Sharmeen Islam, Xinrui Li, M.D. Nazmul Hossain, Zhongyun Kou, Li-Wei Chen, Jeanene Marie Deavila, Mei-Jun Zhu, Min Du
Forty-two percent of American women of childbearing age are obese, impacting offspring muscle and metabolism. The insulin-like growth factor 2 (IGF2) pathway is vital for muscle growth, but its regulation by maternal obesity (MO) remains unclear. H19, a long noncoding RNA, is reciprocally regulated with Igf2, which has multiple promoters (P0–P3). H19 interacts with EZH2, the catalytic subunit of polycomb repressive complex 2 depositing H3K27me3. We found that MO increased fetal H19 expression and investigated how H19 epigenetically regulates Igf2 in offspring muscle. C57BL/6J female mice were fed a control (10% fat) or high-fat diet (45% fat) to induce obesity before mating, continuing through pregnancy and lactation. Neonates were sampled for biochemical analysis, and 3-month-old offspring were used for assessing muscle function and metabolism. MO increased H19 expression, enhancing H19-EZH2 interaction and H3K27me3-mediated repression of Igf2 in the P3 promoter, leading to hypermethylation and impaired muscle function in offspring. In addition, offspring with myogenic cell-specific H19 overexpression were also used. Weaning offspring with H19 overexpression showed reduced muscle mass, strength, and endurance and altered structure. Primary myogenic cells from H19 overexpressing neonates showed suppressed Igf2 expression, promoter activity, and myotube formation, which were recovered upon IGF2 treatment. In C2C12 and human skeletal myoblast cells, H19 overexpression disrupted IGF2 signaling, increased EZH2 recruitment, and reduced myotube formation, while its knockdown had opposite effects. Additionally, EZH2 inhibition reduced H3K27me3 deposition and methylation in the Igf2 P3 promoter. These data show that MO impairs muscle development by disrupting IGF2 signaling through H19-EZH2 interaction, affecting offspring muscle function. Article Highlights H19-mediated epigenetic modifications alter Igf2 promoter activity, leading to persistent Igf2 suppression in maternal obesity (MO) offspring, causing long-term muscle dysfunction. MO increases H19 expression and enhances EZH2 recruitment and H3K27me3 deposition in the Igf2 P3 promoter, leading to higher DNA methylation. H19-EZH2 axis provides a potential therapeutic target for mitigating MO-induced muscle dysfunction and improving offspring metabolic health.
{"title":"Maternal Obesity Leads to Muscle Dysfunction via H19 -Mediated Programming of Insulin-Like Growth Factor 2 Signaling","authors":"Sharmeen Islam, Xinrui Li, M.D. Nazmul Hossain, Zhongyun Kou, Li-Wei Chen, Jeanene Marie Deavila, Mei-Jun Zhu, Min Du","doi":"10.2337/db25-0271","DOIUrl":"https://doi.org/10.2337/db25-0271","url":null,"abstract":"Forty-two percent of American women of childbearing age are obese, impacting offspring muscle and metabolism. The insulin-like growth factor 2 (IGF2) pathway is vital for muscle growth, but its regulation by maternal obesity (MO) remains unclear. H19, a long noncoding RNA, is reciprocally regulated with Igf2, which has multiple promoters (P0–P3). H19 interacts with EZH2, the catalytic subunit of polycomb repressive complex 2 depositing H3K27me3. We found that MO increased fetal H19 expression and investigated how H19 epigenetically regulates Igf2 in offspring muscle. C57BL/6J female mice were fed a control (10% fat) or high-fat diet (45% fat) to induce obesity before mating, continuing through pregnancy and lactation. Neonates were sampled for biochemical analysis, and 3-month-old offspring were used for assessing muscle function and metabolism. MO increased H19 expression, enhancing H19-EZH2 interaction and H3K27me3-mediated repression of Igf2 in the P3 promoter, leading to hypermethylation and impaired muscle function in offspring. In addition, offspring with myogenic cell-specific H19 overexpression were also used. Weaning offspring with H19 overexpression showed reduced muscle mass, strength, and endurance and altered structure. Primary myogenic cells from H19 overexpressing neonates showed suppressed Igf2 expression, promoter activity, and myotube formation, which were recovered upon IGF2 treatment. In C2C12 and human skeletal myoblast cells, H19 overexpression disrupted IGF2 signaling, increased EZH2 recruitment, and reduced myotube formation, while its knockdown had opposite effects. Additionally, EZH2 inhibition reduced H3K27me3 deposition and methylation in the Igf2 P3 promoter. These data show that MO impairs muscle development by disrupting IGF2 signaling through H19-EZH2 interaction, affecting offspring muscle function. Article Highlights H19-mediated epigenetic modifications alter Igf2 promoter activity, leading to persistent Igf2 suppression in maternal obesity (MO) offspring, causing long-term muscle dysfunction. MO increases H19 expression and enhances EZH2 recruitment and H3K27me3 deposition in the Igf2 P3 promoter, leading to higher DNA methylation. H19-EZH2 axis provides a potential therapeutic target for mitigating MO-induced muscle dysfunction and improving offspring metabolic health.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"3 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664508","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}
Lue Ping Zhao, George K. Papadopoulos, Jay S. Skyler, Hemang M. Parikh, William W. Kwok, Terry P. Lybrand, George P. Bondinas, Antonis K. Moustakas, Ruihan Wang, Chul-Woo Pyo, Wyatt C. Nelson, Daniel E. Geraghty, Åke Lernmark
The primary objective of this study was to investigate whether ligand-receptor interactions (LRIs) between IGHG and FCGR gene products are associated with progression to type 1 diabetes (T1D). Using two completed clinical trials (DPT-1 and TN07), we applied next-generation targeted sequencing to genotype IGHG and FCGR genes in a cohort of 1,214 individuals and assessed LRI associations with disease progression. A Cox regression model was used to quantify LRI associations. IGHG or FCGR alone was found to have weak and sporadic associations with progression. Multiple LRIs between IGHG and FCGR gene products were found to be associated with progression, especially LRIs of IGHG2 with multiple FCGR receptors that accelerate progression and those of IGHG4 with multiple FCGR receptors (some overlapping) that delay progression. Furthermore, as several crystal structures of FcγRs complexed with distinct IgG molecules are known, application of this knowledge here was hampered by the absence of any information on the subclass distribution of each of the several T1D-related autoantibodies. It cannot be excluded that their respective state of glycosylation may influence binding affinity to various FcγRs and the function of thus-formed complexes. Our findings suggest that LRIs of the IGHG and FCGR gene products probably influence progression, shedding new insights into some of the immunological mechanisms involved in progression to T1D. Our findings potentially facilitate the search for new immunotherapeutic treatment through intervening at key steps in the progression. Article Highlights This study investigated ligand-receptor interactions (LRIs) between IGHG and FCGR gene products in type 1 diabetes progression. Genes of 1,214 participants from the DPT-1 and TN07 trials were sequenced using next-generation targeted sequencing technology, and LRI associations with the progression time to type 1 diabetes were analyzed using Cox regression modeling. Weak associations were found for IGHG or FCGR variants individually, but multiple LRIs significantly impacted progression. Several IGHG2-FCGR interactions accelerated progression, while a few other IGHG4-FCGR interactions delayed it. The results may provide insights into certain immunogenetic mechanisms of T1D and suggest therapeutic potential of targeting specific LRIs.
{"title":"Profiling Associations Between IGHG-FCGR Ligand-Receptor Interactions and Disease Progression From Stage 1 and 2 to Stage 3 Type 1 Diabetes","authors":"Lue Ping Zhao, George K. Papadopoulos, Jay S. Skyler, Hemang M. Parikh, William W. Kwok, Terry P. Lybrand, George P. Bondinas, Antonis K. Moustakas, Ruihan Wang, Chul-Woo Pyo, Wyatt C. Nelson, Daniel E. Geraghty, Åke Lernmark","doi":"10.2337/db25-0610","DOIUrl":"https://doi.org/10.2337/db25-0610","url":null,"abstract":"The primary objective of this study was to investigate whether ligand-receptor interactions (LRIs) between IGHG and FCGR gene products are associated with progression to type 1 diabetes (T1D). Using two completed clinical trials (DPT-1 and TN07), we applied next-generation targeted sequencing to genotype IGHG and FCGR genes in a cohort of 1,214 individuals and assessed LRI associations with disease progression. A Cox regression model was used to quantify LRI associations. IGHG or FCGR alone was found to have weak and sporadic associations with progression. Multiple LRIs between IGHG and FCGR gene products were found to be associated with progression, especially LRIs of IGHG2 with multiple FCGR receptors that accelerate progression and those of IGHG4 with multiple FCGR receptors (some overlapping) that delay progression. Furthermore, as several crystal structures of FcγRs complexed with distinct IgG molecules are known, application of this knowledge here was hampered by the absence of any information on the subclass distribution of each of the several T1D-related autoantibodies. It cannot be excluded that their respective state of glycosylation may influence binding affinity to various FcγRs and the function of thus-formed complexes. Our findings suggest that LRIs of the IGHG and FCGR gene products probably influence progression, shedding new insights into some of the immunological mechanisms involved in progression to T1D. Our findings potentially facilitate the search for new immunotherapeutic treatment through intervening at key steps in the progression. Article Highlights This study investigated ligand-receptor interactions (LRIs) between IGHG and FCGR gene products in type 1 diabetes progression. Genes of 1,214 participants from the DPT-1 and TN07 trials were sequenced using next-generation targeted sequencing technology, and LRI associations with the progression time to type 1 diabetes were analyzed using Cox regression modeling. Weak associations were found for IGHG or FCGR variants individually, but multiple LRIs significantly impacted progression. Several IGHG2-FCGR interactions accelerated progression, while a few other IGHG4-FCGR interactions delayed it. The results may provide insights into certain immunogenetic mechanisms of T1D and suggest therapeutic potential of targeting specific LRIs.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"169 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664527","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}
Glucagon-like peptide 1 receptor (GLP-1R) agonists have transformed obesity treatment, but weight loss responses to these drugs vary widely. Elucidating behavioral and metabolic phenotypes throughout GLP-1R agonist treatment could identify mechanisms underlying this response spectrum. We characterized food intake, meal patterns, energy expenditure (EE), and substrate oxidation during prolonged semaglutide treatment and posttreatment recovery in obese male mice at room temperature (RT) and thermoneutral temperature (TN). Semaglutide-induced weight loss and posttreatment weight regain were similar at RT and TN. Weight loss was divided into three stages at both temperatures: rapid initial weight loss, slower gradual weight loss, and weight maintenance. Initial weight loss was marked by reduced food intake, smaller and less frequent meals, and increased lipid oxidation. Food intake gradually returned to pretreatment levels through increased meal frequency, whereas meal size remained suppressed. Lipid oxidation gradually decreased, whereas carbohydrate oxidation increased. Weight-adjusted EE remained constant and elevated in semaglutide- versus vehicle-treated mice, and locomotor activity increased throughout semaglutide treatment. Mice rapidly regained weight after treatment cessation as a result of increased food intake, meal size and frequency, carbohydrate oxidation, EE, and activity. Thus, semaglutide-induced weight loss and regain after treatment cessation involve dynamic, stage-specific changes in feeding behavior, EE, and substrate oxidation. Article Highlights Although many studies have demonstrated acute behavioral and metabolic effects of glucagon-like peptide 1 receptor (GLP-1R) agonists, few have assessed long-term effects of these drugs on these phenotypes. We assessed changes in various behavioral and metabolic phenotypes throughout a 21-day treatment regimen with semaglutide and posttreatment. Weight loss in response to prolonged semaglutide treatment can be divided into distinct phases, and each phase is characterized by different effects on food intake, meal patterns, energy expenditure, and substrate oxidation. Our findings suggest that differences in behavioral changes and/or metabolic adaptations may underlie the degree of weight loss responsiveness to GLP-1R agonists.
{"title":"Prolonged Semaglutide Treatment Reveals Stage-Dependent Changes to Feeding Behavior and Metabolic Adaptations in Male Mice","authors":"Harsh Shah, Julio E. Ayala","doi":"10.2337/db25-0678","DOIUrl":"https://doi.org/10.2337/db25-0678","url":null,"abstract":"Glucagon-like peptide 1 receptor (GLP-1R) agonists have transformed obesity treatment, but weight loss responses to these drugs vary widely. Elucidating behavioral and metabolic phenotypes throughout GLP-1R agonist treatment could identify mechanisms underlying this response spectrum. We characterized food intake, meal patterns, energy expenditure (EE), and substrate oxidation during prolonged semaglutide treatment and posttreatment recovery in obese male mice at room temperature (RT) and thermoneutral temperature (TN). Semaglutide-induced weight loss and posttreatment weight regain were similar at RT and TN. Weight loss was divided into three stages at both temperatures: rapid initial weight loss, slower gradual weight loss, and weight maintenance. Initial weight loss was marked by reduced food intake, smaller and less frequent meals, and increased lipid oxidation. Food intake gradually returned to pretreatment levels through increased meal frequency, whereas meal size remained suppressed. Lipid oxidation gradually decreased, whereas carbohydrate oxidation increased. Weight-adjusted EE remained constant and elevated in semaglutide- versus vehicle-treated mice, and locomotor activity increased throughout semaglutide treatment. Mice rapidly regained weight after treatment cessation as a result of increased food intake, meal size and frequency, carbohydrate oxidation, EE, and activity. Thus, semaglutide-induced weight loss and regain after treatment cessation involve dynamic, stage-specific changes in feeding behavior, EE, and substrate oxidation. Article Highlights Although many studies have demonstrated acute behavioral and metabolic effects of glucagon-like peptide 1 receptor (GLP-1R) agonists, few have assessed long-term effects of these drugs on these phenotypes. We assessed changes in various behavioral and metabolic phenotypes throughout a 21-day treatment regimen with semaglutide and posttreatment. Weight loss in response to prolonged semaglutide treatment can be divided into distinct phases, and each phase is characterized by different effects on food intake, meal patterns, energy expenditure, and substrate oxidation. Our findings suggest that differences in behavioral changes and/or metabolic adaptations may underlie the degree of weight loss responsiveness to GLP-1R agonists.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"5 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651235","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}
Masato Uchida, Hajime Yamazaki, Sihao Han, Brian Z. Huang, Shoko Ariyoshi, Yoji Hirayama, Sho Matsushita, Ryosuke Horitani, Róbert Wagner, Martin Heni
Pancreatic fibrosis has been proposed as a contributor to type 2 diabetes (T2D) by impairing islet function, but whether it plays a causal role remains unclear. We investigated this question using two complementary approaches. First, we performed a computed tomography–based retrospective case-control study (T2D case patients: n = 58; control participants: n = 58) assessing extracellular volume fraction as a marker of fibrosis in the pancreas, liver, and myocardium. Greater pancreatic fibrosis was associated with T2D (adjusted odds ratio [OR] per 1 [SD] increase: 1.64; 95% CI 1.00–2.68), independent of age, sex, BMI, liver fibrosis, and myocardial fibrosis. Second, we conducted a Mendelian randomization analysis using genome-wide association study (GWAS) data on multiorgan fibrosis derived from MRI in the UK Biobank (n = 43,881), along with T2D GWAS data from the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium (n = 242,283 T2D case patients and 1,569,734 control participants). Genetically predicted pancreatic fibrosis levels were associated with an increased T2D risk (OR per 1-SD increase: 1.43; 95% CI 1.09–1.89), whereas liver and myocardial fibrosis levels showed no associations. These findings support a potential causal and organ-specific role of pancreatic fibrosis in the pathogenesis of T2D, highlighting pancreatic fibrosis as a mechanistically plausible and potentially targetable target in diabetes prevention. Article Highlights Pancreatic, but not liver or myocardial, fibrosis is specifically and independently linked to type 2 diabetes. Mendelian randomization analysis reveals a causal role of pancreatic fibrosis in diabetes development. Pancreatic fibrosis might be a potential therapeutic target to preserve β-cell function and prevent diabetes.
胰腺纤维化被认为是通过损害胰岛功能而导致2型糖尿病（T2D）的一个因素，但它是否起因果作用尚不清楚。我们使用两种互补的方法来调查这个问题。首先，我们进行了一项基于计算机断层扫描的回顾性病例对照研究（T2D患者：n = 58；对照组：n = 58），评估细胞外体积分数作为胰腺、肝脏和心肌纤维化的标志物。胰腺纤维化加重与T2D相关（校正优势比[OR] / 1 [SD]增加：1.64;95% CI 1.00-2.68），与年龄、性别、BMI、肝纤维化和心肌纤维化无关。其次，我们使用来自英国生物银行MRI的多器官纤维化的全基因组关联研究（GWAS）数据（n = 43,881）以及来自糖尿病遗传学复制和荟萃分析（图）联盟的T2D GWAS数据（n = 242,283例T2D患者和1,569,734例对照参与者）进行了孟德尔随机化分析。遗传预测的胰腺纤维化水平与T2D风险增加相关（OR / 1-SD增加：1.43;95% CI 1.09-1.89），而肝脏和心肌纤维化水平无关联。这些发现支持胰腺纤维化在T2D发病机制中的潜在因果关系和器官特异性作用，强调胰腺纤维化在糖尿病预防中是一个机制合理且潜在可靶向的靶点。胰腺纤维化，而不是肝脏或心肌纤维化，与2型糖尿病有特异性和独立的联系。孟德尔随机化分析揭示了胰腺纤维化在糖尿病发展中的因果作用。胰腺纤维化可能是维持β细胞功能和预防糖尿病的潜在治疗靶点。
{"title":"Multiorgan Fibrosis and Risk of Type 2 Diabetes: Genetic and Observational Evidence Highlighting a Causal Role of Pancreatic Fibrosis","authors":"Masato Uchida, Hajime Yamazaki, Sihao Han, Brian Z. Huang, Shoko Ariyoshi, Yoji Hirayama, Sho Matsushita, Ryosuke Horitani, Róbert Wagner, Martin Heni","doi":"10.2337/db25-0629","DOIUrl":"https://doi.org/10.2337/db25-0629","url":null,"abstract":"Pancreatic fibrosis has been proposed as a contributor to type 2 diabetes (T2D) by impairing islet function, but whether it plays a causal role remains unclear. We investigated this question using two complementary approaches. First, we performed a computed tomography–based retrospective case-control study (T2D case patients: n = 58; control participants: n = 58) assessing extracellular volume fraction as a marker of fibrosis in the pancreas, liver, and myocardium. Greater pancreatic fibrosis was associated with T2D (adjusted odds ratio [OR] per 1 [SD] increase: 1.64; 95% CI 1.00–2.68), independent of age, sex, BMI, liver fibrosis, and myocardial fibrosis. Second, we conducted a Mendelian randomization analysis using genome-wide association study (GWAS) data on multiorgan fibrosis derived from MRI in the UK Biobank (n = 43,881), along with T2D GWAS data from the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium (n = 242,283 T2D case patients and 1,569,734 control participants). Genetically predicted pancreatic fibrosis levels were associated with an increased T2D risk (OR per 1-SD increase: 1.43; 95% CI 1.09–1.89), whereas liver and myocardial fibrosis levels showed no associations. These findings support a potential causal and organ-specific role of pancreatic fibrosis in the pathogenesis of T2D, highlighting pancreatic fibrosis as a mechanistically plausible and potentially targetable target in diabetes prevention. Article Highlights Pancreatic, but not liver or myocardial, fibrosis is specifically and independently linked to type 2 diabetes. Mendelian randomization analysis reveals a causal role of pancreatic fibrosis in diabetes development. Pancreatic fibrosis might be a potential therapeutic target to preserve β-cell function and prevent diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"25 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145645267","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}
Bettina Mittendorfer, Bruce W. Patterson, J. Christopher Eagon, Mihoko Yoshino, Samuel Klein
We used a dual (intravenous and oral) glucose tracer protocol to evaluate rates of glucose appearance in the circulation, insulin-mediated glucose disposal (IMGD), and noninsulin-mediated glucose disposal (NIMGD) for 4 h after consumption of a mixed meal in people with obesity and type 2 diabetes before and after marked (∼20%) weight loss, induced by behavioral diet therapy (BDT, n = 11) or Roux-en-Y gastric bypass (RYGB) surgery (n = 9). Total postprandial glucose appearance rate was lower after compared with before weight loss in both the BDT and RYGB groups because of a decrease in endogenous glucose production, without a difference between groups. However, the decreases in total and incremental postprandial plasma glucose concentration areas under the curve were greater in the BDT group than the RYGB group because IMGD doubled in the BDT group but did not change in the RYGB group. These results demonstrate that the improvement in postprandial glycemia is greater after marked, matched weight loss induced by BDT compared with RYGB in people with obesity and type 2 diabetes, because of increased IMGD after BDT but not RYGB. Nonetheless, these findings do not diminish the potent therapeutic effect of RYGB surgery on glycemic control and even achieving remission of type 2 diabetes. Article Highlights In people with obesity and diabetes, marked (∼20%) weight loss induced by behavioral diet therapy (BDT) causes a greater decrease in postprandial plasma glucose area under the curve than matched weight loss after Roux-en-Y gastric bypass (RYGB), even though insulin sensitivity and postprandial plasma insulin area under the curve are the same in both groups. We studied the effects of marked weight loss after BDT or RYGB on insulin-mediated glucose disposal (IMGD) and non–insulin-mediated glucose disposal. Weight loss induced by BDT, but not RYGB, increased IMGD. Postprandial glycemia improves more after marked weight loss induced by BDT than by RYGB because of increased IMGD after BDT but not RYGB.
我们使用双重（静脉注射和口服）葡萄糖示踪剂方案来评估肥胖和2型糖尿病患者在行为饮食疗法（BDT, n = 11）或Roux-en-Y胃旁路（RYGB）手术（n = 9）诱导体重显著（~ 20%）减轻前后，进食混合餐后4小时内循环中的葡萄糖出现率、胰岛素介导的葡萄糖处置（IMGD）和非胰岛素介导的葡萄糖处置（NIMGD）。与减肥前相比，BDT组和RYGB组的餐后总葡萄糖出现率都较低，这是由于内源性葡萄糖产生的减少，两组之间没有差异。然而，BDT组在曲线下的总血糖浓度和增量血糖浓度的下降幅度大于RYGB组，因为IMGD在BDT组增加了一倍，而RYGB组没有变化。这些结果表明，在肥胖和2型糖尿病患者中，与RYGB相比，BDT诱导的显著、匹配的体重减轻对餐后血糖的改善更大，因为BDT后IMGD增加，而RYGB没有增加。尽管如此，这些发现并没有削弱RYGB手术对血糖控制甚至2型糖尿病缓解的有效治疗效果。在肥胖和糖尿病患者中，行为饮食疗法（BDT）引起的显著（~ 20%）体重减轻比Roux-en-Y胃旁路（RYGB）后体重减轻引起的餐后血糖曲线下面积下降更大，尽管两组的胰岛素敏感性和餐后血浆胰岛素曲线下面积相同。我们研究了BDT或RYGB后体重明显减轻对胰岛素介导的葡萄糖处理（IMGD）和非胰岛素介导的葡萄糖处理的影响。BDT引起的体重减轻增加了IMGD，而RYGB没有。餐后血糖在BDT诱导的显著体重减轻后比RYGB改善更多，因为BDT后IMGD增加，而RYGB没有。
{"title":"Effects of Marked Weight Loss Induced by Gastric Bypass Surgery or Low-Calorie Diet Alone on Postprandial Glucose Disposal in Type 2 Diabetes","authors":"Bettina Mittendorfer, Bruce W. Patterson, J. Christopher Eagon, Mihoko Yoshino, Samuel Klein","doi":"10.2337/db25-0737","DOIUrl":"https://doi.org/10.2337/db25-0737","url":null,"abstract":"We used a dual (intravenous and oral) glucose tracer protocol to evaluate rates of glucose appearance in the circulation, insulin-mediated glucose disposal (IMGD), and noninsulin-mediated glucose disposal (NIMGD) for 4 h after consumption of a mixed meal in people with obesity and type 2 diabetes before and after marked (∼20%) weight loss, induced by behavioral diet therapy (BDT, n = 11) or Roux-en-Y gastric bypass (RYGB) surgery (n = 9). Total postprandial glucose appearance rate was lower after compared with before weight loss in both the BDT and RYGB groups because of a decrease in endogenous glucose production, without a difference between groups. However, the decreases in total and incremental postprandial plasma glucose concentration areas under the curve were greater in the BDT group than the RYGB group because IMGD doubled in the BDT group but did not change in the RYGB group. These results demonstrate that the improvement in postprandial glycemia is greater after marked, matched weight loss induced by BDT compared with RYGB in people with obesity and type 2 diabetes, because of increased IMGD after BDT but not RYGB. Nonetheless, these findings do not diminish the potent therapeutic effect of RYGB surgery on glycemic control and even achieving remission of type 2 diabetes. Article Highlights In people with obesity and diabetes, marked (∼20%) weight loss induced by behavioral diet therapy (BDT) causes a greater decrease in postprandial plasma glucose area under the curve than matched weight loss after Roux-en-Y gastric bypass (RYGB), even though insulin sensitivity and postprandial plasma insulin area under the curve are the same in both groups. We studied the effects of marked weight loss after BDT or RYGB on insulin-mediated glucose disposal (IMGD) and non–insulin-mediated glucose disposal. Weight loss induced by BDT, but not RYGB, increased IMGD. Postprandial glycemia improves more after marked weight loss induced by BDT than by RYGB because of increased IMGD after BDT but not RYGB.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"97 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609851","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}
Jiahui Li, Qinhui Liu, Yimin Xiong, Ying Xu, Jinhang Zhang, Yan Xia, Xiandan Jing, Zijing Zhang, Juan Pang, Cuiyuan Huang, Haiying Song, Ailin Zhang, Yanping Li, Qin Tang, Jinhan He
Metabolic dysfunction–associated steatotic liver disease (MASLD) has emerged as a global epidemic, yet its underlying molecular mechanisms remain elusive, and therapeutic options are limited. The interorgan communication between liver and adipose tissue plays a crucial role in maintaining hepatic lipid homeostasis. This study investigates the role of G-protein–coupled bile acid receptor 1 (TGR5) in adipose tissue-liver communication and its impact on hepatic lipid metabolism during the progression of MASLD. We observed that TGR5 expression in white adipose tissue was significantly upregulated under both fasting and high-fat diet (HFD) conditions, whereas its levels in brown adipose tissue remained unchanged. Notably, mice with adipocyte-specific TGR5 deletion exhibited exacerbated fasting/HFD-induced hepatic steatosis and impaired hepatic fatty acid oxidation. Mechanistically, adipose tissue TGR5 deficiency reduced adiponectin secretion, which in turn suppressed hepatic fatty acid oxidation and aggravated hepatic lipid accumulation; conversely, restoration of circulating adiponectin rescued these metabolic abnormalities. Collectively, our findings highlight a critical role for adipose tissue TGR5 in promoting adiponectin secretion, thereby enhancing hepatic fatty acid oxidation and protecting against hepatic steatosis. Article Highlights Systemic G-protein–coupled bile acid receptor 1 (TGR5) is involved in modulating hepatic triglyceride accumulation, but whether adipose-derived TGR5 regulates hepatic lipid metabolism remains undefined. We investigated whether fasting or a high-fat diet (HFD) altered TGR5 levels in adipose tissue and the effect of TGR5 ablation in adipose tissue on hepatic lipid metabolism. We found that TGR5 protein expression was upregulated in white adipose tissue upon fasting or HFD. Adipose-specific TGR5 deficiency decreased adiponectin secretion, which ultimately suppressed hepatic fatty acid oxidation and exacerbated intrahepatic lipid deposition. Given the limited therapeutic options for metabolic dysfunction–associated steatotic liver disease (MASLD), our findings highlight the therapeutic potential of targeting adipocyte TGR5 for MASLD intervention.
{"title":"Adipose TGR5 Deletion Promotes Hepatic Steatosis Through Decreasing Adiponectin Secretion in Mice","authors":"Jiahui Li, Qinhui Liu, Yimin Xiong, Ying Xu, Jinhang Zhang, Yan Xia, Xiandan Jing, Zijing Zhang, Juan Pang, Cuiyuan Huang, Haiying Song, Ailin Zhang, Yanping Li, Qin Tang, Jinhan He","doi":"10.2337/db25-0344","DOIUrl":"https://doi.org/10.2337/db25-0344","url":null,"abstract":"Metabolic dysfunction–associated steatotic liver disease (MASLD) has emerged as a global epidemic, yet its underlying molecular mechanisms remain elusive, and therapeutic options are limited. The interorgan communication between liver and adipose tissue plays a crucial role in maintaining hepatic lipid homeostasis. This study investigates the role of G-protein–coupled bile acid receptor 1 (TGR5) in adipose tissue-liver communication and its impact on hepatic lipid metabolism during the progression of MASLD. We observed that TGR5 expression in white adipose tissue was significantly upregulated under both fasting and high-fat diet (HFD) conditions, whereas its levels in brown adipose tissue remained unchanged. Notably, mice with adipocyte-specific TGR5 deletion exhibited exacerbated fasting/HFD-induced hepatic steatosis and impaired hepatic fatty acid oxidation. Mechanistically, adipose tissue TGR5 deficiency reduced adiponectin secretion, which in turn suppressed hepatic fatty acid oxidation and aggravated hepatic lipid accumulation; conversely, restoration of circulating adiponectin rescued these metabolic abnormalities. Collectively, our findings highlight a critical role for adipose tissue TGR5 in promoting adiponectin secretion, thereby enhancing hepatic fatty acid oxidation and protecting against hepatic steatosis. Article Highlights Systemic G-protein–coupled bile acid receptor 1 (TGR5) is involved in modulating hepatic triglyceride accumulation, but whether adipose-derived TGR5 regulates hepatic lipid metabolism remains undefined. We investigated whether fasting or a high-fat diet (HFD) altered TGR5 levels in adipose tissue and the effect of TGR5 ablation in adipose tissue on hepatic lipid metabolism. We found that TGR5 protein expression was upregulated in white adipose tissue upon fasting or HFD. Adipose-specific TGR5 deficiency decreased adiponectin secretion, which ultimately suppressed hepatic fatty acid oxidation and exacerbated intrahepatic lipid deposition. Given the limited therapeutic options for metabolic dysfunction–associated steatotic liver disease (MASLD), our findings highlight the therapeutic potential of targeting adipocyte TGR5 for MASLD intervention.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"25 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609834","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}
Christopher S. Wilson, Blair T. Stocks, Alexander C. Falk, Daniel J. Moore
B lymphocytes are thought to drive β-cell destruction in type 1 diabetes (T1D) by activating anti-islet T cells. However, the observation that autoreactive T-cell activation and disease progression can occur without B cells challenges this view. Still, preclinical and clinical studies have shown that B-cell depletion alleviates β-cell destruction, suggesting a critical role for B cells in T1D. Our findings propose an alternative function for B cells, impairing regulatory T cells (Tregs) that would otherwise protect islets. In the NOD islet transplant model, we show that B-cell absence enables transplant tolerance, allowing Tregs to become responsive to immune therapy and confer allograft protection. Extending this to spontaneous diabetes, we have found that insulin-reactive Tregs are reduced in NOD mice in proportion to insulin-reactive B cells, while effector T cells remain unaffected. Moreover, Tregs from B-cell–deficient NOD mice better restrained β-cell destruction than those from B-cell–sufficient environments. Together, these findings indicate that autoreactive B cells primarily erode immune regulation by culling islet-protective Tregs. Thus, therapies that mobilize Tregs could be more effective when combined with B-cell–targeting strategies in islet transplant or T1D prevention. Article Highlights This study expands the role of B lymphocytes in type 1 diabetes by demonstrating how B cells influence the development and function of regulatory T cells (Tregs) during islet transplant and autoimmune progression. This study was done to explain how B lymphocytes regulate the progression of anti-islet immunity, even when they appear dispensable for effector cell activation. B-cell deficiency (using NOD.μMT mice) enables durable islet transplant tolerance, enhances the expansion of Helios+ Tregs, increases the ratio of insulin-reactive Tregs to effector T cells, and enhances islet-protective Treg function. These findings indicate that B lymphocytes accelerate destructive immunity by negatively regulating Treg development and function. Targeting the harmful B-cell–Treg interactions, particularly in the thymic environment, may offer new, more selective therapeutic strategies to prevent anti-islet immunity.
{"title":"B Lymphocytes Impede Tregs to Erode Islet Tolerance in Type 1 Diabetes","authors":"Christopher S. Wilson, Blair T. Stocks, Alexander C. Falk, Daniel J. Moore","doi":"10.2337/db25-0241","DOIUrl":"https://doi.org/10.2337/db25-0241","url":null,"abstract":"B lymphocytes are thought to drive β-cell destruction in type 1 diabetes (T1D) by activating anti-islet T cells. However, the observation that autoreactive T-cell activation and disease progression can occur without B cells challenges this view. Still, preclinical and clinical studies have shown that B-cell depletion alleviates β-cell destruction, suggesting a critical role for B cells in T1D. Our findings propose an alternative function for B cells, impairing regulatory T cells (Tregs) that would otherwise protect islets. In the NOD islet transplant model, we show that B-cell absence enables transplant tolerance, allowing Tregs to become responsive to immune therapy and confer allograft protection. Extending this to spontaneous diabetes, we have found that insulin-reactive Tregs are reduced in NOD mice in proportion to insulin-reactive B cells, while effector T cells remain unaffected. Moreover, Tregs from B-cell–deficient NOD mice better restrained β-cell destruction than those from B-cell–sufficient environments. Together, these findings indicate that autoreactive B cells primarily erode immune regulation by culling islet-protective Tregs. Thus, therapies that mobilize Tregs could be more effective when combined with B-cell–targeting strategies in islet transplant or T1D prevention. Article Highlights This study expands the role of B lymphocytes in type 1 diabetes by demonstrating how B cells influence the development and function of regulatory T cells (Tregs) during islet transplant and autoimmune progression. This study was done to explain how B lymphocytes regulate the progression of anti-islet immunity, even when they appear dispensable for effector cell activation. B-cell deficiency (using NOD.μMT mice) enables durable islet transplant tolerance, enhances the expansion of Helios+ Tregs, increases the ratio of insulin-reactive Tregs to effector T cells, and enhances islet-protective Treg function. These findings indicate that B lymphocytes accelerate destructive immunity by negatively regulating Treg development and function. Targeting the harmful B-cell–Treg interactions, particularly in the thymic environment, may offer new, more selective therapeutic strategies to prevent anti-islet immunity.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"55 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594028","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}
Luke N. Sharp, Uyenlinh L. Mirshahi, Kevin Colclough, Timothy S. Hall, Jeremy S. Haley, Stuart J. Cannon, Thomas W. Laver, Michael N. Weedon, Andrew T. Hattersley, David J. Carey, Kashyap A. Patel
Maturity onset diabetes of the young (MODY) can present after the age of 40 years, but its prevalence and clinical characteristics, and the utility of simple clinical features for selecting cases in this age group remain poorly defined. We analyzed whole-exome and clinical data from 51,619 individuals with diabetes diagnosed after age 40 years from one U.K. and one U.S. cohort. The prevalence of MODY due to a pathogenic variant in the 10 mostcommon MODY genes was 1 in 191 (0.52%) in the U.K. cohort and 1 in 633 (0.16%) in the U.S. cohort. For subtypes with treatment implications (i.e., GCK, HNF1A, HNF4A, ABCC8, KCNJ11), prevalence was 1 in 234 and 1 in 935 in the U.K. and U.S. cohorts, respectively. GCK-MODY was most common, followed by HNF4A and the lower-penetrance RFX6-MODY. Clinical features of MODY largely overlapped with non-MODY diabetes either treated with insulin from diagnosis or not. Only BMI, HbA1c and HDL values were statistically different between patients with MODY and those with non-MODY diabetes in both cohorts (P < 0.0018 for all). Applying strict clinical criteria (i.e., BMI <25, noninsulin treated, and parent with diabetes) only increased the MODY diagnosis to 2.64% and 0.87% in the respective cohorts but missed >86% of cases. MODY is prevalent in later-onset diabetes and has potential for targeted therapy but is challenging to identify. Article Highlights Maturity onset diabetes of the young (MODY) can present later in life, and diagnosis can enable precision treatment. However, individuals with later-onset diabetes are rarely tested. How common is MODY in people diagnosed with diabetes after age 40 years? Can they be identified clinically? MODY affects 1 in 191–633 individuals with diabetes onset after 40 years, but clinical features alone cannot reliably identify them. MODY is relatively common in later-onset diabetes but difficult to detect clinically, limiting routine genetic testing in this group.
{"title":"MODY Is Prevalent in Later-Onset Diabetes and Has Potential for Targeted Therapy but Is Challenging to Identify","authors":"Luke N. Sharp, Uyenlinh L. Mirshahi, Kevin Colclough, Timothy S. Hall, Jeremy S. Haley, Stuart J. Cannon, Thomas W. Laver, Michael N. Weedon, Andrew T. Hattersley, David J. Carey, Kashyap A. Patel","doi":"10.2337/db25-0545","DOIUrl":"https://doi.org/10.2337/db25-0545","url":null,"abstract":"Maturity onset diabetes of the young (MODY) can present after the age of 40 years, but its prevalence and clinical characteristics, and the utility of simple clinical features for selecting cases in this age group remain poorly defined. We analyzed whole-exome and clinical data from 51,619 individuals with diabetes diagnosed after age 40 years from one U.K. and one U.S. cohort. The prevalence of MODY due to a pathogenic variant in the 10 mostcommon MODY genes was 1 in 191 (0.52%) in the U.K. cohort and 1 in 633 (0.16%) in the U.S. cohort. For subtypes with treatment implications (i.e., GCK, HNF1A, HNF4A, ABCC8, KCNJ11), prevalence was 1 in 234 and 1 in 935 in the U.K. and U.S. cohorts, respectively. GCK-MODY was most common, followed by HNF4A and the lower-penetrance RFX6-MODY. Clinical features of MODY largely overlapped with non-MODY diabetes either treated with insulin from diagnosis or not. Only BMI, HbA1c and HDL values were statistically different between patients with MODY and those with non-MODY diabetes in both cohorts (P &lt; 0.0018 for all). Applying strict clinical criteria (i.e., BMI &lt;25, noninsulin treated, and parent with diabetes) only increased the MODY diagnosis to 2.64% and 0.87% in the respective cohorts but missed &gt;86% of cases. MODY is prevalent in later-onset diabetes and has potential for targeted therapy but is challenging to identify. Article Highlights Maturity onset diabetes of the young (MODY) can present later in life, and diagnosis can enable precision treatment. However, individuals with later-onset diabetes are rarely tested. How common is MODY in people diagnosed with diabetes after age 40 years? Can they be identified clinically? MODY affects 1 in 191–633 individuals with diabetes onset after 40 years, but clinical features alone cannot reliably identify them. MODY is relatively common in later-onset diabetes but difficult to detect clinically, limiting routine genetic testing in this group.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"114 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594029","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}
Jian-Jun Liu, Sylvia Liu, Huili Zheng, Chin-Pin Wang, Subrata Debnath, Janus Lee, Lye Siang Lee, Jianhong Ching, Ming Shen Tham, Keven Ang, Resham L. Gurung, Thomas M. Coffman, Kumar Sharma, Su Chi Lim
Preclinical studies suggest that activating branched-chain amino acid (BCAA) catabolism may improve chronic kidney disease (CKD). In this prospective clinical study, we sought to examine the association between urinary BCAA excretion and risk of CKD progression in patients with type 2 diabetes. Baseline urinary BCAAs were measured by mass spectrometry in 1,868 outpatients with type 2 diabetes. The study outcome was a composite of end-stage kidney disease (estimated glomerular filtration rate <15 mL/min/1.73 m2, dialysis, or death resulting from renal causes) or doubling of serum creatinine. During a median of 7.2 years of follow-up, 203 renal events were identified. One SD increment in urinary valine, leucine, and isoleucine concentration was associated with 1.29- (95% CI 1.11–1.51), 1.31- (1.11–1.55) and 1.29-fold (1.09–1.53) increased risk, respectively, of the composite renal outcome after adjustment for clinical risk factors. Mediation analysis showed that urinary MCP-1 mediated 57%, 47%, and 58% of the effects of valine, leucine, and isoleucine on the renal outcome, respectively. High levels of urinary BCAAs were also independently associated with an increased risk of CKD progression in the Chronic Renal Insufficiency Cohort in the U.S. Our data suggest that dysregulation of BCAA metabolism in the kidneys may be involved in intrarenal inflammation and drive CKD progression. Article Highlights Restoration of branched-chain amino acid (BCAA) catabolism improves kidney pathology in animal models, but clinical data on the relationship between urinary BCAA excretion and kidney outcomes are scarce. Are urinary BCAA levels associated with CKD progression independent of clinical risk factors in patients with type 2 diabetes? High levels of urinary BCAAs predicted an increased risk of renal events independent of cardiorenal risk factors, with urinary MCP-1 mediating over 50% of the association. Activating intrarenal BCAA catabolism may potentially improve kidney function in patients with diabetes.
临床前研究表明，激活支链氨基酸（BCAA）分解代谢可能改善慢性肾脏疾病（CKD）。在这项前瞻性临床研究中，我们试图检查尿BCAA排泄与2型糖尿病患者CKD进展风险之间的关系。采用质谱法对1868例2型糖尿病门诊患者进行基线尿液BCAAs测定。研究结果是终末期肾病（估计肾小球滤过率为15 mL/min/1.73 m2，透析或肾脏原因导致的死亡）或血清肌酐加倍的综合结果。在中位7.2年的随访期间，发现203例肾脏事件。调整临床危险因素后，尿缬氨酸、亮氨酸和异亮氨酸浓度每增加一个SD，复合肾脏结局的风险分别增加1.29倍（95% CI 1.11-1.51）、1.31倍（1.11-1.55）和1.29倍（1.09-1.53）。中介分析显示，尿MCP-1分别介导57%、47%和58%的缬氨酸、亮氨酸和异亮氨酸对肾脏预后的影响。在美国慢性肾功能不全队列中，高水平的尿BCAA也与CKD进展风险增加独立相关。我们的数据表明，肾脏BCAA代谢失调可能参与肾脏内炎症并驱动CKD进展。在动物模型中，支链氨基酸（BCAA）分解代谢的恢复改善了肾脏病理，但关于尿BCAA排泄与肾脏预后之间关系的临床数据很少。尿BCAA水平与2型糖尿病患者CKD进展是否独立于临床危险因素相关？尿BCAAs水平高预示着独立于心肾危险因素的肾脏事件风险增加，其中尿MCP-1介导了超过50%的关联。激活肾内BCAA分解代谢可能潜在地改善糖尿病患者的肾功能。
{"title":"Urinary Branched-Chain Amino Acid Excretion and Chronic Kidney Disease Progression in Patients With Type 2 Diabetes","authors":"Jian-Jun Liu, Sylvia Liu, Huili Zheng, Chin-Pin Wang, Subrata Debnath, Janus Lee, Lye Siang Lee, Jianhong Ching, Ming Shen Tham, Keven Ang, Resham L. Gurung, Thomas M. Coffman, Kumar Sharma, Su Chi Lim","doi":"10.2337/db25-0782","DOIUrl":"https://doi.org/10.2337/db25-0782","url":null,"abstract":"Preclinical studies suggest that activating branched-chain amino acid (BCAA) catabolism may improve chronic kidney disease (CKD). In this prospective clinical study, we sought to examine the association between urinary BCAA excretion and risk of CKD progression in patients with type 2 diabetes. Baseline urinary BCAAs were measured by mass spectrometry in 1,868 outpatients with type 2 diabetes. The study outcome was a composite of end-stage kidney disease (estimated glomerular filtration rate &lt;15 mL/min/1.73 m2, dialysis, or death resulting from renal causes) or doubling of serum creatinine. During a median of 7.2 years of follow-up, 203 renal events were identified. One SD increment in urinary valine, leucine, and isoleucine concentration was associated with 1.29- (95% CI 1.11–1.51), 1.31- (1.11–1.55) and 1.29-fold (1.09–1.53) increased risk, respectively, of the composite renal outcome after adjustment for clinical risk factors. Mediation analysis showed that urinary MCP-1 mediated 57%, 47%, and 58% of the effects of valine, leucine, and isoleucine on the renal outcome, respectively. High levels of urinary BCAAs were also independently associated with an increased risk of CKD progression in the Chronic Renal Insufficiency Cohort in the U.S. Our data suggest that dysregulation of BCAA metabolism in the kidneys may be involved in intrarenal inflammation and drive CKD progression. Article Highlights Restoration of branched-chain amino acid (BCAA) catabolism improves kidney pathology in animal models, but clinical data on the relationship between urinary BCAA excretion and kidney outcomes are scarce. Are urinary BCAA levels associated with CKD progression independent of clinical risk factors in patients with type 2 diabetes? High levels of urinary BCAAs predicted an increased risk of renal events independent of cardiorenal risk factors, with urinary MCP-1 mediating over 50% of the association. Activating intrarenal BCAA catabolism may potentially improve kidney function in patients with diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"142 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568009","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}
For many years, brown adipose tissue (BAT) was primarily regarded as a “heat organ” for rodents. Over the past 15 years, however, research in this field has shifted significantly toward understanding of the role of BAT in metabolic health, including systemic glucose homeostasis, lipid metabolism, insulin sensitivity, and protection against cardiometabolic disease. In this award lecture, I highlight key contributions from our laboratory and others that transformed brown fat research, including molecular insights into brown and beige adipocyte biogenesis and the discovery of UCP1-independent pathways through which brown and beige fat influence metabolic health beyond thermogenesis.
{"title":"An Unexpected Journey Into Brown Fat Research for Metabolic Health: The 2025 Outstanding Scientific Achievement Award Lecture","authors":"Shingo Kajimura","doi":"10.2337/dbi25-0026","DOIUrl":"https://doi.org/10.2337/dbi25-0026","url":null,"abstract":"For many years, brown adipose tissue (BAT) was primarily regarded as a “heat organ” for rodents. Over the past 15 years, however, research in this field has shifted significantly toward understanding of the role of BAT in metabolic health, including systemic glucose homeostasis, lipid metabolism, insulin sensitivity, and protection against cardiometabolic disease. In this award lecture, I highlight key contributions from our laboratory and others that transformed brown fat research, including molecular insights into brown and beige adipocyte biogenesis and the discovery of UCP1-independent pathways through which brown and beige fat influence metabolic health beyond thermogenesis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"6 1","pages":"2216-2222"},"PeriodicalIF":7.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559430","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}
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