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PubMed2025

Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation.

Non-energetic roles for glucose are largely unclear, as is the interplay between transcription factors (TFs) and ubiquitous biomolecules. Metabolomic analyses uncovered elevation of intracellular glucose during differentiation of diverse cell types. Human and mouse tissue engineered with glucose sensors detected a glucose gradient that peaked in the outermost differentiated layers of the epidermis. Free glucose accumulation was essential for epidermal differentiation and required the SGLT1 glucose transporter. Glucose affinity chromatography uncovered glucose binding to diverse regulatory proteins, including the IRF6 TF. Direct glucose binding enabled IRF6 dimerization, DNA binding, genomic localization, and induction of IRF6 target genes, including essential pro-differentiation TFs GRHL1, GRHL3, HOPX, and PRDM1. These data identify a role for glucose as a gradient morphogen that modulates protein multimerization in cellular differentiation.

Cell Differentiation↗

PubMed2025

Two-Step Loss of GLUTs in the High-Metabolism Passerines.

Glucose transporters (GLUTs) play vital roles in cellular metabolism. Understanding their evolutionary dynamics in birds is essential for elucidating avian physiology and adaptation. However, the choice of gene detection method in gene family analysis may affect the conclusion. Here, we present a comprehensive investigation of methodologies and GLUT gene loss events in avian lineages, focusing on the loss of GLUT4 and GLUT8. To illustrate the effects of these methods, we first employed BUSCO-based homolog identification, calculated pairwise evolutionary distances between different species, and performed separate blastn and blastp searches to identify homologs in two groups of animals. Our analyses revealed a significant decline in blastn accuracy with increasing evolutionary distance, represented by relative divergence times. Through a more robust blastp-based gene detection pipeline, we provide evidence for the loss of GLUT genes in birds based on 58 vertebrate genomes, including 47 bird species. Our results support the reported early loss of GLUT4 in Aves. We also newly emphasize the absence of GLUT8 in passerines, potentially due to adaptation to high-sugar diets in their ancestors. These findings enhance our knowledge of avian metabolism and the evolution of GLUT genes.

Animals↗

PubMed2025

Exploring the therapeutic potential of extract in targeting localized adiposity.

OBJECTIVE: To determine direct targeting of localized adiposity through Morus alba Linne bark injection based on pharmacology network analysis. METHODS: Male C57BL/6J mice were fed a high-fat diet (HFD) to induce obesity. After 6 weeks on HFD, the water extract of Morus alba L.bark (MAB, 2 mg/mL) was locally injected into one inguinal fat pad, while saline was injected into the other side, 3 times/week for 6 weeks (n = 6/group). The water extract of MAB was freeze-dried and then diluted in saline before use. RESULTS: HFD-fed mice treated with local MAB topical injection showed reduced adipocyte weight and size in inguinal fat pads by dual-energy X-ray absorptiometry. No toxicity changes seen in liver, spleen, kidney tissue, or alanine aminotransferase / aspartate aminotransferase levels in serum by MAB injection. Protein levels of phosphorylated insulin receptor substrate-1 and glucose transporter type 4, and mRNA expression of adiponectin, were increased in inguinal adipose tissue injected with MAB locally. Locally MAB injection led to a decrease in glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, linked to gluconeogenesis, while forkhead box protein O1, which regulates these factors, was increased. Moreover, there was an increase in adenosine 5'-monophosphate-activated protein kinase, related to lipogenesis, as well as elevated levels of hormone-sensitive lipase and fatty acid synthase, both associated with lipolysis. These results support the 'insulin signaling pathway' and 'regulation of lipolysis in adipocytes' identified in the Kyoto Encyclopedia of Genes and Genomes pathway through network analysis. CONCLUSION: This study suggests that MAB topical injection exhibits localized fat reduction by inhibiting insulin resistance, gluconeogenesis and lipogenesis mediator, while activating lipolysis enzymes within targeted adipose site.

Animals↗

PubMed2026

EMPEROR-Preserved Risk Model and Outcomes in the FINEARTS-HF Trial: A Prespecified Secondary Analysis of FINEARTS-HF.

IMPORTANCE: Patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) or preserved EF (HFpEF) show substantial heterogeneity in prognosis. OBJECTIVES: To evaluate the performance of biomarker-driven prognostic models derived from the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved) Trial in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) and to examine whether baseline risk modified the therapeutic effect of finerenone. DESIGN, SETTING, AND PARTICIPANTS: This is a prespecified secondary analysis of the FINEARTS-HF trial, which was conducted across 653 sites in 37 countries among adults aged 40 years and older with symptomatic HF and left ventricular EF (LVEF) of 40% or greater. Patients were randomized between September 2020 and January 2023, and data analysis for this study was conducted from September to October 2025. The median (IQR) follow-up period was 32 (23-37) months. INTERVENTION: Finerenone (titrated to 20 mg or 40 mg) or placebo. MAIN OUTCOMES AND MEASURES: EMPEROR-Preserved risk scores for the outcomes of first HF hospitalization or cardiovascular death, cardiovascular death, and all-cause death were calculated in FINEARTS-HF using models incorporating N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, New York Heart Association functional class, history of chronic obstructive pulmonary disease and diabetes, insulin use, and-depending on outcome-age, hemoglobin and albumin levels, HF duration, time from prior HF hospitalization, and sodium-glucose transporter 2 inhibitor use. Estimated risks were compared with observed event rates, and model performance was assessed using Harrell C statistic. Treatment effects were evaluated across risk quintiles (Q1 to Q5) and across the continuous risk distribution. RESULTS: Among 6001 patients (mean [SD] age, 72.0 [9.6] years; 2732 [45.5%] women; 3003 randomized to finerenone and 2998 randomized to placebo), the EMPEROR-Preserved risk model estimated risk of outcomes, with Q5 vs Q1 hazard ratios (HRs) of 10.49 (95% CI, 8.14-13.52) for the composite of HF hospitalization or cardiovascular death and 13.47 (95% CI, 8.79-20.64) for cardiovascular death. The model demonstrated good discrimination. The treatment effect of finerenone was consistent across risk quintiles for first HF hospitalization or cardiovascular death (Q1: HR, 0.93 [95% CI, 0.58-1.49]; Q2: HR, 1.04 [95% CI, 0.76-1.43]; Q3: HR, 0.82 [95% CI, 0.62-1.07]; Q4: HR, 0.81 [95% CI, 0.65-1.01]; and Q5: HR, 0.88 [95% CI, 0.74-1.05]; P for interaction = .68) and remained uniform across the continuous risk spectrum. CONCLUSIONS AND RELEVANCE: The EMPEROR-Preserved risk models demonstrated good performance in FINEARTS-HF. Baseline risk did not modify the relative treatment effect of finerenone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04435626.

Humans↗

PubMed2026

Proteomic analyses of human islets reveal potential markers of β cell dysfunction during prediabetes.

The mechanisms driving progressive β cell dysfunction in type 2 diabetes remain incompletely understood. This study aimed to identify pancreatic islet proteome changes that could predict diabetes onset. We isolated islets from individuals without diabetes undergoing partial pancreatectomy, previously characterized for glucose tolerance, insulin sensitivity, and insulin secretion, using laser capture microdissection, and analyzed them via high-performance liquid chromatography-mass spectrometry. Proteomic analysis revealed that individuals with impaired glucose tolerance (IGT) had reductions in proteins regulating glycolysis (PGK1, G3P), lipid metabolism (ACBP, ARF1), glucose transport (14-3-3B), and insulin secretion (STARD10, CAPDS) compared with normal glucose-tolerant (NGT) individuals. Additionally, IGT islets showed impaired expression of proteins involved in glucose- and incretin-stimulated insulin response (CREB1, IQGA1). Stratification by β cell glucose sensitivity (βGS) indicated that individuals with lower βGS exhibited reduced levels of insulin maturation (ERO1B) and antiapoptotic proteins (CASP8, PAK2, SKP1), along with increased SEL1L, a factor promoting endocrine precursor differentiation. These findings suggest that early defects in glucose metabolism and insulin secretion characterize IGT, while reduced βGS may trigger compensatory mechanisms, through enhanced β cell survival or neogenesis, to delay type 2 diabetes progression. Overall, proteomic alterations in prediabetic islets provide potential early predictive markers and targets for interventions aimed at preserving β cell function.

Humans↗

PubMed2025

The Streptococcus pyogenes mannose phosphotransferase system (Man-PTS) influences antimicrobial activity and niche-specific nasopharyngeal infection.

Streptococcus pyogenes is a human-adapted pathogen that can cause multiple diseases, including pharyngitis and skin infections. Although this bacterium produces many virulence factors, how S. pyogenes competes with the host microbiota is not well understood. Here, we detected antimicrobial activity from S. pyogenes MGAS8232 that prevented the growth of Micrococcus luteus. This activity was produced when cells were grown in 5% CO2 in M17 media supplemented with galactose; however, the addition of alternative sugars coupled with genome sequencing experiments revealed that the antimicrobial phenotype was not related to classical bacteriocins. To further determine genes involved in the production of this activity, a transposon mutant library in S. pyogenes MGAS8232 identified the mannose phosphotransferase system (Man-PTS), a major sugar transporter, as important for the antimicrobial phenotype. Loss-of-function transposon mutants linked to the antimicrobial activity were identified to also be involved in alternative sugar utilization, and additionally, the Man-PTS was further identified from an inadvertent secondary mutation in a bacteriocin operon mutant. Sugar utilization in the Man-PTS mutants demonstrated that galactose, mannose, and N-acetylglucosamine utilization was impaired. RNA-seq experiments in high and low glucose concentrations further characterized the Man-PTS as a glucose transporter; however, transcriptional regulators or virulence factors were not affected with the loss of the Man-PTS. Deletion of Man-PTS demonstrated defects in a mouse model of nasopharyngeal infection but not skin infection. This work suggests that the ability of S. pyogenes to utilize alternative sugars presented by glycans may play a role in acute infection and interactions with the endogenous microbial population existing in the nasopharynx.IMPORTANCEStreptococcus pyogenes is responsible for over 500,000 deaths per year primarily due to invasive infections and post-infection sequelae, although the most common manifestations include pharyngitis and impetigo. S. pyogenes can adapt to its environment through alternative sugar metabolism. Here, we identified an antimicrobial phenotype that was not bacteriocin-related but a by-product of alternative sugar metabolism. The mannose phosphotransferase system was involved in the production of the antimicrobial and was also important for S. pyogenes to utilize alternative sugars and establish nasopharyngeal infection but not skin infection. Overall, this study identified potential strategies used by S. pyogenes for interactions with the endogenous microbiota and further elucidated the importance of sugar metabolism in acute upper respiratory tract infection.

Streptococcus pyogenes↗

PubMed2026

Disentangling Sex Differences in Sulfonylurea Drug Response With Genome-Wide Association Studies in Individuals With Type 2 Diabetes.

Sulfonylureas are a cornerstone of type 2 diabetes therapy despite interindividual variability in response. Despite well-documented sex-based differences, pharmacogenomic and genome-wide association studies (GWAS) have largely overlooked sex as a biological variable. We conducted the first sex-stratified GWAS of hemoglobin A1c (HbA1c) response to sulfonylureas in Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial participants (N = 871). Variants meeting genome-wide (P < 5.0 × 10-8) and suggestive (P < 5.0 × 10-6) significance were assessed for replication in the Pharmacogenomics of Metformin (PMET1) cohort. Replicated variants were further analyzed in the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) cohort to assess acute insulin and glucose responses to a single glipizide dose. Genome-wide significant loci with sex-specific effects were identified: KAZN, KIF2B, SLC39A10, and SPINK5 (combined-sex); CRACR2A, KCNK2, and TENM2 (male-only); and NACPH2 (female-only). Two suggestive variants in the TMEM64/NECAB1 locus, associated with reduced HbA1c response to sulfonylureas in the male-only ACCORD analysis, were directly replicated in the PMET1 male-only cohort. In SUGAR-MGH, one replicated variant (rs6471250-C) was significantly associated with reduced peak insulin in males (P = 0.035) but not females (P = 0.40), demonstrating sex-specific functional effects. This study identified statistically supported and biologically plausible loci with prior evidence linking nearby genes to pathways relevant to sulfonylurea action, including insulin secretion, insulin regulation/sensitivity, calcium signaling, potassium-channel biology, and glucose transport. The findings highlight sex-specific differences in sulfonylurea response, providing mechanistic insights and underscoring the importance of sex-specific precision medicine. Identification of genetic variants influencing sex-specific response could inform dosing to optimize sulfonylureas.

Humans↗

PubMed2024

Comparison of the antibiotic resistance mechanisms in a gram-positive and a gram-negative bacterium by gene networks analysis.

Nowadays, the emergence of some microbial species resistant to antibiotics, both gram-positive and gram-negative bacteria, is due to changes in molecular activities, biological processes and their cellular structure in order to survive. The aim of the gene network analysis for the drug-resistant Enterococcus faecium as gram-positive and Salmonella Typhimurium as gram-negative bacteria was to gain insights into the important interactions between hub genes involved in key molecular pathways associated with cellular adaptations and the comparison of survival mechanisms of these two bacteria exposed to ciprofloxacin. To identify the gene clusters and hub genes, the gene networks in drug-resistant E. faecium and S. Typhimurium were analyzed using Cytoscape. Subsequently, the putative regulatory elements were found by examining the promoter regions of the hub genes and their gene ontology (GO) was determined. In addition, the interaction between milRNAs and up-regulated genes was predicted. RcsC and D920_01853 have been identified as the most important of the hub genes in S. Typhimurium and E. faecium, respectively. The enrichment analysis of hub genes revealed the importance of efflux pumps, and different enzymatic and binding activities in both bacteria. However, E. faecium specifically increases phospholipid biosynthesis and isopentenyl diphosphate biosynthesis, whereas S. Typhimurium focuses on phosphorelay signal transduction, transcriptional regulation, and protein autophosphorylation. The similarities in the GO findings of the promoters suggest common pathways for survival and basic physiological functions of both bacteria, including peptidoglycan production, glucose transport and cellular homeostasis. The genes with the most interactions with milRNAs include dpiB, rcsC and kdpD in S. Typhimurium and EFAU004_01228, EFAU004_02016 and EFAU004_00870 in E. faecium, respectively. The results showed that gram-positive and gram-negative bacteria have different mechanisms to survive under antibiotic stress. By deciphering their intricate adaptations, we can develop more effective therapeutic approaches and combat the challenges posed by multidrug-resistant bacteria.

Anti-Bacterial Agents↗

PubMed2026

Sodium Glucose Co-Transporter 2 Inhibitors and Ventricular Arrhythmias in Patients with Type 2 Diabetes: A Systematic Review of Observational Studies.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2i) may exert antiarrhythmic effects, but their association with ventricular arrhythmias remains unclear. OBJECTIVE: We conducted a systematic review to evaluate the association between SGLT2i use and the risk of ventricular arrhythmias, cardiac arrest, and sudden cardiac death compared with other antidiabetic medications or no SGLT2i use among patients with type 2 diabetes mellitus. METHODS: MEDLINE, EMBASE, and CENTRAL were searched for observational studies published between March 2013 and March 2026. Quality was assessed using the Risk of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool, alongside evaluation of pharmacoepidemiology-specific biases. RESULTS: A total of 17 studies (16 cohort and one nested case-control) were included. Based on ROBINS-I, seven studies had moderate, eight serious, and two critical risks of bias. Eleven studies had at least one pharmacoepidemiology-specific bias. For ventricular arrhythmias, estimates ranged from a protective effect (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.04-0.97) to a potential increased risk (odds ratio 1.87, 95% CI 0.89-3.95) with SGLT2i use. For cardiac arrest, estimates consistently reported a lower risk with estimates that ranged from HR 0.63 (95% CI 0.59-0.68) to HR 0.85 (95% CI 0.82-0.88). The only study on sudden cardiac death reported a potential risk reduction (HR 0.62, 95% CI 0.38-1.01). CONCLUSIONS: While the association between SGLT2i and ventricular arrhythmias remains inconsistent, the use of SGLT2i likely reduces cardiac arrest and may reduce sudden cardiac death, suggesting a possible protective effect on ventricular arrhythmias among patients with type 2 diabetes.

Journal Article↗

PubMed2026

Effect of SGLT2 inhibitor drugs on triglyceride-glucose (TyG) index in adults: A systematic review and meta-analysis.

BACKGROUND: Insulin resistance is a serious public health concern. The triglyceride-glucose (TyG) index is a simple, cheap, and reproducible surrogate of insulin resistance, and sodium-glucose cotransporter-2 (SGLT2) inhibitors have reshaped cardio-metabolic care beyond glycemic control. METHODS: We followed PRISMA and registered the protocol in PROSPERO (CRD420251056341). We searched PubMed, Scopus, Web of Science, EMBASE, and Cochrane from inception to May 31st, 2026, including observational studies and clinical trials reporting baseline and follow-up TyG in adults. Two reviewers screened records, a third resolved disagreements, data were extracted with a standardized form, and quality was assessed with Cochrane RoB 2.0, the Newcastle-Ottawa Scale, and the JBI checklists. The primary outcome was within-group change in TyG pooled with random-effects (Hartung-Knapp); tests were two-sided with a significance threshold of 0.05. RESULTS: Twelve studies comprising thirteen study arms were included, with a total of 1845 participants. Follow-up ranged from 12 weeks to 5 years. Across studies, SGLT2 inhibitor therapy was associated with a significant reduction in TyG index (mean difference = -0.28, 95% confidence interval [-0.41; -0.14], I2 = 99.5%). Egger's test suggested possible small-study effects, whereas Begg's test and trim-and-fill analysis did not show clear evidence of publication bias; leave-one-out analyses showed that no single study materially influenced the pooled estimate. CONCLUSION: Despite heterogeneity in populations, drug choice, and follow-up duration, SGLT2 inhibitors were associated with a significant decrease in TyG, although small-study effects cannot be excluded.

Humans↗

PubMed2026

Effects of semaglutide and empagliflozin on markers of endothelial function in persons with type 2 diabetes: A post hoc analysis of a randomized clinical trial.

AIMS: The endothelium maintains vascular health by regulating blood flow and protecting against inflammatory damage. In type 2 diabetes (T2DM), however, hyperglycemia, hypertension, and hyperlipidemia place a significant burden on the endothelium, potentially leading to atherosclerosis and cardiovascular disease (CVD). While semaglutide and empagliflozin have been shown to reduce CVD risk in T2DM, it remains unclear whether these benefits are mediated by improved endothelial function. This post-hoc analysis explores the effects of these agents on markers of endothelial function, i.e. the reactive hyperaemic index (RHI) and the endothelial-derived cell adhesion molecules (CAMs) E-Selectin, ICAM-1, P-Selectin, and VCAM-1. METHODS: This was a post-hoc analysis of a 32-week randomized trial evaluating the separate and combined effects of semaglutide and empagliflozin on cardio-renal organ damage. One hundred and twenty participants with type 2 diabetes, age ≥ 50 were randomized to four groups (semaglutide, empagliflozin, the combination or placebo). An increase in RHI and/or a decrease in CAMs were considered beneficial. RESULTS: RHI increased compared to baseline (0.11, 95%CI [0.008;0.21], p = 0.03) but not compared to placebo in the semaglutide group (0.11, 95%CI [-0.04;0.24], p = 0.16). There was no effect on RHI in the empagliflozin group. Compared to placebo, E-Selectin decreased significantly in the semaglutide and combination groups (-9, 95%CI [-14.1;-5.1] p < 0.01 and - 9, 95%CI [-14.3; -5.2] p < 0.01, respectively). VCAM-1 increased in the same groups, compared to placebo (12.3, 95%CI[2.8;20.8] p = 0.01 and 16.2, 95%CI [7.2;24.3], p < 0.01, respectively).P-Selectin and ICAM-1 was not significantly affected in any of the groups, compared to placebo (p ≥ 0.11 and p ≥ 0.09, respectively). CONCLUSION: Semaglutide improved endothelial function compared to baseline, but not significantly versus placebo, which likely is due to limited power. CAM responses were heterogeneous, suggesting distinct roles in endothelial dysfunction and atherosclerosis. ClinicalTrialsRegister.eu: EudraCT 2019-000781-38.

Aged↗

PubMed2026

Cardioprotective glucose-lowering drugs, statins, and secondary major adverse cardiovascular events: a nationwide cohort study of individuals with type 2 diabetes and cardiovascular disease.

BACKGROUND: In type 2 diabetes, cardioprotective glucose-lowering drugs, including sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, and statins reduce the risk of secondary major adverse cardiovascular events. No trials examined the combination of these drugs as withholding statins in high-risk individuals would be unethical. We tested the hypothesis that cardioprotective glucose-lowering drug and statin combined is associated with lower risk of secondary major adverse cardiovascular events than either drug alone. METHODS: Individuals with type 2 diabetes and established cardiovascular disease from December 2012 through 2021 were identified via national Danish health registers. They were analyzed in an active comparator cohort including 15,404 individuals followed from treatment intensification with cardioprotective glucose-lowering drug or dipeptidyl peptidase-4 inhibitor and additionally in a time-varying cohort including 76,853 individuals with yearly updated treatment and covariate status. The treatment groups were: (i) no cardioprotective drug (no use of cardioprotective glucose-lowering drug or statin), (ii) cardioprotective glucose-lowering drug, (iii) statin, and (iv) cardioprotective glucose-lowering drug and statin. The primary outcome was a new major adverse cardiovascular event (myocardial infarction, stroke, or cardiovascular death). RESULTS: During mean 2.7 and 4.7 years of follow-up, 1,843 and 23,051 had major adverse cardiovascular events in the active comparator and time-varying cohorts. In the active comparator cohort, when compared to nonusers of cardioprotective glucose-lowering drug or statin, multivariable adjusted hazard ratios of major adverse cardiovascular events were 0.82 (95% confidence interval: 0.67 to 1.02) for cardioprotective glucose-lowering drug, 0.85 (0.74 to 0.97) for statin, and 0.71 (0.60 to 0.84) for cardioprotective glucose-lowering drug and statin combined. Corresponding hazard ratios in the time-varying cohort were 0.77 (0.69 to 0.86), 0.73 (0.70 to 0.75), and 0.57 (0.54 to 0.60), respectively. When restricting the active comparator cohort to individuals entering observation between 2019 and 2021 with reduced statistical power, the corresponding hazard ratios were 0.86 (0.57 to 1.31), 0.89 (0.60 to 1.30), and 0.79 (0.54 to 1.14), respectively. In both cohorts p for interaction between cardioprotective glucose-lowering drug and statin was > 0.05. CONCLUSIONS AND RELEVANCE: In individuals with type 2 diabetes and established cardiovascular disease, treatment with a cardioprotective glucose-lowering drug and statin in combination was associated with lower risk of secondary major adverse cardiovascular events than using either drug alone. This is important given the persistently suboptimal uptake of both drug classes in real-world practice. Some biases can never be completely excluded in real-world pharmacotherapy use studies such as this one, including confounding by indication, time-related or immortal time biases, and shifting standards of care, rendering causal interpretation unattainable; however, our results seemed consistent across numerous sensitivity analyses and designs.

Humans↗

PubMed2026

Glycemic and Renal Effects of SGLT2 Inhibitors in Monogenic Diabetes: A Real-World National Study.

AIMS: Evidence regarding the efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in monogenic diabetes is limited. We evaluated real-world metabolic, renal, and safety outcomes of SGLT2i therapy in adults with monogenic diabetes. MATERIALS AND METHODS: This multicenter retrospective study included adults with genetically confirmed monogenic diabetes treated with SGLT2i. Clinical and biological data were collected at baseline and after approximately 1 and 2 years. Longitudinal changes were analysed using linear mixed-effects models adjusted for baseline value, age, and sex and treatment intensification. RESULTS: Forty patients (mean age 48.6 ± 15.2 years) with MIDD (n = 16), HNF1B-MODY (n = 9), HNF1A/HNF4A-MODY (n = 11), or other MODY subtypes (ABCC8, INS, RFX6; n = 4) were followed for 23.9 ± 5.9 months. HbA1c remained stable overall but decreased significantly in patients with baseline HbA1c ≥ 8% (9.6% ± 1.3% to 7.6% ± 0.7%; p = 0.001). UACR declined significantly (-35.6% at 1 year and -43.5% at 2 years; p = 0.004), particularly in those with baseline CKD (trend). Genotype-specific trends suggested greater glycemic improvement in HNF1A/HNF4A-MODY and greater UACR reduction in MIDD. eGFR declined modestly over time. Non-serious adverse events occurred in 15% of patients, 7.5% discontinued treatment, and no ketoacidosis, acute kidney injury, or deaths were reported. CONCLUSIONS: In this nationwide cohort of patients with monogenic diabetes-the largest reported to date-SGLT2i therapy was associated with improved glycemic control in individuals with baseline HbA1c ≥ 8%, reduced albuminuria, and showed a favourable safety profile. These findings support SGLT2i as a potential therapeutic option that warrants confirmation in larger controlled studies.

Humans↗

PubMed2025

Impact of sodium-glucose cotransporter-2 inhibitors on aging biomarkers and plasma ceramide levels in type 2 diabetes: beyond glycemic control.

BACKGROUND: Aging is a complex biological process marked by the decline of physiological functions and heightened susceptibility to chronic illnesses, notably cardiometabolic disorders. Ceramides (Cer) are lipid derivatives linked to aging and metabolic diseases. Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i), widely used in managing type 2 diabetes, have an unclear impact on aging biomarkers and Cer profiles. OBJECTIVE: This study explored the association between SGLT2i use, plasma Cer levels (CerC16:0, CerC18:0, CerC22:0, CerC24:0, and CerC24:1), and aging biomarkers-Human Insulin-Like Growth Factor 1 (IGF-1), mammalian target of rapamycin (mTOR), 5-Methylcytosine (5MC), and Human H2AFX (Histone H2AX) in patients with type 2 diabetes mellitus (T2DM). METHODS: In this retrospective study, 95 participants were divided into three groups: patients on SGLT2i (n = 34), patients on non-SGLT2i anti-diabetic treatments (n = 36), and healthy controls (n = 25). Plasma Cer and aging biomarkers were quantified using Liquid Chromatography with tandem mass spectrometry (LC-MS-MS) and ELISA, respectively. Principal component analysis (PCA) assessed group-based clustering, while ANCOVA evaluated group differences with confounder adjustment. RESULTS: SGLT2i-treated patients showed significantly lower CerC16:0, CerC22:0, and CerC24:1 levels (p < 0.01) and decreased 5MC and H2AX (p < 0.05) compared to non-SGLT2i patients. IGF-1 was significantly elevated in the SGLT2i group (p < 0.01), suggesting a possible protective effect on metabolic health. PCA distinguished control from diabetic groups but revealed overlap between SGLT2i and non-SGLT2i groups. CONCLUSION: Beyond glucose control, SGLT2i may improve plasma Cer and aging markers in diabetic patients, supporting their broader therapeutic potential in aging and age-related diseases. Further large-scale studies are warranted to confirm these effects and underlying mechanisms.

Humans↗

PubMed2025

Cellular Adhesion Molecules and Adverse Outcomes in Chronic Heart Failure: Findings From the DAPA-HF Randomized Clinical Trial.

IMPORTANCE: Vascular cell adhesion molecule 1 (VCAM-1) and intracellular cell adhesion molecule 1 (ICAM-1) are responsible for immune cell-cell interactions. Systemic levels of VCAM-1 are associated with incident heart failure (HF). OBJECTIVES: To determine if VCAM-1 and ICAM-1 levels are associated with progression of established HF. DESIGN, SETTING, AND PARTICIPANTS: Participants enrolled in the biomarker substudy of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) randomized clinical trial had VCAM-1 and ICAM-1 levels measured at baseline and 12 months. The DAPA-HF trial was conducted at 410 sites in 20 countries. Patients with HF and reduced ejection fraction (HFrEF) in New York Heart Association (NYHA) class II to IV with elevated natriuretic peptides were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Data were analyzed from January 2023 to January 2025. INTERVENTIONS: Dapagliflozin, 10 mg, once daily vs placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was the composite of a worsening HF event or cardiovascular death. The associations between VCAM-1 and ICAM-1 levels at baseline and the primary outcome, its components, and all-cause death were analyzed using Cox proportional hazards regression models adjusted for known prognostic variables including estimated glomerular filtration rate (eGFR), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hs-TnT), as well as high-sensitivity C-reactive protein. RESULTS: A total of 3051 participants (mean [SD] age, 67.2 [10.5] years; 2386 male [78.2%]) were included in this study. Mean (SD) follow-up time was 17.6 (5.2) months. The median (IQR) baseline VCAM-1 level was 997 (816.7-1218.8) ng/mL. Compared with patients with lower concentrations of VCAM-1, those with higher concentrations of VCAM-1 were older (mean [SD] age T3 vs T1, 69.7 [9.7] years vs 64.1 [10.7] years; P < .001), in worse NYHA class (T3 vs T1, NYHA class III/IV 35.6% [362 of 1017] vs 26.5% [269 of 1017]; P < .001), and had higher NT-proBNP (median [IQR] T3 vs T1, 2018 [1126-3753] pg/mL vs 1118 [693-1830] pg/mL) and hs-TnT (median [IQR] T3 vs T1, 24.7 [17.1-37.5] ng/L vs 16.6 [11.6-24.9] ng/L) concentrations, and lower eGFR (mean [SD] T3 vs T1, 58.4 [17.6] mL/min/1.73 m2 vs 71.7 [18.0] mL/min/1.73 m2). Patients in tertile 3 of VCAM-1, compared with tertile 1, had the highest risk of each outcome (eg, adjusted hazard ratio [HR] for primary outcome 1.40; 95% CI, 1.11-1.77; P = .004). ICAM-1 level was not associated with an elevated risk of any outcome. The benefit of dapagliflozin vs placebo in reducing the risk of the primary outcome was consistent across VCAM-1 tertiles: HR, 0.76 (95% CI, 0.54-1.06), 0.82 (95% CI, 0.59-1.12), and 0.77 (95% CI, 0.61-0.98) for tertiles 1, 2 and 3, respectively (P for interaction = .93). There was no significant change in VCAM-1 level with dapagliflozin at 52 weeks. CONCLUSIONS AND RELEVANCE: Results of this substudy of the DAPA-HF randomized clinical trial demonstrate that higher VCAM-1 levels, possibly reflecting a distinct inflammatory/immune pathophysiological pathway in HFrEF, were associated with worse outcomes, even after adjustment for conventional prognostic variables. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03036124.

Aged↗

PubMed2026

Sodium-glucose cotransporter-2 inhibitors and gastrointestinal neoplasm risk in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

The potential carcinogenic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) remain controversial, particularly regarding site-specific gastrointestinal (GI) neoplasms. This systematic review and meta-analysis aimed to determine the relationship between SGLT2 inhibitors and the risk of GI neoplasms in patients with T2DM. We searched PubMed, EMBASE, Cochrane CENTRAL, Scopus, and Web of Science through March 17, 2025, for RCTs in T2DM comparing SGLT2 inhibitors with placebo or active comparators. Two reviewers independently screened studies, extracted data, and assessed the risk of bias. The primary outcome was GI neoplasms reported in publications, supplementary materials, or trial registries, usually as adverse events rather than centrally adjudicated cancer endpoints. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated in Stata 17.0. In 48 RCTs (n = 48,765), SGLT2 inhibitor therapy was not associated with overall GI neoplasm risk (OR = 1.10, 95% CI: 0.84-1.44; p = 0.46; I² = 0%). Site-specific analyses showed no statistically significant association for esophageal (OR = 1.12, 95% CI 0.37-3.45), gastric (1.20, 0.65-2.23), hepatic (0.62, 0.31-1.22), pancreatic (0.91, 0.51-1.64), colonic (1.28, 0.78-2.08), colorectal (0.76, 0.27-2.17), and rectal neoplasms (0.98, 0.49-1.97), with all p-values > 0.05. Subgroup analyses by agents (e.g., canagliflozin, dapagliflozin, empagliflozin), baseline age, body mass index (BMI), HbA1c, treatment duration, and dose were also non-significant (all p > 0.05). Approximately half of the trials had follow-up of one year or less, limiting our ability to evaluate long-term risk. Available RCT evidence does not show a clear increase in GI neoplasm risk with SGLT2 inhibitors in T2DM. However, limited follow-up, low event counts, and non-cancer-specific outcome ascertainment, the findings should be interpreted as reassuring but not definitive evidence of long-term oncologic safety.Systematic review registration: PROSPERO No. CRD42024619019.

Humans↗

PubMed2026

Empagliflozin and functional aerobic capacity in individuals with increased risk of heart failure: The Empire Prevent Cardiac trial.

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.

Humans↗

PubMed2026

From pathobiology to prescribing in obesity-driven HFpEF: A systematic review and practical therapeutic framework.

Heart failure with preserved ejection fraction (HFpEF) is increasingly driven by obesity and cardiometabolic dysfunction. In this phenotype, the dominant biology extends beyond congestion alone and includes visceral and epicardial adiposity, systemic inflammation, impaired myocardial energetics, endothelial dysfunction, and exertional elevation in filling pressures. We performed a PRISMA-compliant systematic review with structured narrative evidence synthesis to evaluate pharmacological therapy in obesity-driven HFpEF, searching PubMed/MEDLINE, Scopus, Web of Science Core Collection, ClinicalTrials.gov, and WHO ICTRP through December 2025. Eighteen reports were included in the final qualitative synthesis. The available evidence supports sodium-glucose cotransporter 2 inhibitors as the pharmacological foundation because they provide the most mature outcome data across the preserved ejection fraction spectrum. Semaglutide improves symptoms, physical limitations, exercise capacity, and body weight in dedicated obesity-related HFpEF trials, whereas tirzepatide extends this signal by improving clinical status and reducing worsening heart failure events. Finerenone broadens the therapeutic platform in HF with mildly reduced or preserved ejection fraction, although obesity-specific data remain indirect. Conventional neurohormonal therapies retain a selective role, but they are not the principal biological match for this phenotype. Obesity-driven HFpEF should therefore be managed as a cardiometabolic syndrome with heart failure expression, using a phenotype-based sequence that links diagnosis, decongestion, SGLT2 inhibition, obesity-directed therapy, and selective adjunctive intensification.

Humans↗