Metabolism open最新文献

{"title":"Novel causal associations between plasma metabolites and prostate cancer risk revealed by mendelian randomization","authors":"Hanghang Chen ,&nbsp;Huiduo Zhao ,&nbsp;Bingxin Meng ,&nbsp;Qi Liu","doi":"10.1016/j.metop.2025.100421","DOIUrl":"10.1016/j.metop.2025.100421","url":null,"abstract":"<div><h3>Background</h3><div>Prostate cancer (PCa) is a major global health concern for men, yet its underlying metabolic mechanisms are not fully understood. Identifying causal metabolites could reveal novel pathways for risk assessment and prevention.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive two-sample Mendelian randomization (TSMR) study following STROBE-MR guidelines. Genetic instruments for plasma metabolites were derived from two independent sources, including the METSIM study, a cohort exclusively comprising Finnish men, and the Canadian Longitudinal Study on Aging (CLSA). Summary-level data for PCa were obtained from the PRACTICAL consortium and FinnGen. Inverse variance weighted (IVW) was the primary analysis method, supplemented by sensitivity analyses and Bayesian colocalization (coloc) to assess shared causal genetic variants, a key methodological strength enhancing causal inference.</div></div><div><h3>Results</h3><div>Our analysis identified four plasma metabolites with a significant causal relationship with PCa risk. Ribitol was associated with a reduced risk, while N2,N5-diacetylornithine, N-acetylarginine, and N-acetylcitrulline were associated with an elevated risk. These findings were consistent across datasets and robust in sensitivity analyses. Colocalization analysis provided strong evidence (PP.H4 &gt; 0.8) for a shared causal variant at the rs10201159 locus between N2,N5-diacetylornithine and PCa.</div></div><div><h3>Conclusion</h3><div>This study provides robust genetic evidence supporting a causal role of specific plasma metabolites in prostate cancer development. The incorporation of a male-exclusive metabolomic dataset (METSIM) strengthens the validity of our findings for this male-specific cancer. These metabolites represent promising candidates for further mechanistic investigation into prostate cancer etiology and potential translation into clinical biomarkers.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100421"},"PeriodicalIF":2.7,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of pancreatic islet macrophages in type 2 diabetes mellitus: from underlying pathological mechanisms to therapeutic target discovery","authors":"Zhongpeng Qiu ,&nbsp;Dejing Shang","doi":"10.1016/j.metop.2025.100418","DOIUrl":"10.1016/j.metop.2025.100418","url":null,"abstract":"<div><div>The pathogenesis of type 2 diabetes mellitus (T2DM) is closely associated with chronic inflammation within the islet microenvironment, where pancreatic islet macrophages serve as central orchestrators of local immune regulation. This review provides a systematic overview of the ontogeny, phenotypic heterogeneity, and functional roles of pancreatic islet macrophages in T2DM pathology. Pancreatic islet macrophages contribute to β-cell proliferation and the maintenance of islet homeostasis through the secretion of various growth factors, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Under conditions of metabolic stress, including lipotoxicity and glucotoxicity, these macrophages are polarized toward a pro-inflammatory phenotype. In this state, they impair β-cell function by releasing inflammatory mediators, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Furthermore, this article discusses potential clinical strategies that target pancreatic islet macrophages—such as anti-inflammatory agents and immunomodulators—highlighting their promise as novel perspectives for precise intervention in T2DM.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100418"},"PeriodicalIF":2.7,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probiotics, prebiotics, synbiotics, and FMT for glycemic control: A systematic review of clinical efficacy and mechanistic readouts in type 2 diabetes and related dysglycemia","authors":"Neda Shalbaf ,&nbsp;Soheila Sadeghi ,&nbsp;Sina Homaee ,&nbsp;Farnaz Saberian","doi":"10.1016/j.metop.2025.100419","DOIUrl":"10.1016/j.metop.2025.100419","url":null,"abstract":"<div><h3>Objective</h3><div>To systematically evaluate the clinical efficacy of probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT) on glycemic control in adults with type 2 diabetes (T2D) and related dysglycemia, and to synthesize associated mechanistic changes in microbial metabolites and composition.</div></div><div><h3>Methods</h3><div>A systematic review was conducted following PRISMA 2020 guidelines. PubMed/MEDLINE, Scopus, and Web of Science were searched from inception through August 2025 for randomized controlled trials (RCTs) in adults with T2D, prediabetes, or metabolic syndrome. Interventions included probiotics, prebiotics, synbiotics, or FMT compared to control. Outcomes were glycemic indices (e.g., HbA1c, HOMA-IR) and mechanistic biomarkers (e.g., SCFAs, bile acids). Risk of bias was assessed using the Cochrane RoB 2 tool. A narrative synthesis was performed.</div></div><div><h3>Results</h3><div>Thirty studies were included. Multi-strain probiotics, prebiotics, and synbiotics yielded modest but significant improvements in HbA1c (≈−0.2 to −0.4 %), fasting glucose, and HOMA-IR, particularly with durations ≥12 weeks. These benefits were linked to mechanistic shifts, including increased circulating butyrate and ursodeoxycholate, enrichment of SCFA-producing taxa, and reduced endotoxemia. Efficacy was moderated by concomitant medications: metformin use was synergistic, while sulfonylureas attenuated effects. FMT consistently improved clamp-measured insulin sensitivity in insulin-resistant phenotypes, but its effects on HbA1c were less consistent and donor-dependent.</div></div><div><h3>Conclusion</h3><div>Microbiome-targeted interventions, especially multi-strain probiotics and substrate-matched synbiotics, are effective adjuncts for improving glycemic control, with effects mediated through microbial metabolite production. FMT primarily modulates insulin sensitivity. Clinical outcomes are context-dependent, influenced by intervention design, duration, and pharmacomicrobiomic interactions.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100419"},"PeriodicalIF":2.7,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of normal weight obesity among adults in Southeast Asia: Insights from a systematic review and meta-analysis","authors":"K.G. Sruthi ,&nbsp;C. Aditya ,&nbsp;Paramjot Panda ,&nbsp;Jyoti Ranjan Mohanty ,&nbsp;Manas Ranjan Behera","doi":"10.1016/j.metop.2025.100416","DOIUrl":"10.1016/j.metop.2025.100416","url":null,"abstract":"<div><h3>Background</h3><div>Normal Weight Obesity (NWO) describes individuals with a normal body mass index (BMI) but elevated body fat percentage (BF%), placing them at increased risk for cardiometabolic complications. This condition is particularly relevant in Southeast Asian populations, where visceral adiposity occurs at lower BMI thresholds. However, regional pooled prevalence data are limited.</div></div><div><h3>Methods</h3><div>A systematic search was conducted in PubMed, EMBASE, Scopus, Web of Science, and Google Scholar for studies published between January 2010 and May 2025. Eligible studies included observational data on adults (≥18 years) from Southeast Asia reporting NWO prevalence, defined by normal BMI (18.5–24.9 kg/m²) with validated surrogate indices indicative of excess adiposity. Two reviewers independently conducted screening, data extraction, and quality appraisal using the Joanna Briggs Institute (JBI) tool. A random-effects meta-analysis was performed using the Freeman-Tukey double arcsine transformation, with heterogeneity assessed via the I² statistic.</div></div><div><h3>Results</h3><div>Eight studies involving 9028 participants from five Southeast Asian countries (Philippines, Malaysia, Thailand, Myanmar, Singapore) were included. The pooled prevalence of NWO was 57 % (95 % CI: 37 %–75 %), with study-specific estimates ranging from 22.8 % to 82 %. Heterogeneity was high (I² = 98.9 %). Most studies used bioelectrical impedance analysis (BIA) for body fat assessment and were rated as moderate to high quality.</div></div><div><h3>Conclusion</h3><div>NWO is common among adults in Southeast Asia, especially in women and young adults. These findings highlight the limitations of BMI as a screening tool and support the integration of body fat assessments into public health screening and clinical protocols for early risk detection.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100416"},"PeriodicalIF":2.7,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatic activating transcription factor 3 protects against systemic inflammation by attenuating lipotoxicity","authors":"Chencheng Hu ,&nbsp;Qian Yang ,&nbsp;Runzhi Yu ,&nbsp;Shuwei Hu ,&nbsp;Bing Meng ,&nbsp;Yanyong Xu","doi":"10.1016/j.metop.2025.100417","DOIUrl":"10.1016/j.metop.2025.100417","url":null,"abstract":"<div><h3>Background</h3><div>Activating transcription factor 3 (ATF3) is known to play a key role in regulating lipid and lipoprotein metabolism. However, the effects of hepatic ATF3 on systemic inflammation and the underlying mechanisms remain unclear.</div></div><div><h3>Methods</h3><div>An adeno-associated virus with hepatocyte-specific promoter was used to construct mouse models with hepatocyte-specific overexpression or knockdown of ATF3.</div></div><div><h3>Results</h3><div>Overexpression of human ATF3 in hepatocytes prevented high-fat (HF) diet-induced systemic inflammation in <em>C5</em>7BL<em>/6J</em> mice and reversed systemic inflammation in <em>db/db</em> mice. Conversely, hepatocyte-specific loss of ATF3 aggravated diet-induced systemic inflammation. In co-culture studies, the anti-inflammatory effect of hepatocyte ATF3 on adipose tissue was found to be dependent on the presence of free fatty acids mixture. Mechanistically, ATF3 ameliorated HF diet-induced hepatic lipid accumulation and lipotoxicity likely mediated through AMPKα activation.</div></div><div><h3>Conclusion</h3><div>Our findings collectively indicate that hepatocyte ATF3 alleviates systemic inflammation by reducing hepatic lipotoxicity, a mechanism that may involve the activation of AMPKα. Targeting hepatic ATF3 represents a promising therapeutic strategy for systemic inflammation induced by hepatic lipotoxicity.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100417"},"PeriodicalIF":2.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unsaturated alginate oligosaccharides alleviate insulin resistance and fatty liver in non-obese NAFLD mice by regulating bile acid metabolism through gut microbiota","authors":"Qianqian Cha ,&nbsp;Wenrui Zhao ,&nbsp;Liyuan Ran ,&nbsp;Yu Wang ,&nbsp;Xiaofei Wang ,&nbsp;Fei Xu ,&nbsp;Zichao Yu ,&nbsp;Yingjie Wu","doi":"10.1016/j.metop.2025.100412","DOIUrl":"10.1016/j.metop.2025.100412","url":null,"abstract":"<div><div>Despite the rising global incidence of non-obese non-alcoholic fatty liver disease (NAFLD), this condition has received limited attention. Unsaturated alginate oligosaccharides (UAOS) have shown promising potential in the management of metabolic diseases. In this study, we used liver-specific growth hormone receptor (GHR) knockout mice as a model for non-obese NAFLD and treated them with UAOS. Our findings demonstrated that UAOS effectively ameliorated insulin resistance and hepatic steatosis in GHR-deficient mice. Additionally, UAOS improved intestinal barrier integrity, altered gut microbiota composition, and increased the relative abundance of beneficial bacteria, including <em>Dubosiella</em>, <em>Akkermansia</em>, <em>Lachnoclostridium</em>, <em>Faecalibaculum</em>, <em>Romboutsia</em>, and <em>Turicibacter</em>, while reducing the prevalence of harmful bacteria. Fecal metabolomics analysis revealed significant reductions in taurohyodeoxycholic acid and isodeoxycholic acid. Furthermore, UAOS may modulate the synthesis and secretion of secondary bile acids through the gut microbiota, potentially inhibiting hepatic bile acid synthesis and contributing to the maintenance of bile acid homeostasis via the FGF15-FGFR4-CYP7A1 signaling pathway. These mechanisms ultimately contributed to improved hepatic lipid metabolism. Together, these results position UAOS as a promising prebiotic candidate for the treatment of non-obese NAFLD.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100412"},"PeriodicalIF":2.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using metabolic syndrome severity in the “real world”: Associations with diabetes and cardiovascular disease in all of us vs. NHANES","authors":"Mark D. DeBoer ,&nbsp;Matthew J. Gurka ,&nbsp;Marieke K. Jones ,&nbsp;Mark E. Smolkin","doi":"10.1016/j.metop.2025.100415","DOIUrl":"10.1016/j.metop.2025.100415","url":null,"abstract":"<div><h3>Background</h3><div>While the severity of the metabolic syndrome (MetS) is associated with type 2 diabetes and cardiovascular disease (CVD) in research cohorts, it is unclear if this association remains when using clinically-collected data, which is more subject to error and bias.</div></div><div><h3>Methods</h3><div>We used a previously-validated MetS-severity z-score (MetS-Z) to compare the degree of cardiometabolic derangement between clinically-collected data from the electronic health-record (EHR) in the All-of-Us cohort (N = 101,676) with research-collected data from NHANES 2017–2020 (n = 3470). We assessed (separately) the odds of current diabetes and CVD in each cohort based on MetS z-score, adjusted for sex, race/ethnicity, education and income.</div></div><div><h3>Results</h3><div>Mean MetS-Z-scores in All of Us (vs. NHANES) were higher overall (0.41 vs. 0.15), including being slightly higher among those without diabetes (0.03 vs. −0.09) and similar among those with diagnosed diabetes (1.42 vs. 1.50). In All of Us (vs. NHANES) MetS-Z was higher among those without CVD (0.36 vs. 0.10) but similar among those with CVD (0.72 vs. 0.66). Adjusted odds of diagnosed diabetes and CVD based on MetS-Z remained significant when using clinically-collected data in All of Us (diabetes: 3.41 [95 % confidence interval 3.34, 3.49]; CVD: 1.20 [1.18, 1.21]), though not as high as in NHANES (diabetes: 5.83 [4.52, 7.51]; CVD: 1.43 [1.27, 1.61]).</div></div><div><h3>Conclusion</h3><div>While EHR data is limited by selection bias and data accuracy concerns (e.g. lack of fasting laboratory testing), we found overall similar relationships between MetS-severity, diabetes and CVD in EHR-based and research-based cohorts, supporting utility of these data in risk algorithms.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100415"},"PeriodicalIF":2.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The association between the ZJU index and bone mineral density (BMD) among patients with type 2 diabetes mellitus","authors":"Yuan Zhang ,&nbsp;Yali Jing","doi":"10.1016/j.metop.2025.100413","DOIUrl":"10.1016/j.metop.2025.100413","url":null,"abstract":"<div><h3>Background</h3><div>Previous studies have suggested that type 2 diabetes mellitus (T2DM) is associated with poor bone health, including osteoporosis (OP) and osteopenia. The ZJU index, a novel calculation that integrates fasting plasma glucose (FPG), body mass index (BMI), triglyceride (TG), and alanine aminotransferase (ALT) to aspartate aminotransferase (AST) ratio, is strongly associated with glucolipid metabolism and insulin resistance (IR). In this study, we explored the association of ZJU with bone mineral density (BMD) and OP/osteopenia, and investigated the predictive effect of ZJU on OP/osteopenia in patients with T2DM.</div></div><div><h3>Methods</h3><div>This cross-sectional study included 496 patients with T2DM aged&gt;50 years. The clinical data were collected and the BMD of femoral neck (FN), left hip (LH), and lumbar spine (LS) were measured. The association between BMDs and ZJU levels was investigated by adjusting for covariates utilizing multiple linear regression analyses. Multivariable logistic regression was constructed to identify independent factors of OP and osteopenia, and receiver operating characteristic (ROC) curves were used to display the diagnostic performance according to the area under the ROC curve (AUC).</div></div><div><h3>Results</h3><div>OP and osteopenia patients showed significantly higher ZJU levels than those with normal BMD in T2DM (39.387 ± 3.558, 38.112 ± 2.552 vs 35.192 ± 2.600, p &lt; 0.001). Spearman's correlation analysis showed that ZJU was significantly negatively correlated with the BMD of FN (r = −0.39, p &lt; 0.001), LH (r = −0.35, p &lt; 0.001), and LS (r = -0.32, p &lt; 0.001). The multiple linear regression indicated a negative association between ZJU and BMD of FN (β = −0.006, p = 0.009), LS (β = -0.155, p = 0.011) after adjusted for covariates. Meanwhile, the results of logistic regression revealed that the ZJU was a contributing factor to osteopenia and OP risk in T2DM individuals aged&gt;50 years (OR 1.446, 95 % CI: 1.087–1.923, p = 0.011; OR 1.878, 95 % CI: 1.218–3.715, p = 0.039, respectively). ZJU provided the AUC value of 0.695 and 0.716 on osteopenia and OP in T2DM, respectively.</div></div><div><h3>Conclusions</h3><div>A high ZJU index was significantly associated with an increasing risk of osteopenia and OP. The ZJU is expected to be a potential index for detecting decreased BMDs in middle-aged and elderly T2DM patients. Early intervention in T2DM patients with increased ZJU may further reduce the incidence of osteopenia and OP, in addition to focusing on independent biomarker in clinical practice.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100413"},"PeriodicalIF":2.7,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145416364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic target trial emulation and predictive modeling of amylin-pathway therapies for obesity and type 2 diabetes","authors":"Faisal A. Al-Harbi ,&nbsp;Ahmed K. Alsaif ,&nbsp;Atheer G. Almutairi ,&nbsp;Hussam J. Alshehri ,&nbsp;Elan A. Aleidan ,&nbsp;Ghaida S. Alabdulaaly ,&nbsp;Mashael E. Alanazi ,&nbsp;Ahmed Y. Azzam","doi":"10.1016/j.metop.2025.100414","DOIUrl":"10.1016/j.metop.2025.100414","url":null,"abstract":"<div><h3>Introduction</h3><div>Amylin-pathway therapies represent a novel therapeutic class for obesity and type 2 diabetes, however head-to-head comparative data and long-term outcome predictions remain limited. We conducted target trial emulation and computational predictive modeling aiming to predict future trial outcomes and comparative effectiveness across the amylin-pathway development program.</div></div><div><h3>Methods</h3><div>Following PRISMA 2020 and TARGET framework guidelines, we search in the current literature for eligible trials and extracted data from seven randomized controlled trials (N = 5,786 participants) of amylin-pathway therapies published up to September 2025. We reconstructed high-precision synthetic individual patient data (IPD) and developed computational models for virtual head-to-head comparisons, dose-response optimization, longitudinal trajectory prediction, and trial simulation. Network meta-analysis integrated evidence across CagriSema, cagrilintide, and amycretin formulations.</div></div><div><h3>Results</h3><div>Synthetic IPD reconstruction achieved &gt;99 % fidelity to source trials, validated through leave-trial-out cross-validation (efficacy RMSE: 2.9 % points, calibration slope: 0.61; discontinuation RMSE: 0.18, slope: 1.08). Virtual head-to-head modeling confirmed CagriSema superiority over amycretin subcutaneous at matched timepoints (posterior probability &gt;0.95). Dose-response modeling identified optimal amycretin exposures (ED80: 8.88 mg subcutaneous, 95 % CI: 7.12–11.08), with benefit-risk frontier analysis delineating a therapeutic window at 10–20 mg balancing efficacy plateau against tolerability thresholds (GI-AE &lt;75 %, discontinuation &lt;20 %). Longitudinal kinetics showed plateau timing at 52–68 weeks for obesity outcomes and 24–32 weeks for glycemic endpoints. Heterogeneity analysis revealed complete resolution for GI adverse events (I²_DL = 0 %, τ² = 0) and moderate variation for discontinuation (I²_DL = 13 %, τ² = 0.03) after logit-scale correction with proper within-arm variance weighting. Machine learning models predicted treatment response with 82–87 % accuracy using baseline characteristics.</div></div><div><h3>Conclusions</h3><div>Synthetic target trial emulation with structured validation (leave-trial-out, posterior predictive checks, simulation-based calibration) demonstrated promising evidence for amylin-pathway development optimization. Benefit-risk frontier analysis identified an optimal 10–20 mg subcutaneous therapeutic window, and heterogeneity quantification through maximum a posteriori (MAP) predictive interval provides design-ready estimates for confirmatory trials requiring around 800-1,200 participants per arm for 90 % power.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100414"},"PeriodicalIF":2.7,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145416434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and metabolic effects of ketone monoester supplementation: The first simultaneous CKM and CGM study under normal diet and activities","authors":"Toshiya Miyatsu,&nbsp;Connor Tate,&nbsp;Jeremy McAdam,&nbsp;Chandler Massey,&nbsp;Timothy Broderick","doi":"10.1016/j.metop.2025.100411","DOIUrl":"10.1016/j.metop.2025.100411","url":null,"abstract":"<div><div>Exogenous ketone supplementation has gained attention for its potential health and performance benefits, yet its real-world pharmacokinetics and metabolic effects remain underexplored. This study investigated the pharmacokinetics of ketone monoester (KME) supplementation during normal diet and activities, leveraging simultaneous interstitial fluid (ISF) continuous ketone and glucose monitoring (CKM and CGM). In this single-group observational study, twenty healthy adults underwent a 10-day KME supplementation protocol following a 4-day baseline period. Weight-based KME dosing rapidly elevated ISF β-hydroxybutyrate (BHB) levels, peaking within 1 h and sustaining ketosis for approximately 5 h. Exploratory correlational analyses revealed a two-stage influence pattern: larger skeletal/adipose mass slowed and blunted peak BHB levels (<em>r</em> = −.52 to −.63, <em>p</em> = .04–.08), whereas higher habitual activity, better baseline glucose regulation and greater protein intake prolonged BHB elevation and associated glucose-suppression window (<em>r</em> = .47–.58, <em>p</em> = .05–.09). Granger causality analysis confirmed that KME supplementation acutely suppressed ISF glucose, with an initial effect at 5 min and a sustained post-dose suppression phase between 25 and 55 min. Surprisingly, fasting glucose levels increased after 10 days of KME supplementation, suggesting compensatory metabolic adaptation. Additionally, sleep efficiency and quality declined during the intervention phase. These findings highlight the complex metabolic effects of KME use, emphasizing the need for personalized approaches to optimize its benefits. This study demonstrates the feasibility of CKM/CGM for capturing real-time metabolic dynamics and underscores the importance of further research into the physiological implications of exogenous ketone supplementation.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100411"},"PeriodicalIF":2.7,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145416365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}