Insulin resistance in obesity and type 2 diabetes (T2D) is characterized by reduced insulin-stimulated glucose uptake, accumulation of triacylglycerol, mitochondrial dysfunction, and altered protein metabolism in skeletal muscle. This may involve disturbed endoplasmic reticulum (ER) homeostasis, leading to alterations in the unfolded protein response (UPR) and, hence, the protein folding capacity. Here, we investigated whether markers of UPR activity are elevated in skeletal muscle in obesity and T2D and to what extent insulin regulates these UPR markers. In a case-control design, we determined mRNA expression, protein abundance, and phosphorylation of key UPR markers in skeletal muscle biopsies obtained from patients with T2D, matched to glucose-tolerant individuals with obesity and lean individuals, before and after 4-h insulin infusion during a hyperinsulinemic-euglycemic clamp. The mRNA expression or protein abundance of GRP78, the canonical ER stress sensors (ATF6, PERK, and IRE-1α), several downstream UPR markers, and related markers of mitochondrial dynamics did not differ between groups. Insulin increased the mRNA expression of ATF6, ERN1 (encoding IRE-1α), XBP1, DDIT3 (encoding CHOP), and a marker of mitochondrial fission, DNM1l (encoding DRP1), as well as eIF2α Ser51 phosphorylation in skeletal muscle in all groups (all P <0.05), with no between-group differences. Our results demonstrate that markers of UPR activity are not elevated in skeletal muscle in obesity or T2D. Interestingly, insulin increases the expression of UPR markers and activates eIF2α, which is necessary for increasing the protein folding capacity of ER in muscle, and these responses are intact in obesity and T2D.

The pathogenic mitochondrial gene variant m.3243A>G disrupts oxidative phosphorylation and is associated with insulin resistance, both of which may be linked to unfavorable lipid metabolism. However, the metabolic alterations in m.3243A>G carriers, including what differentiates those with and without diabetes, remain incompletely understood. To investigate metabolomic profiles in fasting serum and urine samples from m.3243A>G carriers compared to healthy controls. Metabolomic profiling of serum and urine samples using nuclear magnetic resonance-based metabolomics in m.3243A>G carriers (n = 28) was compared to healthy controls matched for age and sex. Additionally, profiles from m.3243A>G carriers with diabetes (n = 16) were compared with carriers without diabetes (n = 12) to identify potential metabolites associated with the presence of diabetes. Twenty-five metabolites in serum and 16 in urine were identified as metabolites separating m.3243A>G carriers from healthy controls. The m.3243A>G carriers presented with increased triglycerides across lipoprotein particles and altered very-low-density lipoprotein concentrations and composition. In addition, there were alterations in metabolites from a number of metabolic pathways, including glycolysis, the tricarboxylic acid cycle, glutathione, one-carbon, and nucleotide metabolism. A three metabolite-urine signature (uracil, hypoxanthine, and 1-methylnicotinamide) demonstrated discriminating potential between m.3243A>G carriers and controls in exploratory machine learning analyses (area under the curve values 0.94–0.99 and cross-validation prediction of 0.81–0.93). Among m.3243A>G carriers, branched-chain amino acids were higher in individuals with diabetes compared with carriers without diabetes. Dysregulated lipoprotein metabolism represents a significant metabolic fingerprint of m.3243A>G carriers. Furthermore, higher levels of branched-chain amino acids may be associated with the presence of diabetes.

Mitochondrial cristae architecture is a key determinant of oxidative capacity in skeletal muscle. While mitochondrial dysfunction is common in type 2 diabetes, it remains unclear whether cristae density is reduced and whether it can be improved by exercise training. We therefore investigated the mitochondrial cristae density in skeletal muscle of individuals with type 2 diabetes compared with glucose-tolerant individuals with obesity and lean individuals, and examined the effect of high-intensity interval training (HIIT). In a non-randomised intervention study, the effect of an 8 week supervised HIIT intervention combining rowing and cycling was examined in male participants (aged 40–65 years) with type 2 diabetes (n=15), glucose-tolerant individuals with obesity (n=15), and lean individuals (n=18). Muscle biopsies from the vastus lateralis muscle were analysed using transmission electron microscopy to quantify mitochondrial cristae density (cristae surface area per mitochondrial volume) and to derive cristae surface area per muscle volume, integrating mitochondrial abundance and ultrastructure. To ensure high stereological precision, a minimum of 49 mitochondrial profiles per sample were analysed. No differences in mitochondrial cristae density were observed between groups at baseline. HIIT induced a 7

OBJECTIVE:Type 2 diabetes (T2D) is associated with low bone turnover and increased fracture risk. Although impaired insulin signaling is a hallmark of T2D in classical metabolic tissues, it remains unclear whether similar defects occur in bone-forming cells and contribute to impaired bone formation in T2D. DESIGN:Observational study using primary human bone marrow stromal cells (BMSCs). METHODS:Insulin signaling and osteogenic capacity were assessed in BMSCs isolated from 16 adult male and female patients with long-standing T2D. In vitro osteogenic differentiation was quantified by bone alkaline phosphatase activity, and in vivo bone formation rate was assessed in iliac crest bone biopsies. Quantitative phosphoproteomics was performed in BMSCs from patients with T2D and age- and sex-matched healthy controls to define basal and insulin-stimulated signaling responses. Finally, single-cell RNA sequencing was used to characterize cellular distribution of BMSCs, including correlation with fasting insulin levels and HbA1c. RESULTS:Single-cell RNA sequencing identified a BMSC subset enriched for inflammatory genes that correlated with fasting insulin levels. Insulin responsiveness in BMSCs correlated positively with in vitro osteogenic differentiation and in vivo bone formation rate. Phosphoproteomic analyses revealed a shared molecular signature in T2D BMSCs characterized by baseline hyperphosphorylation and attenuated insulin-stimulated canonical Wnt signaling compared with healthy controls. CONCLUSION:These findings demonstrate impaired insulin signaling in human BMSCs from patients with T2D and link reduced insulin responsiveness to diminished osteogenic potential and bone formation. Disrupted insulin-Wnt pathway signaling in BMSCs may contribute to the low bone turnover phenotype observed in T2D.

Liver fibrosis is a serious complication of non-alcoholic fatty liver disease (NAFLD) and the metabolic syndrome (MetS), conditions closely linked to obesity. We investigated the levels and dynamics of liver fibrosis biomarkers and liver fat content during personalized weight loss intervention in individuals with obesity, NAFLD, and MetS (n=30), with assessments at baseline, 1, and 5 months. Liver fat content decreased significantly (p < 0.0001), corresponding with complete resolution of steatosis in 36.7% of the participants, after 1 month of weight loss. Similarily, the fibrosis markers: T1 (p < 0.001), CK18 (p < 0.01), PIIINP (p < 0.05), TIMP1 (p < 0.001), and MACK3 (p < 0.001) dropped after 1 month. CK18 (p < 0.01), PIIINP (p < 0.0001), and MACK3 (p < 0.001) further changed from 1 to 5 months, while FNI decreased after 5 months (p < 0.01). Except for CK18, the dynamics of these changes were more pronounced from baseline to 1 month compared with 1 to 5 months. Finally, MACK3 showed promise for explaining T1. Our study underlines the importance of weight loss in swiftly mitigating liver steatosis and supports the integration of non-invasive biomarkers to monitor fibrosis risk in individuals with obesity, NAFLD, and MetS.

BACKGROUND:Higher maximal oxygen consumption (VO₂ max) is associated with lower risk of developing heart failure (HF). Empagliflozin improves VO2 max in HF with reduced ejection fraction, but the effect on VO2 max in individuals at risk of HF remain unknown. OBJECTIVE:This study aimed to evaluate the effect of 180 days treatment with empagliflozin compared to placebo on VO2 max, daily physical activity level, and quality of life (QoL) in individuals with overweight or obesity and risk of HF. METHOD:This investigator-initiated, double-blinded, randomized, placebo-controlled, multicenter trial included elderly individuals with body mass index >28 kg/m2 and at least one additional risk factor for HF, including hypertension, ischemic heart disease, stroke, or chronic kidney disease. Individuals with HF or type 2 diabetes mellitus were excluded. The primary endpoint was the mean difference in change of VO2 max. The secondary outcome was objectively measured physical activity level. QoL was an explorative outcome. RESULTS:Among 191 randomized individuals (94 empagliflozin, 97 placebo), 89% had hypertension and 66% ischemic heart disease. At baseline, 69% were male, median age was 68 years, median body mass index 31.9 kg/m², mean left ventricular ejection fraction 65 ± 9%, and mean VO₂ max 18.1 ± 4.3 mL/min/kg. Empagliflozin did not change VO2 max with an estimated treatment difference of -0.2 mL/min/kg (97.5% confidence interval -1.2 to 0.8), adjusted P = 1.00. No significant treatment differences were observed for neither daily physical activity nor QoL. CONCLUSIONS:Empagliflozin did not affect VO2 max, physical activity level, or QoL in elderly individuals with overweight or obesity and risk of HF.

AIMS:Care home admission often reflects frailty and limited life expectancy, potentially altering the benefit-harm balance of glucose-lowering drug (GLD) treatment for type 2 diabetes (T2D). Real-world data on treatment patterns in this setting remain limited. We examined GLD use for T2D among Danish care home residents. MATERIALS AND METHODS:We conducted a nationwide, population-based drug utilisation study of all individuals admitted to Danish care homes between 2018 and 2023, using linked national health registries. RESULTS:Among 88 658 residents (median age: 84 years [IQR: 78-90]; 60% women), 13% (n = 11 101) used GLDs for T2D at admission, with 84% continuing treatment beyond 2 years. Residents using GLDs at admission had long-standing diabetes (median duration: 12 years [IQR: 6.8-15]), relatively low glycated haemoglobin levels (median: 6.9% [IQR: 6.3-7.8]; 52 mmol/mol [45-62]) with little change around admission, and 43% used more than one GLD class, most commonly metformin (70%) and insulin (36%; basal: 30%; bolus: 16%). Use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors increased over time but remained limited (13% and 24%, respectively, in 2023), despite a high prevalence of cardiorenal disease (84%), and did not differ by cardiorenal disease status. Overall GLD use remained stable around admission, but initiation spiked 3 months before admission (36 initiators/10 000 residents), often following hospitalisation (63%) and primarily involved bolus insulin initiated by hospital physicians. CONCLUSIONS:GLD use for T2D among Danish care home residents is high and shows limited deintensification and potential misalignment with guideline recommendations.

BackgroundMetformin lowers glucose by acting on the liver and the gastrointestinal tract and may reduce body weight by increasing circulating levels of the stress-induced cytokine GDF15. The tissue responsible for the release of GDF15 and whether this is paralleled by the induction of another, mainly liver derived, stress-responsive cytokine, FGF21, remains unclear.ObjectiveWe examined the effect of metformin on GDF15 and FGF21 in humans and in intestinal cells in vitro.MethodsIn a randomized, cross-over trial, 34 healthy individuals completed a 42-h fast twice, either with or without prior treatment with metformin for a week. Glucose metabolism was assessed using [3-3H]-glucose and indirect calorimetry and blood samples were drawn for the analysis of plasma metformin and serum GDF15 and FGF21. The effects of metformin on the expression and secretion of GDF15 and FGF21, and on mitochondrial respiration and glycolysis were examined in human intestinal epithelial cells (Caco-2).ResultsMetformin increased glucose utilization (p=8.9x10-13) due to increased glycolysis (p=7.6x10-13) in vivo. This was accompanied by increased serum GDF15 (1004±61 vs 607±89 ng/ml; p<0.001), whereas serum FGF21 (146±30 vs 156±29 ng/ml; p=0.65) was unaltered. The change in serum GDF15 did not correlate with plasma metformin levels. In vitro, metformin markedly increased mRNA levels and secretion of GDF15, whereas FGF21 levels were not detectable in Caco-2 cells or media. Moreover, metformin dose-dependently inhibited mitochondrial respiration and increased glycolysis in vitro.ConclusionsThe metformin-induced increase in serum GDF15, but not the liver-derived FGF21, in humans is consistent with the actions of metformin in human intestinal cells in vitro. These findings corroborate with recent studies demonstrating the gastrointestinal tract is an important site of metformin action.Clinical Trial RegistrationClinicalTrials.gov, Identifier NCT01400191.

Context:The coexistence of diabetes and hyperinsulinemic hypoglycemia (HI) within a family is rare. Activating MAFA variants have been described in 3 families with this dual phenotype and are associated with sex-dependent clinical patterns. Methods:We studied a family where members were affected by HI (n = 5), diabetes (n = 5), or both conditions (n = 1). Clinical, biochemical, and imaging data were collected. Genetic testing for variants in known monogenic diabetes and HI genes was performed in the proband, followed by cascade testing in available relatives. Pancreatic tissue was examined by immunohistochemistry and immunofluorescence. Results:A heterozygous, p.(Ser64Phe) MAFA variant was identified in the male proband, who had presented with diabetes at 28 years and developed HI due to insulinomatosis 6 years later. The variant was confirmed in 5 relatives, 4 with HI and 1 with diabetes (including obligate heterozygotes). Among the 5 presenting with HI, 3 were female, whereas 4 of 6 presenting with diabetes were male, consistent with reported sex-dependent patterns.Increased nuclear expression of the transcription factor MafA (MAFA) was detected by immunofluorescence in insulin-positive tumor regions compared to the adjacent islets, supporting a pathogenic role for the variant in beta-cell regulation. Conclusion:We describe the fourth family with a pathogenic MAFA variant and the second individual with the dual phenotype of diabetes and HI. Our findings highlight challenges in clinical management of this condition and underscore the need to consider MAFA in cases of adult-onset HI or those with an atypical course of diabetes especially when there is family history.

A possible association between infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and type 1 diabetes (T1D) development has been reported. Whether SARS-CoV-2 infection affects beta-cell loss in T1D over time is unknown. We investigated this in adults with new-onset T1D. Individuals with new T1D were included from six Danish hospitals between December 2020 and January 2023. Within one month after the diagnosis of T1D, we assessed medical history, previous self-reported COVID-19 infection, COVID-19 vaccination, glycated haemoglobin (HbA1c), and SARS-CoV-2 antibodies (Cov2IgG). A mixed-meal tolerance test (MMTT) was performed after overnight fast at baseline, and after 12 and 24 months to assess plasma glucose and C-peptide at 15–60 min intervals for up to 150 min. The main outcome was C-peptide area under curve (AUCC−peptide), as a measure of residual beta-cell function, in Cov2IgG negative and positive individuals. A total of 94 individuals with T1D were included (34

Background:We investigated whether individuals who likely developed type 2 diabetes (T2D) through predominantly genetic, adverse intrauterine, or lifestyle aetiologies have different clinical presentations and complications. Methods:In this Danish nationwide combined cross-sectional and registry-based follow-up study, we included 7867 individuals with newly diagnosed T2D from the DD2 cohort, enrolled during 2010-2023 through general practices and hospital outpatient clinics across Denmark. Participants were required to have available genotyping and birthweight data; those with GAD antibody levels >30 were excluded. Individuals were grouped by presumed predominant aetiologies: genetic (highest-quartile T2D genetic risk score (GRS), birthweight above lowest quartile; n = 1435); intrauterine (lowest-quartile birthweight, GRS below highest quartile; n = 1195); and lifestyle (birthweight above lowest quartile, GRS below highest quartile; n = 4380). Baseline characteristics at diagnosis were examined using linear and log-binomial or robust Poisson regression. The main follow-up outcomes were standardised 10-year risks of major adverse cardiovascular events and microvascular complications after DD2 enrolment, estimated using the Aalen-Johansen method. Findings:Compared with the genetic group (18%), intrauterine (15%) and lifestyle (56%) aetiologies both showed -6.9% lower Homeostatic Model Assessment-2 (HOMA2) insulin sensitivity, higher triglycerides (+6.6% and +5.3%), higher HOMA2 beta-cell function (+8.9% and +9.6%), and higher high-sensitivity C-reactive protein (+14.8% and +24.1%). Age at T2D diagnosis was 1.2 years lower (intrauterine) and 2.3 year higher (lifestyle). The 10-year risk of major adverse cardiovascular events was 14.8% (intrauterine), 13.2% (lifestyle), and 11.5% (genetic), corresponding to absolute risk differences (RDs) of +3.3% (95% confidence interval [CI] 0.6, 6.0) for intrauterine, and +1.7% (95% CI -0.3, 3.6) for lifestyle, vs. genetic aetiology. The 10-year risk of microvascular complications was 25.9% (intrauterine), 25.4% (lifestyle), and 21.8% (genetic), yielding RDs of +4.1% (95% CI 0.7, 7.5) for intrauterine and +3.5% (95% CI 1.0, 6.1) for lifestyle aetiology. Interpretation:Individuals who developed T2D with predominant intrauterine or lifestyle rather than genetic aetiology exhibited distinct characteristics including higher long-term complication risks. Future studies should validate this framework in more diverse populations and assess whether these proxy-based aetiological domains can improve risk stratification and guide treatment. Funding:This work was funded by Danish Agency for Science, the Danish Health and Medicines Authority, the Danish Diabetes Association, the Region of Southern Denmark, the Swedish Research Council, the Novo Nordisk Foundation, the Swedish ALF for Region Skåne, the Crafoord Foundation, and the Swedish Diabetes Association.

BACKGROUND:Circulating fatty acid profiles are linked to cardiovascular disease risk and mortality. Short-term interventions suggest that low-carbohydrate diets (LCDs) promote cardioprotective shifts in circulating fatty acids in obesity. OBJECTIVES:We examined whether a 6-mo, non-calorie-restricted, LCD high in fat similarly improves circulating fatty acid composition in adults with type 2 diabetes. METHODS:In an open-label, randomized, controlled trial, 71 individuals with type 2 diabetes were randomly assigned 2:1 to an LCD [maximum of 20 E% (energy per cent) carbohydrates] or a control diet (50-60 E% carbohydrates) for 6 mo with no restriction in energy intake. The prespecified secondary outcomes were the mean difference in change between groups in serum phospholipid fatty acids in weight percentage (wt%) measured by gas chromatography and reported as 95% confidence intervals (CIs) and significance adjusted for multiple comparisons (q value). RESULTS:LCD reduced total saturated [-0.6 (CI: -0.9, -0.2)] and monounsaturated fatty acids [-0.9 (CI: -1.4, -0.3)] and increased total polyunsaturated fatty acids [1.3 (CI: 0.6, 2.0)] compared with the control diet (all q < 0.05). Importantly, LCD reduced palmitoleic acid (16:1n-7) [-0.13 (CI: -0.21, -0.06)], a marker of de novo lipogenesis, by 23% and dihomo-γ-linolenic acid (20:3n-6) [-0.38 (CI: -0.67, -0.09)] by 12%, whereas it increased arachidonic acid (20:4n-6) [1.1 (CI: 0.3, 2.0)] by 9% compared with the control diet (all q < 0.05). Moreover, the LCD improved estimated desaturase activities by lowering stearoyl-coenzyme A desaturase 1 [-0.5 (CI: -0.7, -0.2)] and Δ6 desaturase [-0.6 (CI: -0.9, -0.2)] and increasing Δ5 desaturase [1.05 (CI: 0.3, 1.79)] activities, respectively (all q < 0.01). These changes occurred despite a 2.6-fold higher intake of saturated fatty acids in the LCD group. CONCLUSIONS:A 6-mo, non-calorie-restricted LCD modified the circulating composition of fatty acids in adults with type 2 diabetes in a manner consistent with a potentially favorable cardioprotective profile. This trial was registered at www. CLINICALTRIALS:gov as NCT03068078.

We investigated the effect of weight loss on fat accumulation in six different tissues and associated metabolic characteristics in individuals with obesity, non-alcoholic fatty liver disease (NAFLD), and the metabolic syndrome (MetS). Baseline assessments were done for individuals with obesity, NAFLD, and MetS (n=33), individuals with obesity (n=28), and lean individuals (n=27), and at 1 and 5 months for the NAFLD-MetS group during personalized weight loss intervention. All measured fat depots were increased in individuals with obesity compared with lean (p<0.001), whereas pancreas (p=0.024) and visceral fat (p=0.007) were elevated in the NAFLD-MetS group compared with the obesity control group. During weight loss, fat content was reduced in all investigated tissues after 1- and 5-months, except for erector spinae muscle fat that was reduced after 5 months. Finally, reductions in alanine aminotransferase, fasting plasma glucose and insulin, waist circumference, and diastolic blood pressure were key for explaining liver fat content after 5 months. Multiple fat depots were increased simultaneously in individuals with obesity, with personalized weight loss intervention leading to reductions in all investigated tissues, especially after 1 month, in individuals with obesity, NAFLD, and MetS. The trial registry number: NCT05699863.

AIMS:We investigated longitudinal, bidirectional associations between objectively measured moderate to vigorous physical activity (MVPA), health-related quality of life (HRQoL), and emotional well-being (EWB) in individuals recently diagnosed with type 2 diabetes mellitus. METHODS:Participants were 972 adults. MVPA was assessed using accelerometry, HRQoL using the SF-12 (physical [PCS], mental [MCS]), and EWB using the WHO-5. A three-wave cross-lagged panel model tested associations, adjusting for age and sex. RESULTS:Baseline PCS predicted MVPA at 24 months (β = 0.124, p < 0.001), and PCS at 24 months predicted MVPA at 48 months (β = 0.146, p < 0.001). Baseline MCS predicted MVPA at 24 months (β = 0.116, p = 0.001), but not 48 months (β = -0.016, p = 0.653). Baseline EWB predicted MVPA at 24 months (β = 0.080, p = 0.023), but not 48 months (β = 0.068, p = 0.058). Baseline MVPA did not predict PCS at 24 months (β = 0.038, p = 0.184), but MVPA at 24 months predicted PCS at 48 months (β = 0.065, p = 0.024). MVPA did not predict MCS or EWB. CONCLUSIONS:HRQoL and EWB predicted subsequent MVPA, whereas MVPA showed limited and inconsistent effects on later HRQoL or EWB.

BACKGROUND:This scoping review aimed to explore existing clinical trials on the association between semaglutide use and the occurrence of retinal vascular events to detect any potential safety concern. SUMMARY:The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines. A search was performed across PubMed, Embase via Ovid, ClinicalTrials.gov, and Google Scholar on April 16, 2025, and March 5, 2026. We aimed to detect clinical trials reporting retinal vascular events while investigating the effect of semaglutide in patients with type 2 diabetes or obesity. Reports on optic ischemic neuropathy were included as a reference outcome to evaluate whether the method used in the review might be capable of detecting rare ophthalmic vascular adverse events and thereby a potential safety signal. KEY MESSAGES:Thirteen randomized clinical trials (predominantly double-blind and placebo-controlled) were included, comparing 17,478 individuals treated with semaglutide and 17,334 placebos. A total of 15 retinal vascular events were reported in the semaglutide groups compared with four events in placebo arms. In large, long-term trials (SELECT, SOUL, FLOW), incidence rates were consistently low but numerically higher in semaglutide-treated patients, ranging from 0 to 0.33 events per 1,000 person-years versus 0-0.05 in placebo groups. In trials with active comparators, rates ranged from 0 to 5.99 events per 1,000 person-years in semaglutide groups and 0-3.52 in comparator groups. For ischemic optic neuropathies, six events were reported among 11,757 semaglutide-treated patients versus one event among 11,105 placebo-treated individuals; in trials with active comparators, two versus one event were reported. In conclusion, retinal vascular events, especially retinal arterial occlusions, showed a higher pattern of reporting in the semaglutide arm across clinical trials, the majority of which were randomized placebo-controlled trials. Optic ischemic neuropathies were also found to be higher on the semaglutide arm. These findings support the need for further investigation through large-scale registry studies.

Insulin resistance drives cardiometabolic disease, yet its molecular signatures and tissue origins remain incompletely characterized, and scalable assessment methods are lacking. Here, we apply Multi-Workflow Proteomics on plasma from 161 individuals spanning the metabolic spectrum defined by hyperinsulinemic–euglycemic clamp–derived insulin sensitivity. We identify 488 proteins associated with insulin sensitivity, revealing contributions from liver, adipose tissue, and immune cells alongside underappreciated roles for brain and heart. An exercise intervention demonstrated these signatures are modifiable. We developed a model combining 13 proteins, including IGFBP1, LEP, GDF15, PON3, and LDLR, with clinical variables (sex, HbA1c, TG/HDL ratio) that estimates hyperinsulinemic–euglycemic clamp-derived insulin sensitivity (R² = 0.73). Applied to ~20,000 UK Biobank participants, estimated insulin sensitivity outperformed TG/HDL in predicting type 2 diabetes (c-index 0.86 vs. 0.71) and other cardiometabolic outcomes, including obesity, cardiovascular disease, and chronic kidney disease. This proteomic atlas enables scalable insulin resistance assessment and precision risk stratification.

Introduction:Microvascular diseases (MVD) in type 2 diabetes mellitus (T2D) are associated with alterations in the bone microarchitecture, but their association with fracture risk is unclear. We investigated whether MVD (retinopathy, nephropathy, and neuropathy) are associated with higher fracture risk in persons with T2D. Materials and methods:We identified 10 491 persons with T2D, enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes cohort between 2010 and 2022. The primary outcomes were any hospital-diagnosed fracture (except facial and cranial), and major osteoporotic fractures (MOF), defined as clinical vertebral, hip, humerus, and forearm fractures, in persons with hospital-diagnosed MVD vs without MVD. We used Cox proportional hazard models to calculate crude and adjusted hazard ratios (aHRs). Results:During a median follow-up of 7.6 yr IQR (3.5; 9.7), the rates of any fracture were higher in persons with T2D and MVD vs no MVD (aHR 1.31; 95% CI [1.15; 1.51]). Similarly, MOF rate was elevated in persons with MVD (aHR 1.33 [1.09; 161]). The rates for any fracture and MOF were highest in persons with neuropathy (aHR 1.49 [1.24; 1.78] and aHR 1.54 [1.19; 1.99], respectively). Discussion:Fracture risk is elevated in persons with T2D complicated by MVD, particularly in those with neuropathy.

Obesity increases the risk of heart failure (HF), potentially through low-grade inflammatory processes. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been suggested to attenuate inflammation, although data in patients without diabetes and HF are lacking. Moreover, it is unknown whether SGLT2 inhibitors affect adipose tissue dysfunction. We aimed to investigate the effect of the SGLT2 inhibitor empagliflozin on systemic inflammation, uric acid, and adipose tissue dysfunction in high-risk patients with overweight or obesity. Pre-defined secondary analysis of the Empire Prevent Metabolic trial. Outpatients with body mass index (BMI) > 28 kg/m2 and risk factors for HF, excluding diabetes, were randomised to 180 days treatment with empagliflozin 10 mg or placebo. Patients completed blood sampling and subcutaneous abdominal adipose tissue biopsies at baseline and follow-up. Pre-defined endpoints were the baseline-adjusted estimated treatment differences (ETD) or ratios (ETR) for interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP), and uric acid. Furthermore, we explored gene expression changes in selected markers of adipose tissue dysfunction, including inflammation. We randomised 92 patients (empagliflozin: 44, placebo: 48). Median age was 68 years, median BMI was 31.6 kg/m2, while 21 (23