evidence. Our findings reinforce the importance of tailoring T2D management according to sex.

Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene, characterized by early-onset diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration. The condition selectively affects pancreatic {beta} cells and neurons via chronic endoplasmic reticulum (ER) stress, and no proven disease-modifying therapy currently exists. Diabetes mellitus is typically the first manifestation, presenting at a mean age of 6 years as an insulin-dependent phenotype with preserved C-peptide and negative diabetes-related autoantibodies. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well-established agents in the management of type 2 diabetes, augmenting glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting satiety. Preclinical evidence further suggests that GLP-1 RAs preserve {beta}-cell mass, attenuate ER stress, and confer neuroprotective effects, properties of particular therapeutic relevance to Wolfram syndrome. We conducted a retrospective cohort study of 84 participants with genetically confirmed Wolfram syndrome and insulin-dependent diabetes mellitus enrolled in the Washington University Wolfram Syndrome International Registry and Clinical Study. Clinical data were extracted from medical records; for participants concurrently enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study, longitudinal data were obtained from that source as well. Thirty-five percent of eligible participants had received a GLP-1 RA at some point during follow-up. We characterize the prevalence of GLP-1 RA use, documented rationale for initiation, observed effects on glycemic control and visual outcomes, adverse effects, and reasons for discontinuation. No statistically significant changes in hemoglobin A1c (HbA1c) or body mass index (BMI) were observed. Visual acuity declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common and contributed to frequent discontinuation. These observational data provide important clinical context and a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.

(1) Aims and hypothesisLoss-of-function mutations in SLC30A8, encoding the zinc ion (Zn2+) transporter ZnT8 in pancreatic beta cells, lower type 2 diabetes risk dose-dependently, but the underlying mechanisms remain unclear. Here, we combine proteomic, transcriptomic and functional approaches in human stem cell-derived islet-like clusters bearing common alleles or the inactivating variant R138X. We hypothesized that this variant protects against the deleterious effect of Zn2+ depletion on cell survival and function. (2) MethodsHuman embryonic stem cells INS(GFP/w) (MEL1), and CRISPR/Cas9-derived heterozygous or homozygous R138X lines were differentiated into stem cell-derived islet-like clusters. Intracellular Zn2+ levels were reduced using the chelator N,N,N',N'-tetrakis(2-pyridylmethyl)-1,2-ethanediamine (TPEN). Apoptosis was assessed by TUNEL staining and protein expression by immunofluorescence. Glucose-stimulated calcium (Ca2+) dynamics were measured using the intracellular probe (Cal590) and insulin secretion by homogenous time-resolved fluorescence. Transcriptomic profiling was performed by bulk mRNA sequencing and proteomics by liquid chromatography-tandem mass spectrometry. (3) ResultsIntracellular Zn2+ depletion increased apoptosis in wild-type islet-like clusters, whereas R138X clusters were protected. R138X heterozygous clusters showed a mild increase in GCG+ cells and R138X homozygous clusters exhibited increased NKX6.1+ cells, without affecting polyhormonal populations. These changes were reversed under Zn2+ depletion. Transcriptomic and proteomic analyses, assessing genotype effects while accounting for Zn2+ depletion, showed that R138X clusters (versus wild-type) exhibited upregulation of genes and proteins involved in vesicle trafficking, secretion, Ca{superscript 2} signaling and mitochondrial metabolism, consistent with enhanced glucose-stimulated insulin secretion in homozygous clusters. Conversely, genes and proteins associated with extracellular matrix remodeling, metal-ion handling, apoptosis and cellular stress were downregulated. R138X clusters displayed altered Ca2+ signaling, with decreased area under the curve and oscillation amplitude, but increased frequency. These differences were reversed by TPEN, while Zn2+ depletion impaired Ca2+ response in wild-type clusters. Despite lowered overall activity, R138X homozygous clusters showed enhanced overall cell-cell connectivity, reversed by TPEN treatment. The opposite effects were observed in R138X heterozygous clusters, showing improved connectivity and activity under Zn2+ depletion. (4) Conclusion and interpretationIntracellular Zn2+ depletion compromises islet-like cluster identity and function, while the R138X variant confers protection against these effects. Under Zn2+-depleted conditions, ZnT8 deficiency promotes a more mature and metabolically active state of the R138X clusters, with enhanced Ca2+ signaling and insulin secretion, supported by a structural remodeling and the downregulation of apoptosis and cellular stress. These findings highlight the therapeutic potential of targeting ZnT8 in type 2 diabetes and support its relevance for further improving cell-based therapies. Research in ContextO_ST_ABSWhat is already know about this subject?C_ST_ABSO_LIRare inactivating mutations in the insulin granule-associated zinc transporter gene, SLC30A8/ZnT8, drive lowered type 2 diabetes risk. C_LIO_LIPrevious studies have indicated that apoptosis is lowered, and glucose-stimulated insulin secretion enhanced, after ZnT8 inactivation. C_LIO_LIThe molecular mechanisms underlying these changes are unclear. C_LI What is the key question?O_LIHow do inactivating mutations in SL30A8/ZnT8 lead to lowered apoptosis and enhanced insulin secretion from stem cell-derived islet-like clusters, and is altered susceptibility to intracellular zinc depletion involved? C_LI What are the new findings?O_LIThe rare inactivating R138X mutation in SLC30A8 leads to gene dose-dependent changes in the transcriptome and proteome of islet-like clusters. C_LIO_LIChanges include upregulation of maturity and downregulation of immaturity genes. C_LIO_LIDepletion of intracellular Zn2+ exaggerates the protective effects of the inactivating mutation on apoptosis and insulin secretion C_LI How might this impact on clinical practice in the foreseeable future?O_LIOur findings suggest that careful monitoring of both dietary zinc intake and of circulating levels of zinc ions, whose effects are mitigated in SLC30A8 mutation carriers, may be helpful in some populations to lower diabetes risk. C_LI

Variant databases ClinVar and gnomAD are the backbone of clinical variant interpretation, but their population composition is skewed toward European ancestry. Whether this skew creates systematic classification disadvantages for non-European patients with monogenic diabetes has not been examined at the database level. ClinVar variant_summary (GRCh38, April 2026; 4,421,188 variants) was cross-referenced with gnomAD v4.0 genome data for 17 monogenic diabetes genes. Annotation coverage and variant classification rates were computed stratified by genetic ancestry group (AFR, AMR, EAS, SAS, MID, NFE, FIN, ASJ). Of 14,691 gnomAD variants across the 17 genes, only 29.7% had any ClinVar classification (range: 12.7%-61.3% by gene). Among classified variants, non-Finnish European (NFE) variants had the highest variant of uncertain significance (VUS) rate (32.1%) and the lowest benign/likely benign fraction (41.6%), consistent with a large submission volume without functional follow-up. African-ancestry (AFR) variants showed the second-highest VUS rate (29.2%), not statistically distinguishable from NFE after Bonferroni correction, while all other non-European groups had significantly lower rates (all p < 0.001). GCK showed a pattern inversion - non-European VUS rate (18.5%) exceeding European (15.0%) - consistent with progressive reclassification in European populations absent in non-European cohorts. Annotation coverage and VUS divergence were uncorrelated (r = -0.15, p = 0.57). The primary equity problem is a 70% annotation gap combined with a non-European curation deficit, not a simple VUS excess. Ancestry-stratified evaluation of ClinGen Variant Curation Expert Panel (VCEP) criteria performance is warranted across disease domains.

Background and aims: Direct evidence to connect early life metabolism with cardiometabolic diseases in old age is limited due to the rarity of multi-decadal biochemical follow-up studies. To gain deeper insight into metabolic ageing, we conducted a longitudinal study that integrates serial data on clinical biomarkers, metabolomics and clinical events across the human life course. Methods: Children born in 1962-1992 were included from four European cohorts. Time-series of clinical biomarkers and metabolomics data were available for 8,653 participants (ages 0-49 years, 142 molecular and four physiological variables). Comparable data for 13,795 UK Biobank participants at two visits (ages 40-79 years) were linked with retrospective and prospective records of diabetes and cardiovascular disease. Lifetime metabolic trajectories were reconstructed by unsupervised machine learning and local polynomial regression. Results: A stable stratification in metabolic health emerged in children between ages 3 and 12 years and persisted to old age. We summarized this population pattern by assigning each participant into one of seven metabolic subgroups with characteristic biomarker trajectories. Two subgroups (MetDys TG+ and MetDys TG-) featured increased waist-height ratio from childhood, persistently higher C-reactive protein throughout life and rapidly increasing fasting insulin between 30 and 49 years of age. Both subgroups exhibited high risk for diabetes (HR > 13) and ischemic heart disease (HR > 2.5) when compared against the lowest risk subgroup (High HDL ApoB-). Conclusions: This life-course analysis shows that metabolic dysfunction associated with excess weight gain begins in early childhood and is associated with cardiometabolic morbidity in later life.

Abstract Context Lipoprotein(a) [Lp(a)] is a genetically determined and independent cardiovascular risk factor, traditionally considered stable across the lifespan, supporting a single lifetime measurement strategy. However, its longitudinal behavior during childhood and adolescence remains poorly characterized, particularly in individuals with type 1 diabetes who are at increased lifetime risk of cardiovascular disease. Objective We aimed to characterize intra- and inter-individual trajectories of Lp(a) in youth with type 1 diabetes and to assess the implications of variability for cardiovascular risk classification. Methods We conducted a retrospective single-center cohort study of children and adolescents with type 1 diabetes followed at Geneva University Hospitals between 2012 and 2023. Annual fasting Lp(a) concentrations were analyzed longitudinally. Variability was assessed in participants with more than two measurements. Clinically relevant thresholds were used to evaluate risk reclassification. Statistical analyses included paired Wilcoxon tests, Pearson and Kendall correlations, and Holm-adjusted p-values. Results A total of 287 participants contributed 1,408 Lp(a) measurements over a median follow-up of 6.2 years (IQR 2.9-9.6). At baseline, 26% had elevated Lp(a) (above or equal 300 mg/L). Among participants with serial measurements, 32% exhibited intraindividual fluctuations exceeding 50% of their maximum value. Reclassification across the 300 mg/L threshold occurred in 11.9% of participants. Lp(a) concentrations peaked between ages 10 and 13 years and declined thereafter. Modest seasonal variation was observed, with higher levels in autumn and winter (P < 0.05). Conclusions In youth with type 1 diabetes, Lp(a) demonstrates clinically relevant intraindividual variability over time. These findings suggest that reliance on a single lifetime measurement may lead to misclassification of cardiovascular risk and support repeated assessment, particularly during adolescence, to improve risk stratification.

Background: Older in-patients have a higher prevalence of diabetes and cognitive impairment. Cognitive impairment can make blood glucose management more challenging, since patients might not remember to measure blood glucose or report symptoms. Investigating the accuracy of continuous glucose monitoring (CGM) compared to usual care will inform clinical interpretations in this vulnerable population. Aim: To compare CGM derived glucose metrics and point-of-care tests (POCT) in older in-patients with T2DM and cognitive impairment and to investigate CGM accuracy compared to POCT in the hospital settings with the same population. Methods: Thirty-two older people with comorbid T2DM and cognitive impairment were recruited within a tertiary care hospital in the UK. All participants were naive to CGM and were asked to wear blinded Dexcom G7 sensors for up to 10 days. All participants received usual care in their hospital stay including the use of POCT. Key accuracy metrics comprised the mean absolute relative difference (MARD), median absolute relative difference (median ARD), and Clarke Error Grid (CEG), correlation (R2) analysis. In addition, the percentage of CGM readings falling within +/-20% of reference glucose values when the reference was >5.6 mmol/L, or within +/-1.1 mmol/L when the reference was <=5.6 mmol/L (+/-20%/1.1 mmol/L) was calculated to assess analytical and clinical accuracy. Results: Thirty participants completed the study. CGM derived mean glucose for time in range (TIR= 4-10 mmol/mol) was 36.23% (min= 0%, max= 90%), time above range (TAR >= 10 mmol/mol) was 62.87% and time below range (TBR <= 3.9 mmol/mol) was 1.03%. Mean TIR based on available POCT readings was 40.84%, TAR was 57.24% and TBR 1.81%, showing similar readings as CGM derived glucose metrics. Comparison of the two resulted in a MARD of 17.4%, and median ARD of 12.2% and the outcome of +/-20%/1.1 mmol/L analysis was 72.3%. CEG analysis revealed that 99.3% of the data points fell within the clinically acceptable zones (Zone A and Zone B), and there was a strong correlation (R2=0.82) between CGM and POCT. CGM captured more hypoglycaemic readings in our participants. Conclusion: Our study suggests that CGM and POCT derived glucose metrics are largely similar for in-patients with diabetes and cognitive impairment. CGM remains as a safe and clinically acceptable tool, and able to capture more nocturnal hypoglycaemia compared to POCT in a subgroup of patients. These initial findings show that CGM might be a viable alternative for people with comorbid T2DM and cognitive impairment.

Aims The oral glucose tolerance test (OGTT) is effective for detecting post-load dysglycemia, but it is burdensome and therefore not routinely used. Continuous glucose monitoring (CGM) offers a convenient way to capture real-world glucose patterns, yet it remains unclear whether CGM-derived metrics reflect OGTT-defined dysglycemia. We therefore aimed to evaluate CGM-derived and clinical metrics for predicting OGTT 2-hour glucose, classifying OGTT-defined dysglycemia, and assessing day-to-day repeatability. Methods We analyzed a cohort with paired free-living CGM and OGTT. Multiple CGM-derived metrics and clinical measures were compared for prediction of OGTT 2-hour glucose, classification of OGTT-defined dysglycemia, and day-to-day stability. Predictive performance was assessed primarily by leave-one-out (LOO) R^2, and day-to-day repeatability by intraclass correlation coefficients (ICC). Results The glycemic persistence index (GPI), a metric integrating the magnitude and duration of glycemic elevation, was the strongest single predictor of OGTT 2-hour glucose (LOO R^2 = 0.439). GPI also showed strong day-to-day repeatability (ICC = 0.665) and ranked first on a combined prediction-stability score. For classification of OGTT-defined dysglycemia, HbA1c had a slightly higher AUC than GPI, but GPI plus HbA1c performed best overall, indicating complementary information. Conclusions GPI was a strong predictor of OGTT 2-hour glucose and showed a favorable balance between predictive performance and day-to-day stability, supporting its potential utility as a CGM-derived marker of dysglycemia.

This updated systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and obesity related complications. Medline and Embase were searched up to 21 November 2025 for randomized controlled trials comparing OMMs versus placebo or active comparators in adults. The primary endpoint was percentage total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and 3 years, anthropometric, metabolic, mental health and quality of life outcomes, cardiovascular morbidity and mortality, remission of obesity related complications, serious adverse events and all cause mortality. Sixty six RCTs (66 comparisons) were identified: orlistat (22), semaglutide (18), liraglutide (11), tirzepatide (8), naltrexone/bupropion (5) and phentermine/topiramate (2), enrolling 63,909 patients (34,861 and 29,048 with active compound and placebo, respectively). All OMMs showed significantly greater TBWL% versus placebo; tirzepatide and semaglutide exceeded 10% TBWL and showed the most favourable glycaemic effects. Semaglutide reduced major adverse cardiovascular events and all cause mortality. In dedicated complication specific trials, semaglutide and tirzepatide showed benefit on heart failure related outcomes; tirzepatide was associated with improved obstructive sleep apnoea syndrome and semaglutide with knee osteoarthritis pain remission. Tirzepatide and semaglutide were associated with improvements in metabolic dysfunction-associated steatohepatitis remission, and semaglutide with improvement in liver fibrosis. No OMMs were associated with an increased risk of serious adverse events. These updated results reinforce the need to individualize OMMs selection according to weight loss efficacy, complication profile and safety.

Non-invasive glucose monitoring (NIGM) has been pursued for decades, yet no device has achieved regulatory approval despite numerous studies reporting high accuracy. This systematic review and meta-analysis of 32 studies (38 cohorts: 20 NIGM, 18 iCGM; N = 1,693) investigated methodological factors underlying this accuracy-regulatory gap. The pooled Mean Absolute Relative Difference (MARD) for NIGM (10.21%; 95% CI: 8.73-11.69%) showed no significant difference from iCGM (11.82%; 95% CI: 10.36-13.29%; p = 0.13), with extreme heterogeneity (I^2 = 95.2%). Meta-regression revealed that study duration was the strongest predictor of NIGM accuracy ({beta} = 3.94, p < 0.001), with MARD degrading from 8.7% in short-term to 15.2% in long-term studies, while iCGM accuracy remained stable. Only 15% of NIGM cohorts validated in the hypoglycemia range, compared to 89% of iCGM studies (p < 0.001). These findings suggest that reported NIGM accuracy is substantially influenced by methodological asymmetries.

Aims: Although metabolic dysregulation is implicated in DCM, the involvement of metabolic syndrome (MetS) remains unclear. This study aims to systematically examine MetS in DCM pathogenesis. Materials and methods: By leveraging 378,837 UK Biobank participants, instead of the conventional binary MetS, we calculated a continuous metabolic risk score (MRS) and evaluated its influence on DCM risk within a multi-model evidence framework. Bidirectional weighted quantile sum regression identified key MRS components, a nested case-control study assessed 14-year pre-diagnosis MRS trajectories, mediation analyses evaluated MRS mediating lifestyle-DCM links and inflammation mediating MRS-DCM relationships, and Mendelian randomization (MR) evaluated causality for genetically predicted MetS and components on DCM. Results: During a median follow-up period of 13.4 years (interquartile range 12.7~14.1 years), 820 (0.2%) participants developed DCM. Higher MRS (HR=1.26 [1.18~1.34]) was associated with increased DCM risk, and such an association persisted across all robustness assessments even among non-MetS individuals. Waist circumference (WC, HR=1.36 [1.28~1.45], weight=0.58) and glycated hemoglobin (HR=1.23 [1.16~1.30], weight=0.22) dominated MRS' risk contribution. The trajectories of MRS diverged in cases approximately 10 years pre-diagnosis. MRS mediated 5.1~26.2% of lifestyle-related DCM risk, while inflammation mediated 16.4% of the MRS-DCM association. MR analysis further confirmed causal effects of MetS (OR=1.65 [1.45~1.88]), WC (OR=1.79 [1.58~2.03]) on DCM risk. Conclusions: Metabolic dysfunction, which was dominated by central adiposity and hyperglycemia, plays a key role in the occurrence of DCM. Early intervention targeting metabolic factors may prevent DCM onset.

The ability to understand and affect the course of complex, multi-system diseases like diabetes has been limited by a lack of well-designed, high-quality and large multimodal datasets. The NIH Bridge2AI AI-READI project (aireadi.org) aims to address this shortfall by generating an AI-ready dataset to support AI discoveries in type 2 diabetes mellitus (T2DM). This manual of procedures provides a detailed description of the AI-READI protocol.

Background & AimsDiabetes mellitus has been associated with both intestinal barrier dysfunction and peripheral neuropathy leading to increased risk of infection. The mucus layer forms a physical barrier against pathogens and is a critical component of the intestinal barrier that may be impaired in diabetes. This study aimed to assess how diabetes impacts goblet cells (GCs), mucus layer integrity, and innervation in the colon. MethodsFluorescence microscopy was used to investigate GCs, the mucus layer, and innervation in the colon of db/db mice. Custom open-access image analysis pipelines were developed to quantify GC numbers, location and content, mucus thickness, bacterial colonization, and innervation density in intestinal tissue sections. We also treated mice with the clinically used glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide to assess its capacity to reverse pathological changes to GCs and the mucus layer in a model of established type 2 diabetes (T2DM). ResultsThe mucus layer was significantly thinner in the colon of db/db mice with established diabetes and bacteria more readily colonized the epithelium and crypts. Intercrypt GC numbers were significantly reduced in db/db mice. However, there were significantly more GCs per crypt, and crypts were elongated in the db/db colon. Innervation was reduced in the mucosa and external muscle of the colon, consistent with diabetic neuropathic changes. Liraglutide treatment increased the size of GCs but had no effect on GC numbers, mucus thickness, or innervation in this model of established T2DM. ConclusionsMucus barrier dysfunction and GC hyperplasia is evident in the db/db colon. Increased microbial penetrability through the mucus layer suggests potential implications for the increased risk of gastrointestinal infection in diabetes.

AimWe examined associations between smoking and HbA1c among U.S. adults, and whether these associations vary by diabetes status. MethodsWe analyzed NHANES data from 2015-2018 for adults aged [&ge;]20 years. Smoking was assessed by self-report and serum cotinine. Survey-weighted multivariable linear regression was used to evaluate the association between smoking and HbA1c in the full population (N=9,214) and in adults without diabetes (N=7,328), adjusting for demographics, blood pressure, waist circumference, lipids, and C-reactive protein. ResultsAfter adjustment for cardiometabolic covariates, there was no significant association between smoking and HbA1c in the full population (former: {beta}=0.029%, p=0.30; current: {beta}=0.053%, p=0.13). Among adults without diabetes, former smoking was not associated with HbA1c, whereas current smoking remained significantly associated (former: {beta}=-0.001%, p=0.923; current: {beta}=0.067%, p<0.001). These findings were similar when cotinine was used as the exposure measure, with active smoking ([&ge;]3.0 ng/mL) associated with higher HbA1c among non-diabetic adults (p<0.001), but not in the full population. ConclusionsAmong adults without diabetes, current but not former smoking was associated with higher HbA1c. The absence of an association in former smokers suggests that this effect may attenuate following cessation. These findings support early cessation interventions and may inform cessation counseling and diabetes screening.

Abstract Background: Cardiometabolic diseases arise from metabolic dysfunction that develops decades before clinical onset. Conventional genetic risk models are typically derived in middle-aged or older populations, where genetic effects are confounded by cumulative environmental exposures, chronic comorbidities, and clinical interventions. Whether the life stage at which genetic liability is modelled influences the biological signal captured by polygenic scores remains unclear, particularly in underrepresented populations. We therefore tested whether genetic liability modelled in early adulthood, a period of relative physiological stability, is associated with cardiometabolic risk across the life course in Asian populations. Methods: We developed a polygenic score for metabolic syndrome, GenMetS, using data from 1,368 Singaporean women aged 18-45 years. The model integrates 15 established polygenic scores for metabolic traits and applies elastic-net penalized regression to optimize variant weights. GenMetS was evaluated in five cohorts comprising 670,952 individuals aged 0-94 years across population-based and disease-enriched settings, including Asian and European ancestry groups. Associations with metabolic traits, cardiometabolic diseases, multimorbidity, and early-life growth patterns were assessed. Results: In Asian populations, GenMetS explained 5.0-12.4% of the variance in metabolic syndrome in adults and 10.3% in children, with negligible performance in European populations (R squared < 0.001). Higher GenMetS was associated with increased odds of cardiometabolic diseases, including type 2 diabetes, heart failure, and stroke (odds ratios 1.32-1.52 per standard deviation). In UK Biobank participants of Asian ancestry, GenMetS improved discrimination of cardiometabolic multimorbidity beyond age alone. Associations were consistent across sexes. In children, higher GenMetS was associated with obesogenic growth trajectories and increased abdominal adiposity. Conclusions: Genetic liability to metabolic dysfunction modelled in early adulthood captures a stable biological signal associated with metabolic traits, disease risk, and multimorbidity from childhood to adulthood in Asian populations. These findings indicate that the life stage of model derivation shapes the biological signal captured by polygenic scores and support the development of life-stage and ancestry-informed approaches for cardiometabolic risk assessment and prevention.

Lipodystrophies are a group of disorders featuring reduced adipose tissue mass or function, which often leads to significant metabolic disease, reduced lifespan and impaired quality of life. Individuals with congenital generalised lipodystrophy (CGL) have severely reduced adipose tissue mass. The loss of healthy systemic lipid storage typically causes hepatic steatosis and lipoatrophic diabetes. In addition, adipocyte-secreted hormones including leptin and adiponectin are dramatically reduced. Leptin has critical roles regulating appetite and broader effects on lipid and glucose metabolism. Daily injection with recombinant leptin is currently the only specific, approved treatment for CGL. The consequences of adiponectin loss in these patients are not fully understood. Likewise, the potential therapeutic benefit of adiponectin delivery is unclear. Here we examine the effect of delivering leptin or adiponectin by adeno-associated virus (AAV) as potential gene therapy treatment for metabolic disease in CGL using a well-characterised murine model of the condition. AAV-mediated leptin delivery significantly improved hepatic steatosis and hyperinsulinemia. However, adiponectin delivery did not lead to any observed beneficial effects. This demonstrates the potential of gene therapy approaches for long-term delivery of leptin in individuals with lipodystrophy, without the need for continuous supply of perishable therapeutics and painful daily injections.

Excess body weight has been associated with increased cancer risk, but the role of weight change across adulthood remains unclear. We examined body weight trajectories from ages 17 to 60 and their associations with site-specific cancer incidence. Data were based on the ODDS study, a pooled, nationwide cohort study in Sweden, with data on weight spanning 1911 to 2020, and cancer follow-up through 2023. Weight trajectories were estimated with linear mixed effects models in individuals with at least three weight measurements. Cox regressions estimated hazard ratios for associations between weight trajectories and established and potentially obesity-related cancers. Fifth versus first quintile of weight change was associated with many cancers, most strongly with esophageal adenocarcinoma in men (HR 2.25; 95% CI 1.66-3.04), liver cancer in men (HR 2.67; 95% CI 2.15-3.33), endometrial cancer in women (HR 3.78; 95% CI 3.09-4.61), and pituitary tumors in both sexes (men: HR 3.13 [95% CI 2.13-4.61]; women: HR 2.13 [95% CI 1.41-3.22]). Associations varied by sex and age. Heavier weight at age 17 years and earlier obesity onset were also associated with higher cancer incidence. These findings highlight the importance of a life-course approach to weight management and support sex- and age-targeted cancer prevention strategies.