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PubMed2026

Clinical Trial: Phase 3 Trial of Resmetirom Versus Placebo in Metabolic Dysfunction-Associated Steatohepatitis-Reanalysis of Fibrosis Stage 2-3 Subset.

BACKGROUND: Resmetirom is an oral thyroid hormone receptor beta agonist clinically used to treat metabolic dysfunction-associated steatohepatitis (MASH) among adults with stage F2 or F3 fibrosis. AIMS: Because the pivotal, 52-week, randomized, controlled, phase 3 MAESTRO-NASH trial (once-daily oral resmetirom 80 or 100 mg or placebo) included patients with F1, F2, or F3 fibrosis, we conducted a post hoc analysis aimed at assessing treatment response in the subset of patients with stages F2 and F3 fibrosis, consistent with the approved label population. METHODS: Co-primary end points were MASH resolution (hepatocellular ballooning score 0, lobular inflammation score ≤ 1, and ≥ 2-point nonalcoholic fatty liver disease activity score [NAS] reduction from baseline) with no fibrosis worsening, and ≥ 1-stage fibrosis improvement with no NAS worsening at Week 52. RESULTS: Among 917 patients with F2 or F3 fibrosis, metabolic risk factor prevalence was high (hypertension, 78.0%; dyslipidemia, 71.1%; type 2 diabetes, 67.0%). MASH resolution was achieved by 25.7% in the 80-mg group, 29.9% in the 100-mg group, and 9.5% in the placebo group (p < 0.0001 for both comparisons with placebo). Respective percentages with fibrosis improvement were 26.5%, 28.9%, and 17.3% (p < 0.01 for both comparisons). From baseline to Week 24, low-density lipoprotein cholesterol decreased by 11.7% and 13.7% in the 80- and 100-mg resmetirom groups, respectively, and increased by 2.3% with placebo (p < 0.0001 for both comparisons). No new safety signals emerged. CONCLUSION: Results among patients with F2 and F3 fibrosis were consistent with the primary MAESTRO-NASH analysis population, demonstrating efficacy and safety of resmetirom after 52 weeks.

Humans↗

PubMed2026

Incidence of Cirrhosis in Fibrotic Metabolic Dysfunction-Associated Steatohepatitis: A Meta-Analysis of Placebo Arms from Randomized Clinical Trials.

BACKGROUNDS AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) with stage F2-F3 fibrosis represents the main target population for emerging pharmacotherapies. However, data on short-term progression to cirrhosis (F4) in this group remain limited. We aimed to evaluate the incidence of cirrhosis in placebo-treated patients with fibrotic MASH in randomized controlled trials (RCTs). METHODS: In this single-arm meta-analysis, we systematically searched PubMed and Cochrane Library from inception to December 13, 2024, for pharmacological Phase ≥ 2 RCTs reporting cirrhosis events (detected in liver biopsy or clinical signs) among patients with fibrotic MASH receiving placebo. Incidence rates were pooled using generalized linear mixed models with Clopper-Pearson confidence intervals (CIs). RESULTS: We identified a total of 11 RCTs, including 586 patients with fibrotic MASH. Total follow-up was 657.23 person-years (PYs), with 83 cirrhosis events reported. The pooled incidence rate was 13.09 per 100 PYs (95% CI 7.81 to 21.12, I2 = 75.6%, τ2 = 0.682). In subgroup analysis, the incidence of cirrhosis was 3.40 per 100 PYs in MASH F2 (95% CI 1.10 to 10.02, I2 = 0%, τ2 = 0) and 17.90 per 100 PYs (95% CI 10.63 to 28.55, I2 = 70.2%, τ2 = 0.561) in MASH F3, with significant differences between stages (p = 0.006). Sensitivity analyses showed consistent estimates. Most RCTs were judged to have a low risk of bias. CONCLUSIONS: This study provides stage-specific data on cirrhosis incidence in fibrotic MASH, highlighting the high short-term risk associated with MASH F3 in trial settings. These data may inform benchmarks to guide event expectations, enrichment strategies, sample size assumptions, and the interpretation of future MASH clinical trials.

Humans↗

PubMed2026

The glucagon and GLP-1 receptor dual agonist DD01 for metabolic dysfunction-associated steatotic liver disease and steatohepatitis (DD01-DN-02): 12-week results from a randomised, double-blind, multicentre, placebo-controlled, phase 2 trial.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a major public health problem arising in the context of metabolic syndrome and obesity. DD01 is a liver-targeted GLP-1 receptor and glucagon dual agonist being investigated for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH. The DD01-DN-02 trial aimed to evaluate the efficacy and safety of DD01 in adults with MASLD or MASH; this initial analysis reports prespecified 12-week outcomes to assess early hepatic effects. METHODS: DD01-DN-02 is an ongoing, randomised, double-blind, multicentre, placebo-controlled, phase 2 trial conducted at 12 outpatient clinical sites in the USA. Adults aged 18-70 years with obesity or who were overweight (BMI ≥25 kg/m2) were included in the study. Patients with MASLD or MASH underwent liver biopsy and MRI-proton density fat fraction (PDFF) and were eligible if liver fat content was 10% or higher with metabolic risk factors, or if the biopsy confirmed MASH with a non-alcoholic fatty liver disease activity score of at least 4. Participants were randomly assigned (1:1) to receive once-weekly subcutaneous DD01 40 mg or matched placebo over 48 weeks, dose-escalated over 2 weeks, using a centrally administered interactive response technology system. The randomisation sequence was computer-generated by an independent statistician. Participants, investigators, study staff, outcome assessors, and the sponsor were masked to treatment assignment. The primary endpoint was the proportion of participants having at least a 30% relative reduction in liver fat by MRI-PDFF at week 12, which was analysed in all randomly assigned participants receiving at least one dose of study drug or placebo. Safety analyses included all participants who received at least one dose of study drug. Missing primary endpoint data were handled using multiple imputation under a missing-at-random assumption. This trial is registered with ClinicalTrials.gov (NCT06410924) and is ongoing but closed to new participants. FINDINGS: Between June 13, 2024, and Jan 30, 2025, 67 eligible participants were enrolled, of whom 33 were randomly assigned to DD01 and 34 to placebo. The mean age of participants was 48·4 years (SD 10·6), 42 (63%) were female, 25 (37%) were male, 57 (85%) were White, and 52 (78%) participants had biopsy-confirmed MASH. At week 12, 25 (76%) of 33 participants receiving DD01 had a 30% or higher reduction in liver fat versus four (12%) of 34 participants receiving placebo (adjusted common odds ratio 28·8 [95% CI 7·2-115·2]; adjusted relative risk 6·3 [95% CI 2·5-15·9]; p<0·0001). Treatment-emergent adverse events occurred in 28 (85%) of 33 participants receiving DD01 and 23 (68%) of 34 participants receiving placebo. The most common adverse events were nausea (18 [55%] of 33 participants assigned DD01; six [18%] of 34 participants assigned placebo), diarrhoea (nine [27%] of 33; six [18%] of 34), and vomiting (ten [30%] of 33; four [12%] of 34). Treatment-emergent adverse events led to treatment discontinuation in four (12%) of 33 participants in the DD01 group and one (3%) of 34 participants in the placebo group. Two (6%) treatment-emergent serious adverse events occurred in the DD01 group (abdominal pain and acute cholecystitis) and zero in the placebo group. No deaths occurred. INTERPRETATION: In this prespecified 12-week primary analysis, DD01 produced rapid reductions in liver fat compared with placebo, supporting further evaluation in long-term studies. FUNDING: D&D Pharmatech, Neuraly.

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PubMed2026

The Association Between NT-Pro BNP, Nephropathy and Endothelial Dysfunction in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) is an established biomarker of heart failure and has been recommended for cardiovascular risk stratification in type 2 diabetes mellitus (T2DM). However, its relationship with diabetic nephropathy and endothelial dysfunction across varying stages of kidney impairment remains unclear. This study examined the associations of NT-Pro BNP, renal impairment, albuminuria and endothelial dysfunction in patients with T2DM without overt heart failure. METHODS: A comparative cross-sectional study was conducted among 192 adults with T2DM. Participants were stratified by KDIGO eGFR groups (≥ 90, 60-89, 30-59 mL/min/1.73m2). NT-Pro BNP was considered abnormal at a cut-off of ≥ 125 pg/mL. Albuminuria was categorized using the urinary albumin-to-creatinine ratio (uACR). Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). Logistic regression analysis was performed to identify independent factors of elevated NT-Pro BNP, with p-values < 0.05 considered statistically significant. RESULTS: NT-Pro BNP levels were significantly higher in the lower eGFR groups compared with normal eGFR (204.3 vs. 96.8 vs. 62.2 pg/mL, p < 0001). A weak but significant positive correlation was observed between NT-Pro BNP and uACR (r = 0.31, p < 0.001). However, no significant association was found between NT-Pro BNP and FMD (p = 0.388). Following multivariable adjustments, older age (adjusted OR 1.14, 95% CI: 1.06-1.23, p < 0.001), higher systolic blood pressure (adjusted OR 1.05, 95% CI: 1.02-1.08, p = 0.010), lower eGFR (adjusted OR 0.97, 95% CI: 0.95-0.99, p = 0.003) and beta-blocker use (adjusted OR 4.65, 95% CI: 1.61-13.45, p < 0.001) were independently associated with elevated NT-Pro BNP. CONCLUSION: In patients with T2DM without overt heart failure, elevated NT-Pro BNP showed a statistically significant association with lower eGFR and higher albuminuria. Moderate to severe albuminuria becomes an independent factor for elevated NT-Pro BNP after adjustment excluding eGFR. The lack of association with endothelial dysfunction suggests that NT-Pro BNP may reflect different pathophysiological pathways. NT-Pro BNP may serve as a useful biomarker for early cardiovascular risk stratification and identification of individuals at risk of pre-heart failure in diabetic kidney disease.

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PubMed2026

Efficacy and Safety of Bimagrumab in Adults With Obesity and Metabolic Dysfunction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

AIMS: This study aims to systematically evaluate the efficacy of bimagrumab on body composition and glucose parameters in adults with obesity and metabolic dysfunction and its safety profile. METHODS: We searched MEDLINE, PubMed, Embase, and the Cochrane Library on April 20, 2026, for randomized controlled trials (RCTs) assessing bimagrumab treatment in adults with obesity, insulin resistance, or type 2 diabetes mellitus (T2DM). The risk of bias was assessed using the Cochrane Risk of Bias tool (RoB 2), and meta-analyses of efficacy and safety data were conducted using R software. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system was used to assess the strength of evidence. The study was registered with PROSPERO (CRD420261377110). RESULTS: Of the 134 retrieved records, 4 RCTs (enrolling 268 participants) were included. The included population represented a broad spectrum of metabolic dysfunction, from obesity and nondiabetic insulin resistance to established T2DM. Compared with placebo, bimagrumab treatment significantly reduced total weight (mean difference [MD] -4.85 kg, 95% confidence interval [CI] -6.82 to -2.88), fat mass (-4.72 kg [-8.05 to -1.40]), and glycated haemoglobin (HbA1c) (-0.13% [-0.23 to -0.03]) and significantly increased total lean mass (1.66 kg [0.81 to 2.51]). However, bimagrumab led to an increase in low-density lipoprotein (LDL) concentrations of 0.47 mmol/L [0.03 to 0.91] and significantly increased incidences of discontinuation (risk ratio [RR] 5.75 [1.61 to 20.46]), muscle spasms (RR 10.44 [4.23 to 25.75]), and diarrhoea (RR 4.91 [2.38 to 10.11]). CONCLUSION: Bimagrumab effectively reversed adverse effects on body composition in obese individuals, resulting in significant fat reduction, increased skeletal muscle mass, and improved glycemic control, suggesting that bimagrumab is a promising new target for personalized metabolic therapy.

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PubMed2026

Angiography-Based Index of Microcirculatory Resistance in Assessing the MVO and Infarct Size in STEMI Patients.

OBJECTIVES: To evaluate angiography-based index of microcirculatory resistance (angio-IMR) in assessing microvascular obstruction (MVO) and infarct size (IS) in ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The effect of thrombolysis on post-percutaneous coronary intervention (PCI) angio-IMR, and its associations with MVO and IS remains unclear. METHODS: One hundred twenty-three STEMI patients randomized to receive 5 mg intravenous bolus of recombinant staphylokinase (r-SAK) or normal saline (NS) before PCI were recruited. Angio-IMR was computed in infarct-related arteries. MVO and IS were detected by cardiac magnetic resonance imaging. RESULTS: Compared with NS group, r-SAK group exhibited numerically lower post-PCI angio-IMR (39.12 U vs. 42.57 U; p = 0.567), MVO (54.0% vs. 70.9%; p = 0.059), MVO extent (0.70% vs. 1.90%; p = 0.101) and IS (21.30% vs. 24.50%; p = 0.079). Post-PCI angio-IMR was positively correlated with MVO extent (ρ = 0.347; p < 0.001) and IS (ρ = 0.324; p < 0.001). Receiver operating characteristic analyses showed moderate diagnostic performance of angio-IMR for MVO (area under the curve [AUC] = 0.750; p < 0.001), MVO > 2.6% (AUC = 0.735; p < 0.001) and IS > 25% (AUC = 0.712; p < 0.001). The exploratory optimal cut-off values for these endpoints were approximately 40 U. CONCLUSIONS: In STEMI patients, a single bolus of r-SAK before PCI was associated with numeric reductions in post-PCI angio-IMR, MVO, MVO extent and IS. Additionally, angio-IMR exhibited a significantly positive correlation with both MVO extent and IS, demonstrating the diagnostic value of this wire-free method for assessing microvascular injury.

Humans↗

PubMed2026

Revealing the Shared Genetic Architecture of Metabolic Dysfunction-Associated Steatotic Liver Disease-Related Traits Through Genomic Structural Equation Modeling.

Although individual traits related to metabolic dysfunction-associated steatotic liver disease (MASLD) have been investigated through large-scale genome-wide association studies (GWASs), the shared genetic susceptibility across these traits remains unclear. We therefore conducted a multivariate GWAS of key MASLD-related traits to elucidate their common genetic architecture. We applied genomic structural equation modeling to model a latent genetic factor (MASLD-F) underlying genetically correlated MASLD-related traits, leveraging their GWAS-derived genetic correlations. We then performed functional annotations, including fine-mapping, transcriptome-wide association study, and cell- and tissue-type-specific enrichment analyses, and conducted Mendelian randomization analyses to identify modifiable risk factors. Our multivariate MASLD-F GWAS identified 50 independent variants across 48 genomic loci. Transcriptomic imputation identified several MASLD-F-associated genes, including ARNTL, NPC1, BTBD10, VDAC2, TSKU, SFMBT1, and ABHD17C. We observed significant enrichment of MASLD-F-related genetic signals predominantly in brain tissues, pancreatic islets, and the adrenal gland. Additionally, six modifiable risk factors and four modifiable protective factors for MASLD-F were identified. These findings reveal a complex shared genetic architecture underlying MASLD components, thereby expanding our understanding of disease pathogenesis and providing novel insights for precision medicine and public health interventions.

Humans↗

PubMed2026

A Dynamic Nomogram to Predict Metabolic Dysfunction-Associated Fatty Liver Disease in Patients with Metabolic Syndrome.

BACKGROUND: Metabolic syndrome (MetS) involves multiple metabolic disorders. This study aimed to identify high-risk populations for metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with MetS and to establish a dynamic predictive nomogram. METHODS: A total of 627 patients with MetS from six regions in Zhejiang Province were enrolled and categorized into MAFLD and non-MAFLD groups, then randomly assigned to training and validation sets at a ratio of 7:3. Independent predictors of MAFLD were identified using least absolute shrinkage and selection operator regression and multivariable logistic regression analyses. These predictors were then used to construct a dynamic nomogram. RESULTS: A total of 627 patients with MetS were included in the final analysis, of whom 77.0% (483/627) were diagnosed with MAFLD. Multivariable logistic regression analysis identified body mass index (BMI), waist circumference (WC), total cholesterol (TC), alanine aminotransferase (ALT), MetS-defined dysglycemia, and education level as independent risk factors for MAFLD. MetS-defined dysglycemia showed the highest odds ratio (OR) for MAFLD development [OR = 1.87, 95% confidence interval (CI): 1.07-3.29]. Although the number of MetS components and the metabolic syndrome score were significantly associated with MAFLD in univariate analysis, they were not independently associated with MAFLD in the multivariate model. A dynamic nomogram for predicting MAFLD risk in patients with MetS was developed and internally validated. The area under the receiver operating characteristic curve was 0.834 (95% CI: 0.787-0.880) in the training set and 0.839 (95% CI: 0.771-0.899) in the validation set, indicating strong predictive performance. Bootstrap internal validation demonstrated good agreement between predicted and observed outcomes in calibration curves. Decision curve analysis further indicated favorable clinical applicability of the nomogram. CONCLUSION: BMI, WC, TC, ALT, MetS-defined dysglycemia, and education level are independent risk factors for MAFLD. A dynamic nomogram for predicting MAFLD risk in patients with MetS was successfully developed and validated.

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PubMed2026

Vitamin D Deficiency During Pregnancy Is Associated With Greater LDL-C Increase, Elevated β-Hydroxybutyrate and Altered Neonatal Metabolic Markers-A Secondary, Pooled Analysis of the Randomized, Controlled Vitamin D and Lifestyle for Gestational Diabetes Prevention Trial (DALI).

INTRODUCTION: Vitamin D (vitD) plays a role in metabolic regulation, including lipid metabolism and insulin sensitivity. During pregnancy, profound physiological changes in lipid handling and ketogenesis occur to support fetal development. However, the extent to which maternal vitamin D status influences these metabolic adaptations and fetal metabolic markers remains unclear. METHODS: In this secondary analysis, we examined lipid distribution throughout pregnancy-from before 20 weeks' gestation to delivery-in women with overweight or obesity, stratified by vitamin D status (deficiency, insufficiency, or sufficiency), assessing both maternal and cord blood. Main inclusion criteria were: age > =18 years, singleton pregnancy, < 20 weeks' gestation, BMI ≥ 29 kg/m2. Women with GDM < 20 weeks' gestation were excluded. In total, 962 pregnant women were divided into vitD deficient (< 30 nmol/L, n = 102), insufficient (30-50 nmol/L, n = 222) and sufficient (> 50 nmol/L, n = 638) groups. VitD levels and lipid concentrations were assessed at < 20, 24-28 and 35-37 weeks' gestation and in cord blood. RESULTS: Compared with vitD sufficient women, women with vitD deficiency had significantly larger increases in LDL-C throughout pregnancy and ß-OH-butyrate at 24-28 weeks' gestation, in adjusted analysis. VitD in cord blood was highest in offspring of mothers with vitD sufficiency. In cord blood, significantly higher ß-OH-butyrate was observed with vitD deficiency; lipid concentrations were similar between groups. CONCLUSIONS: Early vitamin D deficiency before 20 weeks of gestation was associated with altered metabolic trajectories during pregnancy, including greater increases in LDL cholesterol and ketone body concentrations in women with overweight or obesity, as well as higher cord blood ketone levels in their offspring. These findings suggest that early maternal vitamin D status may influence maternal and fetal metabolic adaptations, although causal relationships and clinical implications require further investigation. TRIAL REGISTRATION: Trial registered at ISRCTN registry (https://doi.org/10.1186/ISRCTN70595832) trial number ISRCTN70595832. Registration date 02/12/2011.

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PubMed2026

Biliary Cirrhosis in Myhre Syndrome: The First Case Report of Liver Transplantation and a Review of Reported Hepatic Findings.

Myhre syndrome is a rare autosomal-dominant disorder caused by gain-of-function pathogenic variants in SMAD4 and is now recognized as a progressive multisystem fibrotic disease. Although transforming growth factor-β (TGF-β) signaling plays a central role in hepatic fibrogenesis, hepatobiliary involvement in Myhre syndrome has not been systematically evaluated. We report the first case of Myhre syndrome complicated by rapidly progressive biliary cirrhosis requiring liver transplantation in a 15-year-old male with a confirmed SMAD4 p.Ile500Val variant. Following an infectious episode, the patient developed severe cholestasis with imaging and histopathologic findings consistent with fibro-obliterative cholangiopathy, ultimately necessitating living donor liver transplantation. A systematic review of 55 published reports comprising 217 patients with Myhre syndrome revealed that hepatic evaluation was rarely performed and that previously reported liver abnormalities were mild and secondary, most commonly related to right heart dysfunction or metabolic disease, with no prior cases of progressive biliary fibrosis. This case suggests that dysregulated SMAD4-TGF-β signaling may predispose selected organs to fibro-obliterative injury and that infection-driven inflammation may act as a critical trigger for hepatic fibrosis in Myhre syndrome, expanding the recognized spectrum of organ involvement in this disorder.

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PubMed2026

Plasma proteome profiling identifies XPNPEP3 as a novel biomarker associated with metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus.

OBJECTIVE: To identify plasma protein differences between type 2 diabetes mellitus (T2DM) patients with and without metabolic dysfunction-associated steatotic liver disease (MASLD), and to evaluate the diagnostic potential of X-prolyl aminopeptidase 3 (XPNPEP3) for identifying MASLD in T2DM patients. METHODS: Twenty T2DM inpatients were categorized into groups with and without MASLD and their plasma samples were analyzed using data-independent acquisition mass spectrometry, followed by bioinformatics analysis to identify differentially expressed proteins. The cohort was then expanded to 84 patients, and plasma XPNPEP3 levels were validated by enzyme-linked immunosorbent assay. Correlation between XPNPEP3 and clinical indicators were evaluated, and diagnostic performance was determined via receiver operating characteristic (ROC) analysis. Immunohistochemistry was employed to compare hepatic XPNPEP3 expression between the two groups. RESULTS: Proteomic analysis identified 176 differentially expressed proteins, with XPNPEP3 exhibiting the most significant down-regulation by fold change. In the validation cohort, plasma XPNPEP3 was significantly lower in T2DM+MASLD versus T2DM alone. XPNPEP3 levels were negatively correlated with diabetes duration, liver function markers, and triglyceride levels, and was identified as an independent factor inversely associated with MASLD in T2DM.ROC analysis demonstrated strong diagnostic performance for XPNPEP3, further enhanced when combined with BMI and diabetes duration.  Immunohistochemistry confirmed reduced hepatic XPNPEP3 expression in T2DM+MASLD patients. CONCLUSIONS: Lower plasma XPNPEP3 is independently associated with MASLD in T2DM patients and demonstrates strong diagnostic potential, positioning XPNPEP3 as a promising biomarker for diagnosing MASLD in T2DM patients and a novel target for non-invasive diagnostic tool development.

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PubMed2026

Efficacy of dapagliflozin on hepatic steatosis and fibrosis in patients with type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease: a pre-specified single-arm analysis from a randomized controlled trial.

AIM: To evaluate the association of dapagliflozin therapy with changes in hepatic steatosis and non-invasive fibrosis surrogate markers in patients with type 2 diabetes mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) over 12 months. METHODS: This is a pre-specified single-arm analysis from a randomised, open-label, parallel-group trial. Of 54 participants randomised to dapagliflozin 10 mg daily, 50 (92.6%) completed the 12-month follow-up and were included in the per-protocol analysis. Assessments at baseline, 3, 6, and 12 months included transient elastography (CAP and LSM), ultrasonography, and biochemical tests. Primary endpoints were changes in hepatic steatosis (CAP) and non-invasive fibrosis surrogates (LSM). RESULTS: Significant reductions were observed in hepatic steatosis (CAP: 316.7 to 245.7 dB/m; mean change - 71.02 dB/m, 95% CI: -63.4 to - 78.6; p < 0.001) and in liver stiffness as a non-invasive fibrosis surrogate (LSM: 8.59 to 7.28 kPa; mean change - 1.31 kPa, 95% CI: -0.92 to - 1.70; p < 0.001). Improvements were also observed in glycaemic control, body weight, lipid profile, liver enzymes, ultrasonographic steatosis grading, and serum fibrosis markers. Genitourinary infections were the most frequently reported adverse events (32%); no serious adverse events were recorded. CONCLUSIONS: Dapagliflozin was associated with significant improvements in hepatic steatosis, non-invasive fibrosis surrogate markers, metabolic parameters, and liver function in T2DM patients with MASLD over 12 months. These findings provide region-specific evidence for an Indian population and support further controlled investigation. However, these findings should be interpreted in light of the pre-specified single-arm design of this analysis, the open-label methodology, relatively small sample size, and the absence of liver biopsy confirmation.

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PubMed2026

Metabolic Stress Testing Reveals Persistent Lipid-Handling Dysfunction in Women With Polycystic Ovary Syndrome Despite Exercise Training.

AIM: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and metabolic dysfunction, yet baseline metabolomic studies show inconsistent findings. We investigated whether metabolic abnormalities in PCOS emerge under physiological stress and how these responses are modified by exercise training. MATERIALS AND METHODS: Twelve women with PCOS and 10 controls completed hyperinsulinaemic-euglycaemic clamps with randomised saline or lipid infusion, before and after 8 weeks of supervised exercise. Plasma metabolomics (163 metabolites) were measured at baseline, post-infusion and post-clamp. Linear mixed-effects models assessed Group × Timepoint × Intervention interactions. RESULTS: No baseline metabolite differences were observed between groups. A significant three-way interaction (p = 0.008) indicated condition-dependent trajectory divergence. Post hoc analysis revealed a specific divergence during post-exercise lipid challenge (p = 0.048). Women with PCOS showed reduced suppression of ether-linked phosphatidylcholines during insulin-stimulated lipid loading (PC ae C44:4, p = 0.031), despite exercise-induced improvements in fitness and normalisation of amino acid profiles. Exploratory metabolite ratios suggested impaired substrate coordination under stress. CONCLUSIONS: Metabolic defects in PCOS are stress-dependent and not detectable at rest. Exercise training improves resting metabolism but reveals persistent impairment in adaptive lipid handling during combined insulin and lipid challenges, suggesting impaired coordination of substrate supply during metabolic stress. TRIAL REGISTRATION: ClinicalTrials.gov identifier: ISRCTN42448814.

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PubMed2026

Effects of multistrain probiotic supplementation on hepatic function and anthropometric parameters in patients with metabolic dysfunction-associated steatotic liver disease: a double-blind, randomized controlled trial.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly prevalent on a global scale. The gut microbiota is integral to its pathogenesis, prompting extensive research into microbiota modulation as a potential adjunctive therapeutic strategy. AIM: The study aimed to evaluate the effect of multistrain probiotics supplementation on hepatic function in patients with MASLD in a double-blind, randomized, controlled trial. The primary outcomes were changes in Fibrosis-4 index (FIB-4) and fatty liver index (FLI). Secondary outcomes included changes in anthropometric parameters, selected biochemical markers, and other liver-related indices. METHODS: A total of 64 patients with MASLD were randomly assigned to two groups receiving either placebo (C) or a probiotic mixture (PRO) containing the following bacterial strains: 50% Lactococcus lactis Rosell-1058, 25% Lacticaseibacillus casei Rosell-215, 12.5% Lactobacillus helveticus Rosell-52, 12.5% Bifidobacterium bifidum Rosell-71 for 12 wk. RESULTS: Significant group × time interactions were observed for FIB-4 (Q = 0.007), with reduction in the PRO group and increase in the C group (-0.05 vs. 0.10; P = 0.002). No significant interaction was found for FLI (Q = 0.942). Significant group × time interactions were also observed for aspartate aminotransferase (-2.87 vs. 1.87 U/L; Q = 0.003) and APRI (-0.03 vs. 0.02; Q = 0.001), favoring the PRO group (P < 0.001 for both). No significant changes were observed in anthropometric parameters, glucose levels, or lipid profile. CONCLUSIONS: In patients with MASLD, the 12-wk probiotic supplementation had a modest but statistically significant effect on FIB-4, aspartate aminotransferase, and APRI, with no significant effect on FLI or anthropometric and metabolic parameters. These findings suggest that this probiotic formulation may have potential benefits for liver function in MASLD. However, long-term studies incorporating imaging-based and histological endpoints are required to determine the clinical significance of these findings.

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PubMed2026

Hypoglycaemia Was Not Associated With Depression, Anxiety, Diabetes Distress or Fear of Hypoglycaemia Scores in People With Type 1 or Insulin-Treated Type 2 Diabetes in the Hypo-METRICS Study.

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Letter↗

PubMed2026

Effects of GLP-1 Receptor Agonists and Dual GIP/GLP-1 Receptor Agonists on Inflammatory and Metabolic Biomarkers in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists improve cardiovascular outcomes in type 2 diabetes mellitus (T2DM), but their effects on inflammatory and oxidative biomarkers are not fully defined. MATERIALS AND METHODS: We searched PubMed, Ovid MEDLINE, Scopus, Web of Science and the Cochrane Library from inception to 19 February 2026 for randomised controlled trials (RCTs) in adults with T2DM comparing a GLP-1RA or dual GIP/GLP-1 agonist with placebo or active therapy, and reporting C-reactive protein (CRP or high-sensitivity CRP [hs-CRP]), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), malondialdehyde (MDA) or adiponectin. Random-effects meta-analyses were conducted using standardised mean differences (SMDs). RESULTS: Forty-one RCTs were included. GLP-1RAs significantly reduced CRP/hs-CRP (27 studies, 1991 participants; SMD -0.37, 95% CI -0.59 to -0.14) and MDA (3 studies, 272 participants; SMD -0.98, 95% CI -1.65 to -0.30), and increased adiponectin (16 studies, 1327 participants; SMD 0.30, 95% CI 0.13 to 0.46). Pooled effects on IL-6 (17 studies, 1068 participants; SMD -0.14, 95% CI -0.37 to 0.10), TNF-α (16 studies, 1164 participants; SMD -0.25, 95% CI -0.61 to 0.12) and MCP-1 (7 studies, 450 participants; SMD -0.27, 95% CI -0.58 to 0.03) were not statistically significant, although MCP-1 decreased in sensitivity analyses. Across biomarkers, heterogeneity was moderate to high. Two tirzepatide RCTs (562 participants) showed a significant reduction in IL-6 (SMD -0.28, 95% CI -0.47 to -0.09) and a non-significant trend towards lower CRP/hs-CRP. CONCLUSIONS: In adults with T2DM, incretin-based therapies consistently lower CRP/hs-CRP, reduce oxidative stress (MDA) and increase adiponectin, while effects on IL-6 and TNF-α are more variable. These data support a selective anti-inflammatory and metabolic regulatory profile of GLP-1-based therapy, but heterogeneity and limited data for some biomarkers warrant cautious interpretation and further mechanistic studies. TRIAL REGISTRATION: PROSPERO number: CRD420261321430.

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PubMed2026

Low Carbohydrate Availability in Energy Balance Alters Bone Turnover and Muscle Proteomic Response With Limited Endocrine Disruption.

Training with low carbohydrate availability (LCA) has been proposed as an independent determinant of physiological perturbations commonly attributed to low energy availability (LEA) and to increase skeletal muscle oxidative machinery, yet the effects of LCA in isolation from LEA remain unclear. We examined whether short-term carbohydrate restriction under energy balance alters endocrine and metabolic markers associated with LEA and skeletal muscle proteomic response. In a randomized crossover design, eight trained males completed 4 days of either a low-carbohydrate high-fat diet (LOW; 12% carbohydrate, 69% fat, 19% protein) or a normal-carbohydrate diet (NORM; 62% carbohydrate, 19% fat, 19% protein), while undertaking daily cycloergometer exercise (15 kcal kg FFM-1 day-1) and maintaining energy availability at 45 kcal kg FFM-1 day-1. LOW induced a clear metabolic shift consistent with LCA, evidenced by elevated circulating free fatty acids, glycerol and β-hydroxybutyrate, in fasting conditions and fat oxidation at rest and during exercise, alongside reduced exercise glucose concentrations. Despite these responses, LOW did not alter insulin, testosterone, triiodothyronine, leptin, hepcidin, or P1NP. In contrast, β-CTX increased and IGF-1 decreased relative to NORM. Muscle glycogen concentration decreased only in LOW (40% ± 14%). Proteomic analysis identified 671 proteins; 57 differentially expressed in LOW relative to NORM were limited to fatty acid metabolism pathways and suppression of ribosomal, sarcomeric, and extracellular matrix proteins. These findings indicate that isolated LCA exerts limited endocrine disruption but may selectively compromise bone turnover and muscle anabolic response, suggesting that without acute LEA, LCA has limited influence on muscle oxidative phenotype.

Male↗

PubMed2026

Cognitive-metabolic relationship in temporal lobe epilepsy: A systematic review.

OBJECTIVE: To summarize the current literature on neurometabolic dysfunction identified through brain imaging and its cognitive correlates in temporal lobe epilepsy (TLE). BACKGROUND: Cognitive decline contributes to chronic disability in TLE. The pathophysiology of cognitive decline in TLE is poorly understood, limiting therapeutic advances. Characterizing metabolic changes in patients with TLE and cognitive impairment may identify biomarkers and inform new treatment strategies. DESIGN/METHODS: We conducted a systematic review of five major databases, gathering studies published through December 2024, in accordance with PRISMA guidelines. We included all observational studies describing associations between metabolic imaging findings and cognitive measures in TLE. RESULTS: Of 1449 reports, 38 met the inclusion criteria, encompassing 1161 patients with TLE aged 5-66 years. Twenty-two studies applied fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) to assess interictal brain glucose metabolism. Two studies utilized PET with other tracers to assess more specific metabolic aspects. Fourteen studies used proton magnetic resonance spectroscopy (1H-MRS) to quantify local concentrations of brain metabolites. Impairment of verbal memory was consistently associated with left temporal lobe metabolite changes. Non-memory cognitive impairments correlated with changes in glucose metabolism, N-acetylaspartate, and gamma-aminobutyrate in both temporal and extratemporal areas. CONCLUSION: 18F-FDG PET remains the most widely used imaging modality to assess cognitive-metabolic correlates in TLE, while other PET tracers and 1H-MRS are potentially underexplored. Verbal memory impairment correlates robustly with left temporal dysmetabolism. Cognitive impairment in TLE is multifaceted and correlates with measurable changes in metabolism in both temporal and extratemporal regions. While our synthesis was restricted by some methodological limitations, these neurometabolic signatures may hold promise as potential biomarkers for identifying risk of cognitive decline and highlight avenues for future research.

Humans↗

Results for “metabolic dysfunction&#x2010;associated steatohepatitis (MASH)”

Results for “metabolic dysfunction‐associated steatohepatitis (MASH)”