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}
Julie E. Gervis, Kenneth E. Westerman, Joanne B. Cole, Jordi Merino, Sara J. Cromer, Miriam S. Udler
TAS2R38 is a bitter taste receptor that influences bitter taste perception and diet and is also found in intestinal L cells that store and secrete glucagon-like peptide 1 (GLP-1). Preclinical studies have linked TAS2R38 activation to postprandial GLP-1 secretion, fueling interest in TAS2R38 as a therapeutic target for glucose regulation; however, evidence in humans remains limited. To further establish TAS2R38 actions in glucose homeostasis, we analyzed data from ∼220,000 European adults without type 2 diabetes in the UK Biobank to test whether functional variants conferring TAS2R38 sensitivity were associated with blood glucose. We found that individuals with two copies of a haplotype increasing receptor sensitivity (PAV) had significantly lower 0–2-h (i.e., postprandial) glucose than those with two copies of a nonfunctional haplotype (AVI), following a dose–response relationship per PAV haplotype. These associations were replicated in published genome-wide association studies of 2-h glucose, persisted after adjustment for diet and lifestyle behaviors related to bitter taste perception, and were not seen for variants in other bitter taste receptors without putative roles in glucose metabolism (TAS2R14 and TAS2R19). Collectively, these findings provide evidence in humans consistent with direct TAS2R38 actions in postprandial glycemia, supporting TAS2R38 as a novel therapeutic target for glucose regulation. Article Highlights The TAS2R38 bitter taste receptor, recently identified within intestinal L cells, has been shown to modulate GLP-1 secretion in preclinical models; however, evidence in humans remains limited. We harnessed functional variants comprising three canonical diplotypes of TAS2R38 to study the role of TAS2R38 in glucose homeostasis in humans. In a large sample of adults without type 2 diabetes, we found that individuals with more sensitive TAS2R38 receptors had lower postprandial glucose levels, independent of diet and lifestyle habits. Our findings provide evidence in humans supporting direct TAS2R38 actions in postprandial glycemia and highlight TAS2R38 as a potential therapeutic target for impaired glucose regulation.
{"title":"Genetic Variants Increasing TAS2R38 Bitter Taste Receptor Sensitivity Are Associated With Lower Postprandial Glycemia","authors":"Julie E. Gervis, Kenneth E. Westerman, Joanne B. Cole, Jordi Merino, Sara J. Cromer, Miriam S. Udler","doi":"10.2337/db25-0614","DOIUrl":"https://doi.org/10.2337/db25-0614","url":null,"abstract":"TAS2R38 is a bitter taste receptor that influences bitter taste perception and diet and is also found in intestinal L cells that store and secrete glucagon-like peptide 1 (GLP-1). Preclinical studies have linked TAS2R38 activation to postprandial GLP-1 secretion, fueling interest in TAS2R38 as a therapeutic target for glucose regulation; however, evidence in humans remains limited. To further establish TAS2R38 actions in glucose homeostasis, we analyzed data from ∼220,000 European adults without type 2 diabetes in the UK Biobank to test whether functional variants conferring TAS2R38 sensitivity were associated with blood glucose. We found that individuals with two copies of a haplotype increasing receptor sensitivity (PAV) had significantly lower 0–2-h (i.e., postprandial) glucose than those with two copies of a nonfunctional haplotype (AVI), following a dose–response relationship per PAV haplotype. These associations were replicated in published genome-wide association studies of 2-h glucose, persisted after adjustment for diet and lifestyle behaviors related to bitter taste perception, and were not seen for variants in other bitter taste receptors without putative roles in glucose metabolism (TAS2R14 and TAS2R19). Collectively, these findings provide evidence in humans consistent with direct TAS2R38 actions in postprandial glycemia, supporting TAS2R38 as a novel therapeutic target for glucose regulation. Article Highlights The TAS2R38 bitter taste receptor, recently identified within intestinal L cells, has been shown to modulate GLP-1 secretion in preclinical models; however, evidence in humans remains limited. We harnessed functional variants comprising three canonical diplotypes of TAS2R38 to study the role of TAS2R38 in glucose homeostasis in humans. In a large sample of adults without type 2 diabetes, we found that individuals with more sensitive TAS2R38 receptors had lower postprandial glucose levels, independent of diet and lifestyle habits. Our findings provide evidence in humans supporting direct TAS2R38 actions in postprandial glycemia and highlight TAS2R38 as a potential therapeutic target for impaired glucose regulation.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"132 1","pages":"2444-2454"},"PeriodicalIF":7.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559354","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}
The hypothalamus monitors blood glucose levels and regulates glucose production in the liver. In response to hypoglycemia, glucose-inhibited (GI) neurons trigger counterregulatory responses (CRRs), which stimulate the release of glucagon, epinephrine, and cortisol to elevate blood glucose. Recurrent hypoglycemia (RH), however, reduces the effectiveness of these CRRs. This study examined the role of hypothalamic prostaglandins in glucose recovery during acute hypoglycemia and RH. Imaging mass spectrometry and liquid chromatography/mass spectrometry showed phospholipid and prostaglandin levels in the hypothalamus of C57BL mice were changed after insulin or 2-deoxy-glucose administration. Ibuprofen, a nonsteroidal anti-inflammatory drug, was infused into the ventromedial hypothalamus (VMH) to analyze its effect on glucose production during hypoglycemia, revealing that prostaglandin inhibition decreased glucagon secretion. Additionally, RH-treated mice decreased glucagon release and glucose production during hypoglycemia. Inhibiting prostaglandin production via shRNA against cytosolic phospholipase A2 (cPLA2) in the hypothalamus restored CRRs diminished by RH via increasing glucagon sensitivity. These findings suggest that hypothalamic prostaglandins play a critical role in glucose recovery from acute hypoglycemia by activating VMH neurons and are also crucial for the attenuation of CRRs during RH. Article Highlights
{"title":"Hypothalamic Prostaglandins Facilitate Recovery From Severe Hypoglycemia but Exacerbate Recurrent Hypoglycemia in Mice","authors":"Takashi Abe, Shucheng Xu, Yuki Sugiura, Yuichiro Arima, Takahiro Hayasaka, Ming-Liang Lee, Taiga Ishimoto, Yudai Araki, Samson Ngurari, Ziwei Niu, Norifumi Iijima, Sabrina Diano, Chitoku Toda","doi":"10.2337/db25-0106","DOIUrl":"https://doi.org/10.2337/db25-0106","url":null,"abstract":"The hypothalamus monitors blood glucose levels and regulates glucose production in the liver. In response to hypoglycemia, glucose-inhibited (GI) neurons trigger counterregulatory responses (CRRs), which stimulate the release of glucagon, epinephrine, and cortisol to elevate blood glucose. Recurrent hypoglycemia (RH), however, reduces the effectiveness of these CRRs. This study examined the role of hypothalamic prostaglandins in glucose recovery during acute hypoglycemia and RH. Imaging mass spectrometry and liquid chromatography/mass spectrometry showed phospholipid and prostaglandin levels in the hypothalamus of C57BL mice were changed after insulin or 2-deoxy-glucose administration. Ibuprofen, a nonsteroidal anti-inflammatory drug, was infused into the ventromedial hypothalamus (VMH) to analyze its effect on glucose production during hypoglycemia, revealing that prostaglandin inhibition decreased glucagon secretion. Additionally, RH-treated mice decreased glucagon release and glucose production during hypoglycemia. Inhibiting prostaglandin production via shRNA against cytosolic phospholipase A2 (cPLA2) in the hypothalamus restored CRRs diminished by RH via increasing glucagon sensitivity. These findings suggest that hypothalamic prostaglandins play a critical role in glucose recovery from acute hypoglycemia by activating VMH neurons and are also crucial for the attenuation of CRRs during RH. Article Highlights","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"18 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559577","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}
There is significant evidence that acute stress, a challenge to an organism’s homeostasis, has dramatic effects on metabolic control. Acute stress impairs blood glucose control in people with both type 1 and type 2 diabetes. In addition, growing evidence suggests that metabolic responses to stress in people without diabetes may be a crucial determinant of health. Acute dysregulation of blood glucose in the hospital setting, including both hyper- and hypoglycemia, predicts short- and long-term morbidity and mortality in patients with critical illnesses. Animal studies indicate that exposure to physiological and psychological stressors activates a highly conserved network of neural circuits that ultimately coordinate the functions of multiple organs to increase blood glucose. In this article, we provide an overview of the neural populations and circuits that increase blood glucose in response to acute stress, including our research funded by the American Diabetes Association Pathway to Stop Diabetes program, highlighting the impacts on clinical outcomes and opportunities for the development of therapies for diabetes. This article is part of a series of perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program. Article Highlights Internal and external stressors rapidly increase blood glucose, a highly conserved metabolic response. Multiple stress-modulated neural populations in the brain stem, hypothalamus, and forebrain contribute to regulation of the hypothalamo-pituitary-adrenal axis and sympathetic nervous system to elicit hyperglycemia. Exaggerated or diminished glucose responses to acute stress are associated with increased risk of type 2 diabetes and poor health outcomes. A greater understanding of the neural circuitry contributing to stress hyperglycemia and how these circuits are disrupted has the potential to provide new approaches to improve glycemic control.
{"title":"Neural Regulation of Blood Glucose in Acute Stress: A Report on Research Supported by Pathway to Stop Diabetes","authors":"Sarah A. Stanley","doi":"10.2337/dbi24-0051","DOIUrl":"https://doi.org/10.2337/dbi24-0051","url":null,"abstract":"There is significant evidence that acute stress, a challenge to an organism’s homeostasis, has dramatic effects on metabolic control. Acute stress impairs blood glucose control in people with both type 1 and type 2 diabetes. In addition, growing evidence suggests that metabolic responses to stress in people without diabetes may be a crucial determinant of health. Acute dysregulation of blood glucose in the hospital setting, including both hyper- and hypoglycemia, predicts short- and long-term morbidity and mortality in patients with critical illnesses. Animal studies indicate that exposure to physiological and psychological stressors activates a highly conserved network of neural circuits that ultimately coordinate the functions of multiple organs to increase blood glucose. In this article, we provide an overview of the neural populations and circuits that increase blood glucose in response to acute stress, including our research funded by the American Diabetes Association Pathway to Stop Diabetes program, highlighting the impacts on clinical outcomes and opportunities for the development of therapies for diabetes. This article is part of a series of perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program. Article Highlights Internal and external stressors rapidly increase blood glucose, a highly conserved metabolic response. Multiple stress-modulated neural populations in the brain stem, hypothalamus, and forebrain contribute to regulation of the hypothalamo-pituitary-adrenal axis and sympathetic nervous system to elicit hyperglycemia. Exaggerated or diminished glucose responses to acute stress are associated with increased risk of type 2 diabetes and poor health outcomes. A greater understanding of the neural circuitry contributing to stress hyperglycemia and how these circuits are disrupted has the potential to provide new approaches to improve glycemic control.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"103 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545691","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}
Eden Engal, Adi Gershon, Shiri Melamed, Aveksha Sharma, Hadas Ner-Gaon, Shiri Jaffe-Herman, Yuval Nevo, Alena Kirzhner, Oren Barak, Edi Vaisbuch, Gillian Kay, Anne Cathrine Staff, Ralf Dechend, Florian Herse, Tal Shay, Maayan Salton, Tal Schiller
Gestational diabetes mellitus (GDM) is defined as hyperglycemia first identified during pregnancy and can lead to adverse maternal and neonatal outcomes. The molecular mechanisms leading to these outcomes are currently poorly understood. While transcriptomics of GDM placentas has been previously studied, the effect on precursor mRNA splicing remains largely unknown. This study explores the impact of GDM on placental splicing and identifies its regulatory mechanisms. Using RNA sequencing data from Norwegian and Chinese cohorts, we uncovered thousands of differential splicing events. Pathway enrichment analysis revealed significant associations with metabolic and diabetes-related pathways. Splicing factor motif and cross-linking and immunoprecipitation sequencing analyses highlighted serine/arginine-rich splicing factor 10 (SRSF10) as a key regulator in this process, with its binding enriched at misspliced exons. Silencing SRSF10 in placental cells mirrored GDM-associated missplicing in key genes. These findings underscore splicing dysregulation as a critical process in GDM pathogenesis, suggesting that targeting SRSF10 could be a potential therapeutic approach to mitigate the deleterious effects of GDM. Article Highlights Gestational diabetes mellitus (GDM) causes hyperglycemia during pregnancy and adverse maternal and neonatal outcomes. Bulk placental gene expression has been reported largely unchanged. RNA sequencing of Norwegian and Chinese GDM placentas reveals hundreds of differential splicing events enriched for metabolic- and diabetes-related pathways. Motif enrichment and cross-linking and immunoprecipitation sequencing integration identify serine/arginine splicing factor 10 as a key regulator of GDM-associated missplicing. Silencing serine/arginine splicing factor 10 in placental models recapitulates the GDM-associated missplicing program.
{"title":"Gestational Diabetes Mellitus Alters Placental Precursor mRNA Splicing","authors":"Eden Engal, Adi Gershon, Shiri Melamed, Aveksha Sharma, Hadas Ner-Gaon, Shiri Jaffe-Herman, Yuval Nevo, Alena Kirzhner, Oren Barak, Edi Vaisbuch, Gillian Kay, Anne Cathrine Staff, Ralf Dechend, Florian Herse, Tal Shay, Maayan Salton, Tal Schiller","doi":"10.2337/db25-0333","DOIUrl":"https://doi.org/10.2337/db25-0333","url":null,"abstract":"Gestational diabetes mellitus (GDM) is defined as hyperglycemia first identified during pregnancy and can lead to adverse maternal and neonatal outcomes. The molecular mechanisms leading to these outcomes are currently poorly understood. While transcriptomics of GDM placentas has been previously studied, the effect on precursor mRNA splicing remains largely unknown. This study explores the impact of GDM on placental splicing and identifies its regulatory mechanisms. Using RNA sequencing data from Norwegian and Chinese cohorts, we uncovered thousands of differential splicing events. Pathway enrichment analysis revealed significant associations with metabolic and diabetes-related pathways. Splicing factor motif and cross-linking and immunoprecipitation sequencing analyses highlighted serine/arginine-rich splicing factor 10 (SRSF10) as a key regulator in this process, with its binding enriched at misspliced exons. Silencing SRSF10 in placental cells mirrored GDM-associated missplicing in key genes. These findings underscore splicing dysregulation as a critical process in GDM pathogenesis, suggesting that targeting SRSF10 could be a potential therapeutic approach to mitigate the deleterious effects of GDM. Article Highlights Gestational diabetes mellitus (GDM) causes hyperglycemia during pregnancy and adverse maternal and neonatal outcomes. Bulk placental gene expression has been reported largely unchanged. RNA sequencing of Norwegian and Chinese GDM placentas reveals hundreds of differential splicing events enriched for metabolic- and diabetes-related pathways. Motif enrichment and cross-linking and immunoprecipitation sequencing integration identify serine/arginine splicing factor 10 as a key regulator of GDM-associated missplicing. Silencing serine/arginine splicing factor 10 in placental models recapitulates the GDM-associated missplicing program.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"98 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545692","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}
Adriana Pané, Laura Videla, Àngels Calvet-Mirabent, Sara Castro-Barquero, Judith Viaplana, Lídia Vaqué-Alcázar, Ainitze Ibarzabal, Mateus Rozalem-Aranha, Alexandre Bejanin, Violeta Moize, Josep Vidal, Ana de Hollanda, Emilio Ortega, Isabel Barroeta, Valle Camacho, Gemma Chiva-Blanch, Juan Fortea, Amanda Jiménez
Preclinical studies show that dietary or central administration of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) can reduce food intake, enhance energy expenditure, and attenuate hypothalamic inflammation (HI), whereas saturated fatty acids (SFAs) promote weight gain, HI, and neuronal injury. However, whether hypothalamic exposure to different fatty acids similarly influences HI and body weight in humans remains unclear. In this longitudinal study, we compared cerebrospinal fluid (CSF) free fatty acid (FFA) profiles between 19 normal-weight control participants and 44 individuals with obesity, both at baseline and 1 year after bariatric surgery (BS). We also examined associations between CSF FFA composition, MRI-based markers of HI (i.e., increased hypothalamic mean diffusivity [MD] and volume), and postoperative weight loss. At baseline, individuals with obesity had similar CSF concentrations of total FFA, SFA, and MUFA compared with control participants but significantly lower PUFA levels, mainly due to reduced docosahexaenoic acid (DHA) levels. BS did not substantially alter CSF FFA profiles. Lower baseline CSF DHA levels were associated with higher hypothalamic MD and independently predicted less weight loss at 1 year. Postoperative increases in CSF DHA levels correlated with reductions in hypothalamic MD. These findings suggest brain DHA level may influence hypothalamic microstructure and contribute to body weight regulation in human obesity. Article Highlights Whether hypothalamic exposure to free fatty acid (FFA) species contributes to obesity and hypothalamic inflammation (HI) in humans is not yet defined. We compared cerebrospinal fluid FFA profiles between normal-weight control participants and individuals with obesity, before and after bariatric surgery (BS), and examined their associations with postoperative weight trajectories and neuroimaging biomarkers of HI. Individuals with obesity had reduced cerebrospinal fluid levels of docosahexaenoic acid (DHA) before and after BS. Lower cerebrospinal fluid DHA levels correlated with biomarkers of HI and were independently associated with less weight loss after BS. The findings highlight the potential of DHA in modulating hypothalamic function.
{"title":"Cerebrospinal Fluid Fatty Acids, Hypothalamic Inflammation, and Weight Loss in Human Obesity: A Longitudinal Study","authors":"Adriana Pané, Laura Videla, Àngels Calvet-Mirabent, Sara Castro-Barquero, Judith Viaplana, Lídia Vaqué-Alcázar, Ainitze Ibarzabal, Mateus Rozalem-Aranha, Alexandre Bejanin, Violeta Moize, Josep Vidal, Ana de Hollanda, Emilio Ortega, Isabel Barroeta, Valle Camacho, Gemma Chiva-Blanch, Juan Fortea, Amanda Jiménez","doi":"10.2337/db25-0595","DOIUrl":"https://doi.org/10.2337/db25-0595","url":null,"abstract":"Preclinical studies show that dietary or central administration of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) can reduce food intake, enhance energy expenditure, and attenuate hypothalamic inflammation (HI), whereas saturated fatty acids (SFAs) promote weight gain, HI, and neuronal injury. However, whether hypothalamic exposure to different fatty acids similarly influences HI and body weight in humans remains unclear. In this longitudinal study, we compared cerebrospinal fluid (CSF) free fatty acid (FFA) profiles between 19 normal-weight control participants and 44 individuals with obesity, both at baseline and 1 year after bariatric surgery (BS). We also examined associations between CSF FFA composition, MRI-based markers of HI (i.e., increased hypothalamic mean diffusivity [MD] and volume), and postoperative weight loss. At baseline, individuals with obesity had similar CSF concentrations of total FFA, SFA, and MUFA compared with control participants but significantly lower PUFA levels, mainly due to reduced docosahexaenoic acid (DHA) levels. BS did not substantially alter CSF FFA profiles. Lower baseline CSF DHA levels were associated with higher hypothalamic MD and independently predicted less weight loss at 1 year. Postoperative increases in CSF DHA levels correlated with reductions in hypothalamic MD. These findings suggest brain DHA level may influence hypothalamic microstructure and contribute to body weight regulation in human obesity. Article Highlights Whether hypothalamic exposure to free fatty acid (FFA) species contributes to obesity and hypothalamic inflammation (HI) in humans is not yet defined. We compared cerebrospinal fluid FFA profiles between normal-weight control participants and individuals with obesity, before and after bariatric surgery (BS), and examined their associations with postoperative weight trajectories and neuroimaging biomarkers of HI. Individuals with obesity had reduced cerebrospinal fluid levels of docosahexaenoic acid (DHA) before and after BS. Lower cerebrospinal fluid DHA levels correlated with biomarkers of HI and were independently associated with less weight loss after BS. The findings highlight the potential of DHA in modulating hypothalamic function.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"145 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535252","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}
Valentina Pita-Grisanti, Flavia Leticia Martins Peçanha, Ruy A. Louzada, Manuel Blandino-Rosano, Camillo Jaramillo, Natalia Arenas, Allison Bayer, Ernesto Bernal-Mizrachi
Type 1 diabetes (T1D) is an autoimmune disease characterized by β-cell destruction promoted by autoreactive T cells. Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) and 4E-BP2 are translational repressors and downstream targets of mammalian target of rapamycin complex 1 (mTORC1). Activation of the 4E-BP2/eIF4E pathway by 4E-BP2 deletion promotes translation initiation, inducing β-cell expansion and proliferation and regulating adaptive immunity. However, the involvement of 4E-BP2 in T1D remains unexplored. This study aimed to determine the role of 4E-BP2/eIF4E signaling in T1D prevention. We used the NOD mouse model of T1D and generated mice with global 4E-BP2 deletion in the NOD background (Eif4ebp2−/−). We assessed T1D development, glucose homeostasis, pancreas morphometry, and immune responses in Eif4ebp2−/− and littermate control mice. We found that Eif4ebp2−/− male mice exhibited reduced diabetes incidence, which did not occur in female mice, as well as preserved β-cell mass, improved insulin secretion in vitro, and comparable insulitis. Characterization of T-cell compartments showed decreased splenic CD8+ cytotoxic T-cell proliferation and increased pancreatic regulatory T-cell infiltration in Eif4ebp2−/− mice, potentially resulting from increased proliferation and suppressive capacity. Adoptive transfer studies demonstrated that Eif4ebp2−/− male lymphocytes were less diabetogenic than those of controls. In conclusion, activation of 4E-BP2/eIF4E by 4E-BP2 deletion protected against T1D, supporting 4E-BP2 as a potential therapy target. Article Highlights Mammalian target of rapamycin complex 1 (mTORC1) signaling is essential to β-cell mass, function, and adaptive immunity; however, its specific downstream mediators in type 1 diabetes (T1D) remain poorly defined. We investigated eukaryotic translation initiation factor 4E–binding protein 2 (4E-BP2), a major translational regulator downstream of mTORC1, by using global 4E-BP2–knockout mice on the NOD background. Loss of 4E-BP2 protected male NOD mice from T1D through preservation of β-cell mass and function, coupled with attenuation of autoimmune responses. These findings identify 4E-BP2 as a novel immunometabolic node, highlighting its potential as a therapeutic target for T1D prevention and treatment.
{"title":"Protection Against Type 1 Diabetes Development in Mice With 4E-BP2 Deletion","authors":"Valentina Pita-Grisanti, Flavia Leticia Martins Peçanha, Ruy A. Louzada, Manuel Blandino-Rosano, Camillo Jaramillo, Natalia Arenas, Allison Bayer, Ernesto Bernal-Mizrachi","doi":"10.2337/db25-0348","DOIUrl":"https://doi.org/10.2337/db25-0348","url":null,"abstract":"Type 1 diabetes (T1D) is an autoimmune disease characterized by β-cell destruction promoted by autoreactive T cells. Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) and 4E-BP2 are translational repressors and downstream targets of mammalian target of rapamycin complex 1 (mTORC1). Activation of the 4E-BP2/eIF4E pathway by 4E-BP2 deletion promotes translation initiation, inducing β-cell expansion and proliferation and regulating adaptive immunity. However, the involvement of 4E-BP2 in T1D remains unexplored. This study aimed to determine the role of 4E-BP2/eIF4E signaling in T1D prevention. We used the NOD mouse model of T1D and generated mice with global 4E-BP2 deletion in the NOD background (Eif4ebp2−/−). We assessed T1D development, glucose homeostasis, pancreas morphometry, and immune responses in Eif4ebp2−/− and littermate control mice. We found that Eif4ebp2−/− male mice exhibited reduced diabetes incidence, which did not occur in female mice, as well as preserved β-cell mass, improved insulin secretion in vitro, and comparable insulitis. Characterization of T-cell compartments showed decreased splenic CD8+ cytotoxic T-cell proliferation and increased pancreatic regulatory T-cell infiltration in Eif4ebp2−/− mice, potentially resulting from increased proliferation and suppressive capacity. Adoptive transfer studies demonstrated that Eif4ebp2−/− male lymphocytes were less diabetogenic than those of controls. In conclusion, activation of 4E-BP2/eIF4E by 4E-BP2 deletion protected against T1D, supporting 4E-BP2 as a potential therapy target. Article Highlights Mammalian target of rapamycin complex 1 (mTORC1) signaling is essential to β-cell mass, function, and adaptive immunity; however, its specific downstream mediators in type 1 diabetes (T1D) remain poorly defined. We investigated eukaryotic translation initiation factor 4E–binding protein 2 (4E-BP2), a major translational regulator downstream of mTORC1, by using global 4E-BP2–knockout mice on the NOD background. Loss of 4E-BP2 protected male NOD mice from T1D through preservation of β-cell mass and function, coupled with attenuation of autoimmune responses. These findings identify 4E-BP2 as a novel immunometabolic node, highlighting its potential as a therapeutic target for T1D prevention and treatment.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"13 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509210","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}
Aaron J. Deutsch, Andrew S. Bell, Dominika A. Michalek, Adam B. Burkholder, Stella Nam, Raymond J. Kreienkamp, Seth A. Sharp, Alicia Huerta-Chagoya, Ravi Mandla, Ruth Nanjala, Yang Luo, Richard A. Oram, Jose C. Florez, Suna Onengut-Gumuscu, Stephen S. Rich, Maggie C.Y. Ng, Alison A. Motsinger-Reif, Alisa K. Manning, Josep M. Mercader, Miriam S. Udler
Polygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we leveraged recent multiancestry genome-wide association studies to create a Type 1 Diabetes Multi-Ancestry Polygenic Score (T1D MAPS). We trained the score in the Mass General Brigham (MGB) Biobank (372 individuals with type 1 diabetes) and tested the score in the All of Us program (86 individuals with type 1 diabetes). We evaluated the area under the receiver operating characteristic curve (AUC), and we compared the AUC to two published single-ancestry scores for European (EUR) and African (AFR) populations: T1D Genetic Risk Score 2 (GRS2EUR) and T1D GRSAFR. We also developed an updated score (T1D MAPS2) that combines T1D GRS2EUR and T1D MAPS. Among individuals with non-European ancestry, the AUC of T1D MAPS was 0.90, significantly higher than T1D GRS2EUR (0.82) and T1D GRSAFR (0.82). Among individuals with European ancestry, the AUC of T1D MAPS was slightly lower than T1D GRS2EUR (0.89 vs. 0.91). However, T1D MAPS2 performed equivalently to T1D GRS2EUR in European ancestry (0.91 vs. 0.91) and performed better in non-European ancestry (0.90 vs. 0.82). Overall, these findings advance the accuracy of type 1 diabetes genetic risk prediction across diverse populations. Article Highlights Type 1 diabetes polygenic scores are highly predictive of disease risk, but their performance varies based on genetic ancestry. Can we develop a polygenic score that accurately predicts type 1 diabetes risk across diverse populations? Our novel polygenic score performs similar to existing scores in European populations, and it demonstrates superior performance in non-European populations. This polygenic score will improve prediction of type 1 diabetes risk in genetically diverse populations.
{"title":"Development and Validation of a Type 1 Diabetes Multi-Ancestry Polygenic Score","authors":"Aaron J. Deutsch, Andrew S. Bell, Dominika A. Michalek, Adam B. Burkholder, Stella Nam, Raymond J. Kreienkamp, Seth A. Sharp, Alicia Huerta-Chagoya, Ravi Mandla, Ruth Nanjala, Yang Luo, Richard A. Oram, Jose C. Florez, Suna Onengut-Gumuscu, Stephen S. Rich, Maggie C.Y. Ng, Alison A. Motsinger-Reif, Alisa K. Manning, Josep M. Mercader, Miriam S. Udler","doi":"10.2337/db25-0772","DOIUrl":"https://doi.org/10.2337/db25-0772","url":null,"abstract":"Polygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we leveraged recent multiancestry genome-wide association studies to create a Type 1 Diabetes Multi-Ancestry Polygenic Score (T1D MAPS). We trained the score in the Mass General Brigham (MGB) Biobank (372 individuals with type 1 diabetes) and tested the score in the All of Us program (86 individuals with type 1 diabetes). We evaluated the area under the receiver operating characteristic curve (AUC), and we compared the AUC to two published single-ancestry scores for European (EUR) and African (AFR) populations: T1D Genetic Risk Score 2 (GRS2EUR) and T1D GRSAFR. We also developed an updated score (T1D MAPS2) that combines T1D GRS2EUR and T1D MAPS. Among individuals with non-European ancestry, the AUC of T1D MAPS was 0.90, significantly higher than T1D GRS2EUR (0.82) and T1D GRSAFR (0.82). Among individuals with European ancestry, the AUC of T1D MAPS was slightly lower than T1D GRS2EUR (0.89 vs. 0.91). However, T1D MAPS2 performed equivalently to T1D GRS2EUR in European ancestry (0.91 vs. 0.91) and performed better in non-European ancestry (0.90 vs. 0.82). Overall, these findings advance the accuracy of type 1 diabetes genetic risk prediction across diverse populations. Article Highlights Type 1 diabetes polygenic scores are highly predictive of disease risk, but their performance varies based on genetic ancestry. Can we develop a polygenic score that accurately predicts type 1 diabetes risk across diverse populations? Our novel polygenic score performs similar to existing scores in European populations, and it demonstrates superior performance in non-European populations. This polygenic score will improve prediction of type 1 diabetes risk in genetically diverse populations.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"184 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509211","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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