Pub Date : 2025-11-07DOI: 10.1016/j.metop.2025.100416
K.G. Sruthi , C. Aditya , Paramjot Panda , Jyoti Ranjan Mohanty , Manas Ranjan Behera
Background
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.
Methods
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.
Results
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.
Conclusion
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.
{"title":"Prevalence of normal weight obesity among adults in Southeast Asia: Insights from a systematic review and meta-analysis","authors":"K.G. Sruthi , C. Aditya , Paramjot Panda , Jyoti Ranjan Mohanty , 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/m<sup>2</sup>) 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 I<sup>2</sup> 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 (I<sup>2</sup> = 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}
Pub Date : 2025-11-05DOI: 10.1016/j.metop.2025.100417
Chencheng Hu , Qian Yang , Runzhi Yu , Shuwei Hu , Bing Meng , Yanyong Xu
Background
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.
Methods
An adeno-associated virus with hepatocyte-specific promoter was used to construct mouse models with hepatocyte-specific overexpression or knockdown of ATF3.
Results
Overexpression of human ATF3 in hepatocytes prevented high-fat (HF) diet-induced systemic inflammation in C57BL/6J mice and reversed systemic inflammation in db/db 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.
Conclusion
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.
{"title":"Hepatic activating transcription factor 3 protects against systemic inflammation by attenuating lipotoxicity","authors":"Chencheng Hu , Qian Yang , Runzhi Yu , Shuwei Hu , Bing Meng , 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}
Pub Date : 2025-11-04DOI: 10.1016/j.metop.2025.100412
Qianqian Cha , Wenrui Zhao , Liyuan Ran , Yu Wang , Xiaofei Wang , Fei Xu , Zichao Yu , Yingjie Wu
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 Dubosiella, Akkermansia, Lachnoclostridium, Faecalibaculum, Romboutsia, and Turicibacter, 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.
{"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 , Wenrui Zhao , Liyuan Ran , Yu Wang , Xiaofei Wang , Fei Xu , Zichao Yu , 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}
Pub Date : 2025-11-04DOI: 10.1016/j.metop.2025.100415
Mark D. DeBoer , Matthew J. Gurka , Marieke K. Jones , Mark E. Smolkin
Background
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.
Methods
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.
Results
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]).
Conclusion
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.
虽然代谢综合征（MetS）的严重程度在研究队列中与2型糖尿病和心血管疾病（CVD）相关，但在使用临床收集的数据时，尚不清楚这种关联是否仍然存在，这些数据更容易出现误差和偏倚。方法：我们使用先前验证的MetS-severity z-score （MetS-Z）来比较All-of-Us队列中电子健康记录（EHR）的临床收集数据（N = 101,676）与NHANES 2017-2020的研究收集数据（N = 3470）之间的心脏代谢紊乱程度。我们根据MetS z-score分别评估了每个队列中当前糖尿病和心血管疾病的几率，并根据性别、种族/民族、教育和收入进行了调整。结果All of Us （vs. NHANES）的平均met - z评分总体较高（0.41 vs. 0.15），其中非糖尿病患者的平均met - z评分略高（0.03 vs. - 0.09），诊断为糖尿病的患者的平均met - z评分相似（1.42 vs. 1.50）。在All of Us中（与NHANES相比），met - z在没有心血管疾病的患者中较高（0.36比0.10），但在有心血管疾病的患者中相似（0.72比0.66）。在All of Us中使用临床收集的数据时，基于MetS-Z的诊断糖尿病和CVD的调整几率仍然显著（糖尿病：3.41[95%可信区间3.34,3.49];CVD: 1.20[1.18, 1.21]），尽管没有NHANES的高（糖尿病：5.83 [4.52,7.51];CVD: 1.43[1.27, 1.61]）。结论：尽管电子病历数据受到选择偏差和数据准确性问题（例如缺乏禁食实验室测试）的限制，但我们发现基于电子病历和基于研究的队列中met -严重程度、糖尿病和心血管疾病之间的总体关系相似，支持这些数据在风险算法中的实用性。
{"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 , Matthew J. Gurka , Marieke K. Jones , 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}
Pub Date : 2025-10-31DOI: 10.1016/j.metop.2025.100413
Yuan Zhang , Yali Jing
Background
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.
Methods
This cross-sectional study included 496 patients with T2DM aged>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).
Results
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 < 0.001). Spearman's correlation analysis showed that ZJU was significantly negatively correlated with the BMD of FN (r = −0.39, p < 0.001), LH (r = −0.35, p < 0.001), and LS (r = -0.32, p < 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>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.
Conclusions
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.
背景先前的研究表明，2型糖尿病（T2DM）与骨质疏松（OP）和骨质减少等骨质健康不良相关。ZJU指数是一种综合空腹血糖（FPG）、体重指数（BMI）、甘油三酯（TG）和谷丙转氨酶（ALT）与天冬氨酸转氨酶（AST）比值的新型计算方法，它与糖脂代谢和胰岛素抵抗（IR）密切相关。在本研究中，我们探讨了ZJU与骨密度（BMD）和OP/osteopenia的关系，并探讨了ZJU对T2DM患者OP/osteopenia的预测作用。方法本横断面研究纳入496例50岁的2型糖尿病患者。收集临床资料，测量股骨颈（FN）、左髋关节（LH）和腰椎（LS）的骨密度。利用多元线性回归分析调整协变量，研究bmd与ZJU水平之间的关系。构建多变量logistic回归，确定OP和骨质减少的独立因素，并根据ROC曲线下面积（AUC）采用受试者工作特征（ROC）曲线显示诊断效果。结果T2DM患者血清中ZJU水平明显高于骨密度正常者（39.387±3.558,38.112±2.552 vs 35.192±2.600,p < 0.001）。Spearman相关分析显示，ZJU与FN （r = - 0.39, p < 0.001）、LH （r = - 0.35, p < 0.001）、LS （r = -0.32, p < 0.001）的BMD呈显著负相关。多元线性回归结果显示，校正协变量后，ZJU与FN （β = - 0.006, p = 0.009）、LS （β = -0.155, p = 0.011）骨密度呈负相关。同时，logistic回归结果显示，ZJU是50岁T2DM患者骨质减少和OP风险的一个因素（OR为1.446,95% CI: 1.087 ~ 1.923, p = 0.011； OR为1.878,95% CI: 1.214 ~ 3.715, p = 0.039）。浙江大学提供的T2DM患者骨质减少和OP的AUC值分别为0.695和0.716。结论高ZJU指数与骨量减少和op风险增加有显著相关性，有望成为检测中老年T2DM患者骨密度下降的潜在指标。在临床实践中，除了注重独立的生物标志物外，早期干预ZJU升高的T2DM患者可进一步降低骨质减少和OP的发生率。
{"title":"The association between the ZJU index and bone mineral density (BMD) among patients with type 2 diabetes mellitus","authors":"Yuan Zhang , 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>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 < 0.001). Spearman's correlation analysis showed that ZJU was significantly negatively correlated with the BMD of FN (r = −0.39, p < 0.001), LH (r = −0.35, p < 0.001), and LS (r = -0.32, p < 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>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}
Pub Date : 2025-10-31DOI: 10.1016/j.metop.2025.100414
Faisal A. Al-Harbi , Ahmed K. Alsaif , Atheer G. Almutairi , Hussam J. Alshehri , Elan A. Aleidan , Ghaida S. Alabdulaaly , Mashael E. Alanazi , Ahmed Y. Azzam
Introduction
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.
Methods
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.
Results
Synthetic IPD reconstruction achieved >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 >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 <75 %, discontinuation <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.
Conclusions
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.
{"title":"Synthetic target trial emulation and predictive modeling of amylin-pathway therapies for obesity and type 2 diabetes","authors":"Faisal A. Al-Harbi , Ahmed K. Alsaif , Atheer G. Almutairi , Hussam J. Alshehri , Elan A. Aleidan , Ghaida S. Alabdulaaly , Mashael E. Alanazi , 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 >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 >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 <75 %, discontinuation <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 (I<sup>2</sup>_DL = 0 %, τ<sup>2</sup> = 0) and moderate variation for discontinuation (I<sup>2</sup>_DL = 13 %, τ<sup>2</sup> = 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}
Pub Date : 2025-10-29DOI: 10.1016/j.metop.2025.100411
Toshiya Miyatsu, Connor Tate, Jeremy McAdam, Chandler Massey, Timothy Broderick
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 (r = −.52 to −.63, p = .04–.08), whereas higher habitual activity, better baseline glucose regulation and greater protein intake prolonged BHB elevation and associated glucose-suppression window (r = .47–.58, p = .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.
外源性酮补充剂因其潜在的健康和性能益处而受到关注，但其现实世界的药代动力学和代谢效应仍未得到充分探讨。本研究通过同时进行间质液（ISF）连续酮和葡萄糖监测（CKM和CGM），研究了在正常饮食和活动中补充酮单酯（KME）的药代动力学。在这项单组观察性研究中，20名健康成年人在4天的基线期后接受了10天的KME补充方案。基于体重的KME剂量迅速提高了ISF β-羟基丁酸（BHB）水平，在1小时内达到峰值，并维持酮症约5小时。探索性相关分析揭示了两阶段的影响模式：较大的骨骼/脂肪质量减慢并减弱了BHB峰值水平（r = -）。52 ~−。63, p = .04 -。08)，而较高的习惯性活动、更好的基线血糖调节和更多的蛋白质摄入延长了BHB升高和相关的葡萄糖抑制窗口（r = 0.47 -）。58, p = 0.05 - 0.09)。格兰杰因果分析证实，补充KME可急性抑制ISF葡萄糖，其初始作用发生在5分钟，持续的给药后抑制期为25 - 55分钟。令人惊讶的是，补充KME 10天后，空腹血糖水平升高，表明代偿代谢适应。此外，在干预阶段，睡眠效率和质量下降。这些发现强调了KME使用的复杂代谢效应，强调需要个性化的方法来优化其益处。这项研究证明了CKM/CGM捕捉实时代谢动力学的可行性，并强调了进一步研究外源性酮补充的生理意义的重要性。
{"title":"Pharmacokinetics and metabolic effects of ketone monoester supplementation: The first simultaneous CKM and CGM study under normal diet and activities","authors":"Toshiya Miyatsu, Connor Tate, Jeremy McAdam, Chandler Massey, 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}
Pub Date : 2025-10-27DOI: 10.1016/j.metop.2025.100410
Sofia Rozani , Maria Dalamaga , Georg Weber , Robert Grützmann
The global obesity epidemic has reshaped the landscape of liver transplantation (LT). Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the leading indications for LT in Western countries, while excess adiposity simultaneously complicates donor and recipient selection, surgical outcomes, and long-term graft survival. Although previous studies have examined obesity, MASLD, and LT separately, an integrative overview of their bidirectional relationship and its clinical implications is lacking. This mini-review addresses that gap by synthesizing current evidence on how obesity influences LT candidacy, perioperative risk, graft outcomes, and metabolic complications after transplantation. We further highlight emerging concepts of “metabolic fitness,” the role of prehabilitation, novel pharmacotherapies, and bariatric interventions, while underscoring the urgent need for transplant-specific metabolic guidelines. Without upstream prevention and coordinated system-level adaptation, transplant programs will face an unsustainable burden of obesity-related liver disease.
{"title":"Liver transplantation in the era of obesity: A metabolic public health crisis meets a surgical frontier","authors":"Sofia Rozani , Maria Dalamaga , Georg Weber , Robert Grützmann","doi":"10.1016/j.metop.2025.100410","DOIUrl":"10.1016/j.metop.2025.100410","url":null,"abstract":"<div><div>The global obesity epidemic has reshaped the landscape of liver transplantation (LT). Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the leading indications for LT in Western countries, while excess adiposity simultaneously complicates donor and recipient selection, surgical outcomes, and long-term graft survival. Although previous studies have examined obesity, MASLD, and LT separately, an integrative overview of their bidirectional relationship and its clinical implications is lacking. This mini-review addresses that gap by synthesizing current evidence on how obesity influences LT candidacy, perioperative risk, graft outcomes, and metabolic complications after transplantation. We further highlight emerging concepts of “metabolic fitness,” the role of prehabilitation, novel pharmacotherapies, and bariatric interventions, while underscoring the urgent need for transplant-specific metabolic guidelines. Without upstream prevention and coordinated system-level adaptation, transplant programs will face an unsustainable burden of obesity-related liver disease.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100410"},"PeriodicalIF":2.7,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145416431","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}
Pub Date : 2025-10-26DOI: 10.1016/j.metop.2025.100409
Angeliki Margoni , Kostas A. Papavassiliou , Athanasios G. Papavassiliou
{"title":"Deliberating the striking effect of dual GLP-1R and GIPR agonists on “Diabesity” in light of precision medicine and pharmacogenomics","authors":"Angeliki Margoni , Kostas A. Papavassiliou , Athanasios G. Papavassiliou","doi":"10.1016/j.metop.2025.100409","DOIUrl":"10.1016/j.metop.2025.100409","url":null,"abstract":"","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100409"},"PeriodicalIF":2.7,"publicationDate":"2025-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145416432","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}
Pub Date : 2025-10-24DOI: 10.1016/j.metop.2025.100408
Rui Sun, Yang Xu, Zhenjun Ji, Xingxing Li, Zaixiao Tao, Weichen Luo, Yuyu Yao, Lijuan Chen, Genshan Ma
This review summarizes current insights into the molecular mechanisms by which hyperglycemia and dyslipidemia contribute to chronic diabetic wounds. It discusses the roles of key metabolic pathways, including the hexosamine biosynthetic and polyol pathways, along with the significance of inflammatory mediators and oxidative stress in this process. In addition, emerging therapeutic strategies are evaluated, such as the use of metformin to activate AMPK, PPAR agonists, SGLT2 inhibitors, and GLP-1 receptor agonists, which hold promise for modulating the inflammatory microenvironment and restoring cellular function. Combination therapies, advanced wound dressings, negative pressure wound therapy (NPWT), hyperbaric oxygen therapy (HBOT), and regenerative approaches such as stem cell therapies and bioengineered skin substitutes are also reviewed as integrated strategies that target both systemic metabolic dysregulation and local wound-specific challenges. These findings underscore the critical role of improved glucose and lipid control in optimizing diabetic wound healing and suggest that personalized, multimodal therapeutic approaches may offer enhanced clinical outcomes for patients with diabetic ulcers and other chronic wounds.
{"title":"Update on the impact of lipid and glucose control on diabetic wound healing","authors":"Rui Sun, Yang Xu, Zhenjun Ji, Xingxing Li, Zaixiao Tao, Weichen Luo, Yuyu Yao, Lijuan Chen, Genshan Ma","doi":"10.1016/j.metop.2025.100408","DOIUrl":"10.1016/j.metop.2025.100408","url":null,"abstract":"<div><div>This review summarizes current insights into the molecular mechanisms by which hyperglycemia and dyslipidemia contribute to chronic diabetic wounds. It discusses the roles of key metabolic pathways, including the hexosamine biosynthetic and polyol pathways, along with the significance of inflammatory mediators and oxidative stress in this process. In addition, emerging therapeutic strategies are evaluated, such as the use of metformin to activate AMPK, PPAR agonists, SGLT2 inhibitors, and GLP-1 receptor agonists, which hold promise for modulating the inflammatory microenvironment and restoring cellular function. Combination therapies, advanced wound dressings, negative pressure wound therapy (NPWT), hyperbaric oxygen therapy (HBOT), and regenerative approaches such as stem cell therapies and bioengineered skin substitutes are also reviewed as integrated strategies that target both systemic metabolic dysregulation and local wound-specific challenges. These findings underscore the critical role of improved glucose and lipid control in optimizing diabetic wound healing and suggest that personalized, multimodal therapeutic approaches may offer enhanced clinical outcomes for patients with diabetic ulcers and other chronic wounds.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100408"},"PeriodicalIF":2.7,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519830","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}
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