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}
Diabetic kidney disease (DKD) progression involves intricate interactions among senescence, oxidative stress, inflammation, and fibrosis. This study systematically investigates the regulatory role and molecular mechanisms of NUAK1 in DKD pathogenesis. Bioinformatics analysis of Gene Expression Omnibus data sets identified NUAK1 as a differentially expressed gene, validated in human kidney proximal tubule epithelial (HK-2) cells, high-fat diet and streptozotocin-induced DKD mice, d-galactose–induced senescent mice, and human peripheral blood mononuclear cells. Functional studies demonstrated that NUAK1 inhibition via siRNA knockdown, pharmacological inhibitors, or kidney tubule-targeted adeno-associated virus serotype carrying shRNA against NUAK1 delivery attenuated reactive oxygen species–tumor protein 53 (ROS/P53) axis-mediated renal tubular senescence, oxidative stress, inflammation, and fibrosis in vitro and in vivo. Mechanistically, chromatin immunoprecipitation quantitative PCR revealed that transcription factor ETS1 directly binds to the NUAK1 promoter, driving its transcriptional activation in DKD. Furthermore, molecular docking and dynamics simulations identified Asiatic acid (AA) as a potent NUAK1 inhibitor, with a stable binding affinity. AA suppressed NUAK1 expression and downstream pathological processes, ameliorating renal injury in DKD models. These findings elucidate the role and regulatory mechanisms of NUAK1 in modulating ROS/P53 axis-driven tubular senescence and oxidative stress, providing a theoretical basis for structure optimization in drug development targeting NUAK1. Article Highlights Mechanisms linking renal tubular senescence to diabetic kidney disease (DKD) progression remain poorly understood. Systematic elucidation of the regulatory role of NUAK1 in the pathogenesis of DKD and its regulatory mechanisms is provided. NUAK1 is upregulated in DKD, promoting senescence via reactive oxygen species–tumor protein 53 under transcriptional activation by E26 transformation–specific 1, while Asiatic acid (AA) directly binds NUAK1 to suppress these pathological processes. NUAK1 emerges as a therapeutic target for DKD, and AA provides a natural scaffold for NUAK1 inhibitor development, offering a strategy to combat diabetes-related renal decline.
{"title":"NUAK1 Promotes Diabetic Kidney Disease by Accelerating Renal Tubular Senescence via the ROS/P53 Axis","authors":"Lei Guo, Peili Wu, Qing Li, Qijian Feng, Xiaochun Lin, Yuling Luo, Yuan Wang, Minghai Wu, Feifei Cai, Jin Zhang, Yuxuan Hu, Huiyun Wang, Yu Wang, Sirui Luo, Linlin Tian, Xinzhao Fan, Ling Wang, Yaoming Xue, Meiping Guan","doi":"10.2337/db25-0417","DOIUrl":"https://doi.org/10.2337/db25-0417","url":null,"abstract":"Diabetic kidney disease (DKD) progression involves intricate interactions among senescence, oxidative stress, inflammation, and fibrosis. This study systematically investigates the regulatory role and molecular mechanisms of NUAK1 in DKD pathogenesis. Bioinformatics analysis of Gene Expression Omnibus data sets identified NUAK1 as a differentially expressed gene, validated in human kidney proximal tubule epithelial (HK-2) cells, high-fat diet and streptozotocin-induced DKD mice, d-galactose–induced senescent mice, and human peripheral blood mononuclear cells. Functional studies demonstrated that NUAK1 inhibition via siRNA knockdown, pharmacological inhibitors, or kidney tubule-targeted adeno-associated virus serotype carrying shRNA against NUAK1 delivery attenuated reactive oxygen species–tumor protein 53 (ROS/P53) axis-mediated renal tubular senescence, oxidative stress, inflammation, and fibrosis in vitro and in vivo. Mechanistically, chromatin immunoprecipitation quantitative PCR revealed that transcription factor ETS1 directly binds to the NUAK1 promoter, driving its transcriptional activation in DKD. Furthermore, molecular docking and dynamics simulations identified Asiatic acid (AA) as a potent NUAK1 inhibitor, with a stable binding affinity. AA suppressed NUAK1 expression and downstream pathological processes, ameliorating renal injury in DKD models. These findings elucidate the role and regulatory mechanisms of NUAK1 in modulating ROS/P53 axis-driven tubular senescence and oxidative stress, providing a theoretical basis for structure optimization in drug development targeting NUAK1. Article Highlights Mechanisms linking renal tubular senescence to diabetic kidney disease (DKD) progression remain poorly understood. Systematic elucidation of the regulatory role of NUAK1 in the pathogenesis of DKD and its regulatory mechanisms is provided. NUAK1 is upregulated in DKD, promoting senescence via reactive oxygen species–tumor protein 53 under transcriptional activation by E26 transformation–specific 1, while Asiatic acid (AA) directly binds NUAK1 to suppress these pathological processes. NUAK1 emerges as a therapeutic target for DKD, and AA provides a natural scaffold for NUAK1 inhibitor development, offering a strategy to combat diabetes-related renal decline.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"6 1","pages":"2405-2417"},"PeriodicalIF":7.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559387","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}
Early postprandial glucagon concentrations are higher in type 1 diabetes (T1D) than in individuals with no diabetes (ND). To determine the cause, we infused stable [13C9, 15N1]glucagon before, during, and after a mixed meal in 16 ND and 16 T1D individuals to measure glucagon turnover. In a subcohort of 9 ND and 12 T1D individuals, we estimated [13C9, 15N1]glucagon kinetics during steady state. A linear, single-compartment model described [13C9, 15N1]glucagon kinetics and allowed precise estimation of the volume of distribution (VD) and clearance rate (CL). Model parameters were similar between groups, with the VD of [13C9, 15N1]glucagon at 42.1 ± 3.3 mL/kg, implying that [13C9, 15N1]glucagon distributes in a single compartment and with VD approximating the plasma volume and CL at 10.6 ± 0.9 mL/kg/min. Higher early (0–120 min after meal ingestion) postprandial glucagon concentrations (1,907.9 ± 373.4 vs. −93.6 ± 240.5 pg/mL · 120 min P < 0.001) observed in T1D was due to higher rates of glucagon appearance (3.39 ± 2.8 vs. −3.95 ± 2.0 ng/kg · 120 min, P < 0.04) and disappearance (2.13 ± 2.6 vs. −5.28 ± 2.1 ng/kg · 120 min, P < 0.04) compared with ND. We have determined postprandial glucagon turnover in humans and have demonstrated that changes in postprandial glucagon concentrations in T1D are due to increased rates of glucagon turnover during the early postprandial period. Article Highlights This study was conducted to determine postprandial glucagon metabolism in people with and without type 1 diabetes. We wanted to determine the cause for higher early postprandial glucagon concentrations in type 1 diabetes. We found that higher early postprandial glucagon turnover is the cause of higher early postprandial glucagon concentrations in type 1 diabetes Strategies that decrease early post prandial glucagon fluxes could improve postprandial glucose concentrations in type 1 diabetes.
1型糖尿病患者（T1D）餐后早期胰高血糖素浓度高于非糖尿病患者（ND）。为了确定原因，我们在16例ND和16例T1D患者混合餐前、餐中和餐后注入稳定的[13C9, 15N1]胰高血糖素，测量胰高血糖素的转化。在9名ND和12名T1D个体的亚队列中，我们估计了稳定状态下的胰高血糖素动力学[13C9, 15N1]。线性单室模型描述了[13C9, 15N1]胰高血糖素动力学，并允许精确估计分布体积（VD）和清除率（CL）。各组间模型参数相似，[13C9, 15N1]胰高血糖素的VD为42.1±3.3 mL/kg，表明[13C9, 15N1]胰高血糖素分布于单室，VD与血浆体积相近，CL为10.6±0.9 mL/kg/min。T1D患者早期（进食后0-120分钟）餐后胰高血糖素浓度较高（1,907.9±373.4 vs. - 93.6±240.5 pg/mL·120分钟P &；lt; 0.001），这是由于胰高血糖素出现率（3.39±2.8 vs. - 3.95±2.0 ng/kg·120分钟，P < 0.04）和消失率（2.13±2.6 vs. - 5.28±2.1 ng/kg·120分钟，P < 0.04）高于ND。我们已经确定了人类餐后胰高血糖素的转换，并证明了T1D患者餐后胰高血糖素浓度的变化是由于餐后早期胰高血糖素转换速率的增加。本研究旨在确定1型糖尿病患者和非1型糖尿病患者餐后胰高血糖素代谢。我们想要确定1型糖尿病患者餐后早期胰高血糖素浓度升高的原因。我们发现较高的早期餐后胰高血糖素转换是1型糖尿病患者较高的早期餐后胰高血糖素浓度的原因，降低早期餐后胰高血糖素通量的策略可以改善1型糖尿病患者的餐后血糖浓度。
{"title":"Postprandial Glucagon Metabolism in Healthy and Type 1 Diabetes","authors":"F.N.U. Ruchi, Michele Schiavon, Akhilesh Pandey, Chiara Dalla Man, Claudio Cobelli, Rita Basu, Ananda Basu","doi":"10.2337/db25-0587","DOIUrl":"https://doi.org/10.2337/db25-0587","url":null,"abstract":"Early postprandial glucagon concentrations are higher in type 1 diabetes (T1D) than in individuals with no diabetes (ND). To determine the cause, we infused stable [13C9, 15N1]glucagon before, during, and after a mixed meal in 16 ND and 16 T1D individuals to measure glucagon turnover. In a subcohort of 9 ND and 12 T1D individuals, we estimated [13C9, 15N1]glucagon kinetics during steady state. A linear, single-compartment model described [13C9, 15N1]glucagon kinetics and allowed precise estimation of the volume of distribution (VD) and clearance rate (CL). Model parameters were similar between groups, with the VD of [13C9, 15N1]glucagon at 42.1 ± 3.3 mL/kg, implying that [13C9, 15N1]glucagon distributes in a single compartment and with VD approximating the plasma volume and CL at 10.6 ± 0.9 mL/kg/min. Higher early (0–120 min after meal ingestion) postprandial glucagon concentrations (1,907.9 ± 373.4 vs. −93.6 ± 240.5 pg/mL · 120 min P &lt; 0.001) observed in T1D was due to higher rates of glucagon appearance (3.39 ± 2.8 vs. −3.95 ± 2.0 ng/kg · 120 min, P &lt; 0.04) and disappearance (2.13 ± 2.6 vs. −5.28 ± 2.1 ng/kg · 120 min, P &lt; 0.04) compared with ND. We have determined postprandial glucagon turnover in humans and have demonstrated that changes in postprandial glucagon concentrations in T1D are due to increased rates of glucagon turnover during the early postprandial period. Article Highlights This study was conducted to determine postprandial glucagon metabolism in people with and without type 1 diabetes. We wanted to determine the cause for higher early postprandial glucagon concentrations in type 1 diabetes. We found that higher early postprandial glucagon turnover is the cause of higher early postprandial glucagon concentrations in type 1 diabetes Strategies that decrease early post prandial glucagon fluxes could improve postprandial glucose concentrations in type 1 diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"76 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559388","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}
Atherosclerotic cardiovascular disease (ASCVD) risk begins increasing years before the clinical onset of type 2 diabetes, driven in part by ectopic lipid accumulation. Many individuals predisposed to diabetes often gain weight rapidly and have limited capacity to expand subcutaneous fat, leading to central fat storage and ectopic lipid deposition—especially in the liver. Hepatic fat contributes to metabolic dysfunction and elevated triglyceride-rich lipoproteins (TRLs), which are atherogenic. Alongside higher blood pressure, these factors accelerate atherosclerosis even before hyperglycemia is evident. Although traditional cardiovascular risk factors like LDL cholesterol (LDL-C) and smoking have declined, rising obesity—particularly among younger individuals—is shifting ASCVD risk more toward pathways linked to ectopic lipid accumulation and prolonged exposure to diabetes-related metabolic disturbances. Ethnic variation plays a significant role in modifying this risk. South Asians, for example, develop type 2 diabetes at lower BMIs and tend to have higher hepatic fat and TRL levels than White individuals, contributing to their increased ASCVD burden. Conversely, people of African ancestry often have lower hepatic fat and TRL levels at similar BMIs, correlating with lower ASCVD risk despite elevated diabetes risk. Risk profiles in other ethnic groups remain understudied. These findings highlight the need for early obesity prevention and ethnically tailored strategies for ASCVD risk assessment and management. Without targeted interventions, rising global rates of obesity and type 2 diabetes, especially in low- and middle-income countries, will increase ectopic lipid accumulation, TRLs, and blood pressure, ultimately accelerating ASCVD progression and reversing prior gains made in cardiovascular prevention.
{"title":"Atherosclerotic Cardiovascular Risk Before and After Type 2 Diabetes Onset and the Roles of Ectopic Fat and Ethnic Variation: The 2025 Edwin Bierman Award Lecture","authors":"Naveed Sattar","doi":"10.2337/dbi25-0025","DOIUrl":"https://doi.org/10.2337/dbi25-0025","url":null,"abstract":"Atherosclerotic cardiovascular disease (ASCVD) risk begins increasing years before the clinical onset of type 2 diabetes, driven in part by ectopic lipid accumulation. Many individuals predisposed to diabetes often gain weight rapidly and have limited capacity to expand subcutaneous fat, leading to central fat storage and ectopic lipid deposition—especially in the liver. Hepatic fat contributes to metabolic dysfunction and elevated triglyceride-rich lipoproteins (TRLs), which are atherogenic. Alongside higher blood pressure, these factors accelerate atherosclerosis even before hyperglycemia is evident. Although traditional cardiovascular risk factors like LDL cholesterol (LDL-C) and smoking have declined, rising obesity—particularly among younger individuals—is shifting ASCVD risk more toward pathways linked to ectopic lipid accumulation and prolonged exposure to diabetes-related metabolic disturbances. Ethnic variation plays a significant role in modifying this risk. South Asians, for example, develop type 2 diabetes at lower BMIs and tend to have higher hepatic fat and TRL levels than White individuals, contributing to their increased ASCVD burden. Conversely, people of African ancestry often have lower hepatic fat and TRL levels at similar BMIs, correlating with lower ASCVD risk despite elevated diabetes risk. Risk profiles in other ethnic groups remain understudied. These findings highlight the need for early obesity prevention and ethnically tailored strategies for ASCVD risk assessment and management. Without targeted interventions, rising global rates of obesity and type 2 diabetes, especially in low- and middle-income countries, will increase ectopic lipid accumulation, TRLs, and blood pressure, ultimately accelerating ASCVD progression and reversing prior gains made in cardiovascular prevention.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"7 1","pages":"2223-2230"},"PeriodicalIF":7.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559578","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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