Diabetes最新文献

{"title":"The Effect of Obesity on the α-Cell Response to Hyperglycemia in the Presence of Amino Acids","authors":"Sneha Mohan,Federica Boscolo,Hannah E. Christie,Aoife M. Egan,Kent R. Bailey,Michael D. Jensen,K. Sree Nair,Chiara Dalla Man,Adrian Vella","doi":"10.2337/db26-0502","DOIUrl":"https://doi.org/10.2337/db26-0502","url":null,"abstract":"Hyperglycemia in prediabetes is accompanied by increased amino acid (AA) concentrations and impaired suppression of glucagon secretion by glucose. It is unknown whether an abnormal response to AA contributes or hepatic steatosis exacerbates α-cell dysfunction. Therefore, lean participants and participants with obesity (with and without hepatic steatosis) were studied on two occasions in random order using a graded glucose infusion. Saline or an AA mixture was infused. The glucagon secretion rate (GSR) was derived from peripheral glucagon concentrations, and the change in glucose required to reduce GSR by 50% (G50) was calculated for each participant. AAs were measured during the experiment. On both occasions, experimental conditions produced a progressive rise in insulin secretion and an inverse exponential suppression of glucagon. G50 did not differ between groups in response to glucose alone. AA infusion did not change G50 in lean participants. G50 increased during AA infusion in participants with obesity with and without hepatic steatosis, leading us to report these participants as a single group. The relative change in AA concentrations across study days was generally similar between groups. We conclude that despite a normal response to glucose, obesity increases α-cell responses to AA in humans. Article Highlights The aim of this study was to understand the pathogenesis of α-cell dysfunction in prediabetes. The primary hypothesis was that α-cell responsivity to glucose (reduction of the glucagon secretion rate by 50%) is impaired by amino acid (AA) infusion. A secondary hypothesis was that this abnormal response is exacerbated by hepatic steatosis. AA infusion impaired α-cell suppression in response to rising glucose in participants with obesity, but not in lean participants, despite a normal response to glucose alone. This abnormal response was unaffected by the presence or absence of hepatic steatosis. It seems likely that an abnormal α-cell response to AAs precedes an abnormal response to glucose alone.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"18 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Repeated Protein Measurements in a Multiethnic Cohort Identify Novel Diabetes Biomarkers That Reveal Unique Disease Pathways","authors":"Zsu-Zsu Chen, Michael Y. Mi, Jacob Barber, Gaurav Tiwari, Charleen D. Adams, Shuliang Deng, Christopher Y. Shin, Laurie Farrell, Prashant Rao, Daniel E. Cruz, James G. Wilson, Magdalena Sevilla-Gonzalez, Yii-Der Ida Chen, Xiuqing Guo, Mark O. Goodarzi, Kent D. Taylor, Usman A. Tahir, Stephen S. Rich, Alexis C. Wood, Robert E. Gerszten, Jerome I. Rotter","doi":"10.2337/db26-0148","DOIUrl":"https://doi.org/10.2337/db26-0148","url":null,"abstract":"Circulating diabetes biomarkers have been identified with proteomics measured at a single time point, but what is additionally provided by longitudinal repeated measurements in the same individuals, over many years, is unknown. We studied participants in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 5,322; mean baseline age, 61.7 years) at exams 1 (2000–2002), 5 (2010–2012), and 6 (2016–2018) profiled with the Olink Explore (3 K) platform. Associations with incident diabetes, mostly of type 2, were modeled using Cox proportional hazards with exam 1 proteins (i.e., single time point) and time-updating Cox with proteins from all three exams (i.e., longitudinal repeated) adjusted for clinical risk factors. We identified 27 novel single time point associations and up to a fourfold increase in longitudinal associations (false discovery rate < 0.05), with a proportional increase in the number consistent with causality via cis-Mendelian randomization (∼5%) and a smaller overlap in MESA longitudinal versus single associations with UK Biobank single time point findings (42% vs. 87%, respectively). Compared with small-molecule metabolism pathway enrichment among the shared proteins, proteins unique to the longitudinal analyses enriched for protein and cellular processing pathways. We conclude that longitudinal repeated measurements identify a number of distinct disease biomarkers, in part by revealing the progression of relevant biological processes within an individual closer to a clinical diabetes diagnosis versus single measurements. ARTICLE HIGHLIGHTS There is up to a fourfold increase in diabetes biomarkers identified with longitudinal repeated versus single time point proteomic measurements. The increase in biomarkers identified with longitudinal repeated measurements is supported by a similar proportion being nominated as causal for type 2 diabetes with Mendelian randomization. Proteins unique to the longitudinal repeated analyses highlighted biological pathways (e.g., posttranslational protein modification and cellular structure and cycle regulation) that were distinct from pathways enriched among the shared proteins (e.g., small-molecule metabolic and catabolic processes). Longitudinal protein measurements identify additional novel disease biomarkers and disparate biological pathways compared with single measurement analyses.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"31 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148909182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What Proportion of Antibody-Negative Type 1 Diabetes Cases Have a Nonautoimmune Etiology? A Genetics-Based Estimate","authors":"Jacob L. Nicodemo, Angeliki Makri, Constantin Polychronakos","doi":"10.2337/db25-1110","DOIUrl":"https://doi.org/10.2337/db25-1110","url":null,"abstract":"Among patients with young-onset type 1 diabetes, 10–15% are autoantibody (aAb) negative. How many of these are autoimmune versus nonautoimmune is unknown. To estimate this proportion, we used the only high-confidence evidence of autoimmunity in these cases, the presence of an aAb(+) sibling. In the 2,500 affected sibling pairs of the Type 1 Diabetes Genetics Consortium cohort, we compared the Type 1 Diabetes Genetic Risk Score (GRS2) between 379 aAb(−) patients with an aAb(+) sibling (autoimmune cause) and 253 aAb(−) patients with no aAb(+) siblings (unknown cause), under the assumption that siblings’ diabetes must be of the same etiology. The GRS2 distribution for the unknown cause group showed a distinct minor mode, representing high-confidence nonautoimmune cases (1.2%). An increase in the frequency of scores <9.83 in the unknown cause group compared with the autoimmune cause group coincided with the peak in unaffected control individuals’ scores. The difference between area under the curve over this range represented the maximum-likelihood proportion of nonautoimmune individuals (7.6%). These findings support aAb testing for type 1 diabetes and genetic testing for aAb(−) individuals. Article Highlights Accurate diagnosis of diabetes has important therapeutic consequences, yet 10–15% of individuals with type 1 diabetes are autoantibody negative, leaving the etiology of diabetes unconfirmed. We estimated what proportion of autoantibody negative, clinically diagnosed type 1 diabetes is misdiagnosed nonautoimmune diabetes. Upwards of 7.6% of autoantibody negative individuals are nonautoimmune. Our findings support the use of autoantibody screening and genetic testing of autoantibody negative patients as standard of care for type 1 diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"6 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148806389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Irisin Gene Delivery Elicits Sustained Amelioration of Diabetes in Akita Mice via Insulin-Independent Regulation of Hepatic Glucose Metabolism","authors":"Wen-Bin Lu, Yi-Shan Huang, Jian-Ching Wu, Lee-Wei Chen, I-Wen Lin, Pei-Chin Chen, Po-Han Chen, Cheng-Yi Huang, Tzu-Teng Tai, Shu-Hung Huang, Sheng-Hua Wu, Feng-Sheng Wang, Hsu-Wen Chao, Ming-Hong Tai","doi":"10.2337/db25-1158","DOIUrl":"https://doi.org/10.2337/db25-1158","url":null,"abstract":"Insulin has been regarded as the central regulator of systemic glucose homeostasis through regulation of hepatic glucose metabolism. Loss of insulin leads to dysregulation of glucose homeostasis in diabetes. Physical activity improves glycemic control in insulin-resistant and insulin-deficient states. However, it remains unclear whether exercise regulates hepatic glucose metabolism independently of insulin signaling. Irisin, an exercise-induced myokine cleaved from fibronectin type III domain-containing 5 (FNDC5), has been implicated in systemic metabolic regulation; however, its role in hepatic glucose metabolism plasticity under insulin-deficient conditions remains unknown. To address this question, we used persistent insulin-deficient Akita mice and found that circulating and hepatic irisin levels were reduced in Akita mice, accompanied by impaired hepatic glucose metabolism. To restore irisin level, adenoviral vectors encoding full-length FNDC5 and secreted form irisin were generated and administered. Notably, the secreted form of irisin was more effective in restoring circulating irisin levels and contributed to improving diabetic phenotypes. Dose- and time-dependent analyses further demonstrated that, upon reaching an effective dose, irisin gene delivery improved diabetic phenotypes for up to 10–12 weeks. Mechanistically, irisin was associated with coordinated changes in hepatic glucose metabolism, including increased expression of glucose uptake–related genes (peroxisome proliferator–activated receptor-γ/GLUT2/GCK), enhanced glycogen synthesis–related signaling (GSK-dependent and GSK-independent pathways), and reduced gluconeogenic activity, accompanied by reduced phosphoenolpyruvate carboxykinase expression and increased AMPK phosphorylation, despite no changes in circulating insulin or glucagon levels. In summary, our findings suggest that irisin may contribute to the regulation of hepatic glucose metabolism under insulin-deficient conditions and represent a potential insulin-independent pathway for improving systemic glucose homeostasis. Article Highlights The exercise-induced hormone irisin plays an important role in the regulation of glucose homeostasis; however, its underlying mechanisms under insulin-deficient conditions remain unclear. We investigated whether irisin can directly regulate hepatic glucose metabolism and manage diabetic phenotypes in insulin-deficient Akita mice. Irisin improved diabetic phenotypes and was associated with enhanced glucose uptake (peroxisome proliferator–activated receptor-γ/GLUT2/GCK axis), increased glycogen storage (GSK-3β–dependent and GSK-3β–independent pathways), and reduced gluconeogenic activity, accompanied by increased AMPK phosphorylation independently of increases in insulin levels. These findings identify irisin as an insulin-independent regulator in hepatic glucose metabolism and suggest a potential therapeutic strategy for insulin-deficient diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"18 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HGF Endogenously Produced by Pancreatic Pericytes Regulates β-Cell Function","authors":"Shani Puyesky, Mohammed Egbaria, Dunia Ali Naser, Anat Schonblum, Lena Kabha, Iael Fuhrman, Limor Landsman","doi":"10.2337/db26-0227","DOIUrl":"https://doi.org/10.2337/db26-0227","url":null,"abstract":"Hepatocyte growth factor (HGF)/c-Met signaling is a well-established pathway through which external signals regulate β-cell resilience and function. Yet the endogenous source of HGF in the islets and its physiological role in this context remain unclear. Here, we combined human islet single-cell transcriptomics with mouse pancreatic-cell profiling to show that pericytes, rather than endothelial cells, are the primary source of HGF in healthy islets. Using transgenic mouse tools and culture systems, we found that pericyte-derived HGF is required for β-cell function and glucose homeostasis. Adult mice lacking pericytic HGF in their pancreata developed glucose intolerance while maintaining β-cell mass and insulin sensitivity. Mechanistically, HGF secreted by pancreatic pericytes is required for proper insulin production and secretion by regulating the expression of key β-cell genes, including Pdx1, Slc2a2, and Ins1. In addition, neonatal and pregnant mice lacking mesenchymal/pericytic HGF had lower β-cell mass, indicating its context-dependent requirement for β-cell expansion. Thus, we suggest that pericytic HGF is required for insulin production and secretion during homeostasis and for supporting β-cell expansion during embryogenesis and pregnancy. Together, our findings establish pericytes as a significant endogenous source of HGF, coupling the islet microvasculature to insulin production and glucose homeostasis. Article Highlights Despite extensive research on the role of the hepatocyte growth factor (HGF)/c-Met pathway in β-cells and glucose homeostasis, the endogenous source of HGF in islets remains unclear. This study characterizes the pancreatic source of HGF and its physiological requirement in vivo. Pericytes were identified as the primary endogenous source of HGF in human and mouse islets. Pericytic HGF loss causes glucose intolerance by impairing insulin production through the regulation of key β-cell genes. Establishing β-cell mass during embryogenesis and pregnancy depends on mesenchymal/pericytic HGF. This study establishes the islet vasculature as a source of trophic factors required for glycemic control.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"3 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148767624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baseline Serum Metabolites as Predictors of Teplizumab Response in Individuals With Type 1 Diabetes","authors":"Elizabeth R. Flammer, Lauren E. Higdon, Srinath Sanda, Todd M. Brusko, Timothy J. Garrett, Heba M. Ismail","doi":"10.2337/db26-0158","DOIUrl":"https://doi.org/10.2337/db26-0158","url":null,"abstract":"We analyzed baseline serum samples from 41 individuals newly diagnosed with type 1 diabetes (T1D) enrolled in the Autoimmunity-blocking Antibody for Tolerance (AbATE) trial (NCT00129259) to identify metabolic predictors of teplizumab response. Responders to teplizumab were defined as individuals who exhibited <45% decline in baseline C-peptide levels at 2 years after start of treatment. We used a semitargeted metabolomics approach via liquid chromatography–high-resolution tandem mass spectrometry. We identified 15 significant (P < 0.05) metabolites, including amino acids and their derivatives, tricarboxylic acid (TCA) cycle intermediates, and microbially derived metabolites. Responders exhibited higher levels of TCA cycle metabolites, amino acid derivatives, and microbial metabolites, whereas nonresponders showed elevated glutamate and acylcarnitines. These metabolites were used to train a supervised random forest (RF) model to predict treatment response. Model performance was evaluated using a 70:30 training-to-testing split, fivefold cross-validation, bootstrap resampling (1,000 iterations), and permutation testing (1,000 permutations). The RF classifier achieved an accuracy of 0.769 and an area under the receiver operating characteristic curve of 0.881 in the test data set. These findings suggest baseline serum metabolomic signatures have the potential to predict responders to teplizumab with accuracy. This could potentially be applicable to other immunotherapies in T1D preventative efforts. Further validation of our findings is needed. Article Highlights We believed that baseline serum metabolomic signatures can predict response to immunotherapies to identify which individuals will benefit most from treatment. We aimed to identify whether baseline serum metabolomic profiles can distinguish responders from nonresponders to teplizumab. Fifteen metabolites were identified as significantly different. Our findings suggest that baseline serum metabolomic signatures could be used to predict which newly diagnosed type 1 diabetes patients will respond to teplizumab, enabling more personalized treatment decisions.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"6 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing the Independent Effects of Weight Loss or Exercise Training on Skeletal Muscle Lipid Localization and Insulin Sensitivity in Humans","authors":"Simona Zarini, Karin Zemski Berry, Amanda Garfield, Emily Macias, Purevsuren Jambal, Sophia Bowen, Melanie G. Cree, Janet K. Snell-Bergeon, Chris Johnson, P. Darrell Neufer, Ian Tamburini, Marcus Seldin, Bryan C. Bergman","doi":"10.2337/db26-0239","DOIUrl":"https://doi.org/10.2337/db26-0239","url":null,"abstract":"Localized subcellular muscle lipid accumulation associates with insulin resistance, but independent effects of weight loss or exercise training are unknown. Forty-six men and women with obesity completed 12-week weight loss only, endurance exercise training only without weight loss, or delayed control interventions. Following weight loss, body weight decreased 10% along with a 42% increase in insulin sensitivity. After exercise training, VO2peak increased 9% along with a 23% increase in insulin sensitivity. Whole muscle triacylglycerols (TAGs) increased in the control group, while mitochondrial/endoplasmic reticulum (ER) TAG decreased after weight loss and cytosolic TAGs increased after exercise training. Exercise training increased whole muscle total and 1,2-diacylglycerols (1,2-DAGs) through enhanced cytosolic storage. Total mitochondrial DAGs decreased after weight loss yet increased following exercise training and control. Exercise training increased cytosolic storage of most sphingolipids. Differential gene expression analysis revealed exercise increased mitochondrial function, whereas weight loss reduced inflammation and immune signaling. Only exercise training prevented the inhibition of mitochondrial respiration following exogenous administration of ceramides and di-C18:0-DAG. These data reveal weight loss and exercise training increase cytosolic storage of sphingolipids, weight loss decreases mitochondrial/ER TAG accumulation, and exercise training increases mitochondrial/ER and cytosolic DAGs, suggesting changes in specific subcellular lipid localization may impact muscle insulin sensitization. Skeletal Muscle Diacylglycerol and Sphingolipids – Impact of Localization and Species on Insulin Resistance in Humans, NCT03077360, ClinicalTrials.gov. Article Highlights Subcellular accumulation of lipids is linked to insulin resistance, but changes in localization from weight loss or exercise training have not been thoroughly explored. We evaluated the independent effects of two insulin-sensitizing interventions, weight loss and exercise training, on lipid subcellular distribution in fractionated skeletal muscle, muscle mitochondrial function, and gene expression. Exercise training increased cytosolic storage of diacylglycerols and sphingolipids, and weight loss increased cytosolic sphingosine and decreased mitochondrial/endoplasmic reticulum triacylglycerol and diacylglycerol accumulation. Exercise training prevented the negative effects of mitochondrial lipids on mitochondrial function. Changes in specific subcellular lipid storage help explain muscle insulin sensitization following lifestyle interventions.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"11 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organelle-Specific Lipid Profiles Underlie Metabolic Health in a Nutrition-Dependent Manner","authors":"Cassandra Tabasso, Chaitanya K. Gavini, Karin Zemski Berry, Hadi Salem, Axel K.F. Aguettaz, Sylviane Lagarrigue, Bryan C. Bergman, Virginie Mansuy-Aubert, Francesca Amati","doi":"10.2337/db26-0066","DOIUrl":"https://doi.org/10.2337/db26-0066","url":null,"abstract":"Western diet (WD), characterized by high energy density and saturated fat, promotes obesity and insulin resistance (IR), yet how dietary lipid overload remodels skeletal muscle lipids at the subcellular level remains unclear. We investigated whether WD alters lipid class distribution and fatty acid (FA) incorporation within distinct muscle organelles and whether these changes relate to metabolic health. C57BL/6 J mice were fed WD or control chow for 12 weeks. Mitochondria and lipid droplets (LDs) were isolated from soleus for organelle-resolved lipidomics. WD induced obesity, dyslipidemia, early IR, and intramyocellular lipid accumulation without changes in mitochondrial content. Organelle-resolved analyses revealed compartment-specific lipid remodeling, hidden in whole muscle. Diacylglycerol (DAG) FA composition closely reflected dietary FA supply across compartments, whereas phospholipid remodeling was class and organelle dependent, with coordinated changes between mitochondria and LDs. Several phospholipid classes and LD-associated sn-1,3-DAG were associated with insulin sensitivity and substrate use in metabolically healthy mice, but WD disrupted these relationships. These findings demonstrate that lipid class identity, FA composition, and subcellular localization critically shape skeletal muscle responses to nutritional excess. By identifying organelle-specific lipid pools linked to early metabolic dysfunction, this study provides a framework that may inform future translational investigations of IR in human skeletal muscle. Article Highlights Skeletal muscle insulin resistance is linked to lipid metabolism, yet whole-tissue analyses obscure how subcellular lipid remodeling contributes to metabolic dysfunction. We investigated whether Western diet induces compartment-specific changes in skeletal muscle lipid classes and fatty acid (FA) composition and how these relate to metabolic health. Western diet disrupts the relationship between lipids and metabolism. Diacylglycerol FA composition reflected dietary supply. Phospholipid remodeling was class and compartment specific. Lipid droplet-localized 1,3-diacylglycerol, phosphatidylethanolamine, and phosphatidylglycerol reflected muscle health. These results highlight subcellular lipid organization as a key determinant of muscle insulin resistance and provide a framework for identifying early lipid signatures relevant to human diabetes research.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"24 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Body Composition–Driven Phenotyping Reveals Obesity and Cardiometabolic Heterogeneity in Children Using a Tree-Like Representation","authors":"Pei Xiao, Hong Cheng, Jingfan Xiong, Yinkun Yan, Junting Liu, Li Liu, Hongbo Dong, Yan Li, Peiyu Ye, Liwan Fu, Liwang Gao, Fangfang Chen, Xinying Shan, Lina Lan, Yanyan Li, Jie Mi","doi":"10.2337/db26-0136","DOIUrl":"https://doi.org/10.2337/db26-0136","url":null,"abstract":"Traditional measures such as BMI do not fully capture obesity-related metabolic risks. Here, we examined DXA-derived body composition patterns in children (n = 11,238) using the discriminative dimensionality reduction tree algorithm, which was validated in an independent cohort (n = 2,001). The tree structure revealed a continuous landscape of body composition phenotypes, with distinct spatial gradients for fat and lean mass. Within the phenotypic tree, fat-dominant phenotypes clustered in the region of low dimension 1 and low dimension 2 (corresponding to the lower left branches), where they demonstrated significant spatial overlap with high-risk clusters for hypertension, elevated LDL cholesterol (LDL-C), total cholesterol, and triglycerides (TG) (Moran I >0.3, all P < 0.001). Meanwhile, phenotypes characterized by elevated lean mass coupled with increased adiposity were localized in the region of low dimension 1 and high dimension 2 (upper left branches), demonstrating an increased risk of low HDL-C and high TG (Moran I >0.6, all P < 0.001). In contrast, lean-dominant phenotypes clustered in the region of high dimension 1 and high dimension 2 (upper right branches), which were associated with a relatively low risk of hyperglycemia, insulin resistance, and high LDL-C (Moran I >0.1, all P < 0.001). For practical utility, we developed a publicly available web application to map individual data on the reference tree architecture, allowing for assessment of cardiometabolic risk. Our findings highlight the value of more precise body composition measures for early identification and prevention of obesity-related health problems. Article Highlights Childhood obesity shows large differences in body composition and health risk that are not well captured by BMI or simple metabolic classifications, prompting the need for more precise characterization. This study aimed to determine whether a data-driven framework integrating detailed body composition measures could better describe obesity-related phenotypic heterogeneity and its relationship with cardiometabolic risk in children. We delineated a continuous body composition manifold encompassing fat-dominant, lean-dominant, and concomitant high-mass phenotypes, which captured diverging cardiometabolic risk trajectories and yielded modest incremental improvements in risk prediction. These findings support more precise risk stratification and provide a practical tool to improve early identification and prevention of obesity-related health complications in children.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"67 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Loss-of-Function ZNRF3 Mutation Impairs Adipose Thermogenesis and Drives Subcutaneous Fat Expansion","authors":"Ningning Zhang, Peng Lu, Yangyi Tong, Zhiwen Cao, Yinmeng Zhu, Yujia Gong, Nan Yin, Ruikai Yang, Muye Tong, Na Chen, Yuxiao Zhao, Chao Wu, Qian Li, Zhongyun Zhang, Xinyuan Zhou, Dongqin Gu, Yansong Liu, Qianyun Cheng, Zhiguo Zhang, Jieli Lu, Yufang Bi, Yong Geng, Weiqing Wang, Guang Ning, Jie Hong, Weiqiong Gu, Ruixin Liu, Jiqiu Wang","doi":"10.2337/db25-1108","DOIUrl":"https://doi.org/10.2337/db25-1108","url":null,"abstract":"Zinc and ring finger protein 3 (ZNRF3) functions as a transmembrane E3 ubiquitin ligase. Although genome-wide association studies have implicated ZNRF3 in body fat distribution, the evidence from human genetics and animal models has been lacking. Here, through whole-exome sequencing of 1,944 obese individuals and 2,161 healthy lean control individuals, we identified a rare loss-of-function mutation in human ZNRF3 (p.V228L) observed exclusively in 8 obese individuals. These carriers exhibit increased hip circumference and subcutaneous fat area and lower fasting glucose levels compared with noncarriers. In mice, adipocyte-specific Znrf3 deletion leads to progressive adiposity, with expansion of subcutaneous white adipose tissue (sWAT) and improved glucose tolerance after a long-term high-fat diet. Furthermore, Znrf3 deficiency impairs the browning capacity of sWAT and cold-induced thermogenesis. A knock-in mouse model harboring the homologous human p.V228L mutation recapitulates key features of carriers and knockout mice, including reduced sWAT thermogenic function, altered fat distribution, and improved glucose tolerance. Mechanistically, Znrf3 loss attenuates the cAMP/cAMP-dependent protein kinase signaling pathway, suppressing UCP1 expression and mitochondrial respiration. Collectively, these findings provide genetic and biological evidence that ZNRF3 regulates thermogenic capacity and remodeling of sWAT, offering new insights into obesity heterogeneity. Article Highlights A rare loss-of-function variant in ZNRF3 (p.V228L) is enriched in individuals with obesity and is associated with increased subcutaneous white adipose tissue (sWAT) accumulation and lower fasting glucose levels. Both adipocyte-specific Znrf3 knockout and global variant knock-in impair sWAT browning, increase sWAT expansion, and improve glucose tolerance in mice. These findings establish ZNRF3 as a genetic regulator of fat distribution and thermogenic capacity, informing precise phenotyping of obesity. GWAS has implicated ZNRF3 in human fat distribution, yet its role in adipose tissue biology remains unknown.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"337 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}