Ellen Vercalsteren, Dimitra Karampatsi, Maria Neicu, Mihaela Oana Romanitan, Thomas Nyström, Thomas Klein, Cesare Patrone, Vladimer Darsalia
Prestroke hyperglycemia and insulin resistance (IR) independently correlate with poor stroke outcomes in type 2 diabetes (T2D), although their causative effect is undetermined. Interestingly, an increasing body of evidence points toward the importance of IR in determining stroke outcomes. Filling this gap is fundamental to identifying effective anti-T2D strategies to improve stroke prognosis in people with T2D. The aim of this study was to determine experimentally whether normalizing IR rather than hyperglycemia before stroke improves stroke outcomes in T2D. To address this research question, hyperglycemia or IR was normalized with intermediate-acting insulin or long-acting selective glucagon receptor agonist (La-GCGRa), respectively, in obese/T2D mice before inducing stroke. Functional recovery (primary outcome) was assessed by neurological testing. Systemic inflammation, infarct size, and neuroinflammation (secondary outcomes) were assessed by ELISA and immunohistochemistry, respectively. The results showed that insulin treatment normalized hyperglycemia without affecting IR and did not improve functional recovery. On the contrary, La-GCGRa normalized IR without affecting hyperglycemia and improved functional recovery. This effect occurred in association with reduced systemic and stroke-induced neuroinflammation. Neither treatment affected infarct size. The data demonstrate that targeting IR in T2D is crucial for improving stroke outcomes and may have significant implications for human therapy. Article Highlights Hyperglycemia and insulin resistance independently correlate with poor stroke outcomes in type 2 diabetes, although their causative role is unclear. The aim of this study was to determine experimentally whether normalizing insulin resistance rather than hyperglycemia before stroke improves stroke outcomes in type 2 diabetes. To answer this question, we specifically normalized either hyperglycemia or insulin resistance in obese, type 2 diabetic mice before inducing stroke. We show that targeting insulin resistance, rather than hyperglycemia, before stroke in type 2 diabetes is crucial to improving stroke outcomes.
{"title":"Normalization of Insulin Resistance, Rather Than Hyperglycemia, Before Stroke Improves Functional Outcomes in a Mouse Model of Type 2 Diabetes","authors":"Ellen Vercalsteren, Dimitra Karampatsi, Maria Neicu, Mihaela Oana Romanitan, Thomas Nyström, Thomas Klein, Cesare Patrone, Vladimer Darsalia","doi":"10.2337/db25-0532","DOIUrl":"https://doi.org/10.2337/db25-0532","url":null,"abstract":"Prestroke hyperglycemia and insulin resistance (IR) independently correlate with poor stroke outcomes in type 2 diabetes (T2D), although their causative effect is undetermined. Interestingly, an increasing body of evidence points toward the importance of IR in determining stroke outcomes. Filling this gap is fundamental to identifying effective anti-T2D strategies to improve stroke prognosis in people with T2D. The aim of this study was to determine experimentally whether normalizing IR rather than hyperglycemia before stroke improves stroke outcomes in T2D. To address this research question, hyperglycemia or IR was normalized with intermediate-acting insulin or long-acting selective glucagon receptor agonist (La-GCGRa), respectively, in obese/T2D mice before inducing stroke. Functional recovery (primary outcome) was assessed by neurological testing. Systemic inflammation, infarct size, and neuroinflammation (secondary outcomes) were assessed by ELISA and immunohistochemistry, respectively. The results showed that insulin treatment normalized hyperglycemia without affecting IR and did not improve functional recovery. On the contrary, La-GCGRa normalized IR without affecting hyperglycemia and improved functional recovery. This effect occurred in association with reduced systemic and stroke-induced neuroinflammation. Neither treatment affected infarct size. The data demonstrate that targeting IR in T2D is crucial for improving stroke outcomes and may have significant implications for human therapy. Article Highlights Hyperglycemia and insulin resistance independently correlate with poor stroke outcomes in type 2 diabetes, although their causative role is unclear. The aim of this study was to determine experimentally whether normalizing insulin resistance rather than hyperglycemia before stroke improves stroke outcomes in type 2 diabetes. To answer this question, we specifically normalized either hyperglycemia or insulin resistance in obese, type 2 diabetic mice before inducing stroke. We show that targeting insulin resistance, rather than hyperglycemia, before stroke in type 2 diabetes is crucial to improving stroke outcomes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"7 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383342","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 retinopathy (DR) is a leading cause of vision loss in working-age adults and often progresses to proliferative diabetic retinopathy (PDR) with irreversible complications. Anti–vascular endothelial growth factor (VEGF) therapy remains the first-line treatment; however, resistance poses a significant challenge, necessitating alternative therapeutic targets. This study explores the role of angiopoietin-like protein 4 (ANGPTL4) in PDR pathogenesis, emphasizing vascular-immune-lymphatic interactions. We found significantly elevated ANGPTL4 and VEGF-C levels in the vitreous humor of patients with PDR, which were not affected by anti-VEGF therapy. In vivo, full-length ANGPTL4 and its C-terminal fragment promoted pathological angiogenesis and lymphatic-like remodeling in diabetic murine retinas, characterized by increased lymphatic vessel endothelial hyaluronan receptor 1, prospero homeobox 1, and VEGF receptor 3 (VEGFR3) expression. Single-cell sequencing further revealed ANGPTL4-driven immune dysregulation, with abnormal infiltration of CD4+ T cells and dendritic cells. Knockdown of ANGPTL4 in mice with oxygen-induced retinopathy alleviated retinal hypoxia, neovascularization, and vascular leakage. Mechanistically, retinal hypoxia markedly increased ANGPTL4 expression levels in the retina, which activated the activator protein-1 (AP-1) transcription factor complex and promoted Cd83 transcription in mouse heart microvascular endothelial cells. Additionally, ANGPTL4 bound to neuropilin-1 (NRP1)/VEGFR3, driving human lymphatic endothelial cell proliferation and lymphatic vessel ingrowth from the optic nerve sheath into the retina, a finding that suggests a novel pathway independent of angiopoietin-Tie signaling. These findings establish ANGPTL4 as a key mediator of immune–vascular interactions in PDR and a potential therapeutic target to address both pathological angiogenesis and lymphatic dysfunction. Article Highlights Some patients with proliferative diabetic retinopathy (PDR) have poor responses to anti–vascular endothelial growth factor (anti-VEGF) therapy. This situation highlights the need for additional therapeutic approaches. In proliferative diabetic retinopathy, what is the role of ANGPTL4 that differs from VEGF? We found that ANGPTL4 is elevated in the vitreous humor of patients with PDR who are poorly responsive to anti-VEGF therapy. ANGPTL4, particularly its C-terminal fragment, causes retinal lymphatic-like remodeling in diabetic mice. This study provides novel insights into the complex interplay between immune activation, neovascularization, and lymphatic-like remodeling in PDR. Our findings deepen our understanding of PDR pathophysiology and propose a promising therapeutic target.
{"title":"ANGPTL4 Induces Aberrant Lymphatic-Like Remodeling in Proliferative Diabetic Retinopathy","authors":"Ziwen Li, Lipeng Guan, Tong Mu, Haoyuan Zhou, Tianyi Zong, Chengye Tan, Chenyu Yang, Tianhua Xie, Miao Zhuang, Jiahui Yang, Qian Yang, Meili Wu, Yong Yao, Xiaolu Wang","doi":"10.2337/db25-0445","DOIUrl":"https://doi.org/10.2337/db25-0445","url":null,"abstract":"Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults and often progresses to proliferative diabetic retinopathy (PDR) with irreversible complications. Anti–vascular endothelial growth factor (VEGF) therapy remains the first-line treatment; however, resistance poses a significant challenge, necessitating alternative therapeutic targets. This study explores the role of angiopoietin-like protein 4 (ANGPTL4) in PDR pathogenesis, emphasizing vascular-immune-lymphatic interactions. We found significantly elevated ANGPTL4 and VEGF-C levels in the vitreous humor of patients with PDR, which were not affected by anti-VEGF therapy. In vivo, full-length ANGPTL4 and its C-terminal fragment promoted pathological angiogenesis and lymphatic-like remodeling in diabetic murine retinas, characterized by increased lymphatic vessel endothelial hyaluronan receptor 1, prospero homeobox 1, and VEGF receptor 3 (VEGFR3) expression. Single-cell sequencing further revealed ANGPTL4-driven immune dysregulation, with abnormal infiltration of CD4+ T cells and dendritic cells. Knockdown of ANGPTL4 in mice with oxygen-induced retinopathy alleviated retinal hypoxia, neovascularization, and vascular leakage. Mechanistically, retinal hypoxia markedly increased ANGPTL4 expression levels in the retina, which activated the activator protein-1 (AP-1) transcription factor complex and promoted Cd83 transcription in mouse heart microvascular endothelial cells. Additionally, ANGPTL4 bound to neuropilin-1 (NRP1)/VEGFR3, driving human lymphatic endothelial cell proliferation and lymphatic vessel ingrowth from the optic nerve sheath into the retina, a finding that suggests a novel pathway independent of angiopoietin-Tie signaling. These findings establish ANGPTL4 as a key mediator of immune–vascular interactions in PDR and a potential therapeutic target to address both pathological angiogenesis and lymphatic dysfunction. Article Highlights Some patients with proliferative diabetic retinopathy (PDR) have poor responses to anti–vascular endothelial growth factor (anti-VEGF) therapy. This situation highlights the need for additional therapeutic approaches. In proliferative diabetic retinopathy, what is the role of ANGPTL4 that differs from VEGF? We found that ANGPTL4 is elevated in the vitreous humor of patients with PDR who are poorly responsive to anti-VEGF therapy. ANGPTL4, particularly its C-terminal fragment, causes retinal lymphatic-like remodeling in diabetic mice. This study provides novel insights into the complex interplay between immune activation, neovascularization, and lymphatic-like remodeling in PDR. Our findings deepen our understanding of PDR pathophysiology and propose a promising therapeutic target.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"44 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383343","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}
Magnus F.G. Grøndahl, Iben Rix, Lars F. Garvey, Casper K. Nielsen, Malte P. Suppli, Gro L. Willemoe, Merete J. Kønig, Elizaveta Chabanova, Samuel A.J. Trammell, Trisha J. Grevengoed, Bolette Hartmann, Jens J. Holst, Carsten P. Hansen, Asger B. Lund, Filip K. Knop
Individuals who undergo pancreatic resection are at increased risk of developing hepatic steatosis. Glucagon is a key regulator of hepatic glucose, amino acids, and lipid metabolism, and the change in circulating glucagon is suggested to contribute to the pathogenesis of postoperative steatotic liver disease. Here, we aimed to elucidate hepatic and metabolic changes induced by pancreatic resection. Fifty individuals scheduled to undergo pancreatic surgery were recruited and evaluated by blood samples and a liver biopsy obtained during surgery. One year after surgery, 21 eligible participants (15 following pancreaticoduodenectomy, 6 following total pancreatectomy) met for a follow-up visit, with the remaining being excluded because of recurrent disease, comorbidities, or death. Follow-up MRS indicated increased liver fat in 12 of 19 participants despite a mean numerical decrease in body weight. Five eligible participants underwent a liver biopsy at follow-up, demonstrating increased liver fat content (largest individual increase: 80 percentage points). Circulating glucagon and C-peptide were significantly reduced at follow-up, with no detection of either following total pancreatectomy. No significant changes in fasting plasma glucose or HbA1c were observed, attributed to relevant exogenous insulin supplementation. Amino acids were markedly increased after both pancreaticoduodenectomy and total pancreatectomy, correlating negatively with remnant endocrine pancreatic function. In conclusion, our data suggest that reduced circulating glucagon levels may contribute to the increased liver fat content and hyperaminoacidemia observed after pancreatic resection. Article Highlights Previous studies have demonstrated increased risk of hepatic steatosis in patients following pancreatic resection, which might be linked to decreased pancreatic function. Here, we evaluated liver fat content, circulating pancreatic hormones, amino acids, and more, before and 1 year after either total pancreatectomy or pancreaticoduodenectomy. At 1-year follow-up, we found increased liver fat content in more than half (63%) of the participants, evaluated both by liver histology and magnetic resonance imaging. The participants were characterized by hyperaminoacidemia, which correlated negatively with remnant endocrine pancreatic function. These findings further elucidate the relationship between glucagon, circulating amino acids, and hepatic metabolism.
{"title":"Effects of Pancreatic Resection on Liver Fat Content and Amino Acid, Lipid, and Glucose Metabolism: A Prospective 1-Year Follow-up Study","authors":"Magnus F.G. Grøndahl, Iben Rix, Lars F. Garvey, Casper K. Nielsen, Malte P. Suppli, Gro L. Willemoe, Merete J. Kønig, Elizaveta Chabanova, Samuel A.J. Trammell, Trisha J. Grevengoed, Bolette Hartmann, Jens J. Holst, Carsten P. Hansen, Asger B. Lund, Filip K. Knop","doi":"10.2337/db25-0902","DOIUrl":"https://doi.org/10.2337/db25-0902","url":null,"abstract":"Individuals who undergo pancreatic resection are at increased risk of developing hepatic steatosis. Glucagon is a key regulator of hepatic glucose, amino acids, and lipid metabolism, and the change in circulating glucagon is suggested to contribute to the pathogenesis of postoperative steatotic liver disease. Here, we aimed to elucidate hepatic and metabolic changes induced by pancreatic resection. Fifty individuals scheduled to undergo pancreatic surgery were recruited and evaluated by blood samples and a liver biopsy obtained during surgery. One year after surgery, 21 eligible participants (15 following pancreaticoduodenectomy, 6 following total pancreatectomy) met for a follow-up visit, with the remaining being excluded because of recurrent disease, comorbidities, or death. Follow-up MRS indicated increased liver fat in 12 of 19 participants despite a mean numerical decrease in body weight. Five eligible participants underwent a liver biopsy at follow-up, demonstrating increased liver fat content (largest individual increase: 80 percentage points). Circulating glucagon and C-peptide were significantly reduced at follow-up, with no detection of either following total pancreatectomy. No significant changes in fasting plasma glucose or HbA1c were observed, attributed to relevant exogenous insulin supplementation. Amino acids were markedly increased after both pancreaticoduodenectomy and total pancreatectomy, correlating negatively with remnant endocrine pancreatic function. In conclusion, our data suggest that reduced circulating glucagon levels may contribute to the increased liver fat content and hyperaminoacidemia observed after pancreatic resection. Article Highlights Previous studies have demonstrated increased risk of hepatic steatosis in patients following pancreatic resection, which might be linked to decreased pancreatic function. Here, we evaluated liver fat content, circulating pancreatic hormones, amino acids, and more, before and 1 year after either total pancreatectomy or pancreaticoduodenectomy. At 1-year follow-up, we found increased liver fat content in more than half (63%) of the participants, evaluated both by liver histology and magnetic resonance imaging. The participants were characterized by hyperaminoacidemia, which correlated negatively with remnant endocrine pancreatic function. These findings further elucidate the relationship between glucagon, circulating amino acids, and hepatic metabolism.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"53 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368039","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}
Davide Raineri, Silvia Savastio, Simonetta Bellone, Lorenza Scotti, Camilla Barbero-Mazzucca, Giuseppe Cappellano, Flavia Prodam, Erica Pozzi, Ivana Rabbone, Annalisa Chiocchetti
Type 1 diabetes (T1D) is the most common chronic autoimmune disease in children, driven by a breakdown in self-tolerance and T cell–mediated immune attack of pancreatic β-cells. There are no biomarkers to effectively diagnose autoimmunity before disease onset and clinical symptom development. Here, we applied deep multiparametric immunophenotyping to compare immune landscapes in 38 patients with new-onset T1D, 24 siblings, and 18 healthy control participants (HCs). Patients with T1D underwent clinical and metabolic evaluations. Immune populations in fresh whole-blood samples were analyzed using a panel of 26 antibodies, detecting 39 different cell populations. Memory regulatory T cells (memory Tregs) were significantly increased in patients with T1D (P < 0.05) and their siblings (P < 0.01) compared with HCs but not between patients with T1D and siblings. Memory Tregs were associated with disease status and age in multivariable analysis. There was a positive correlation between age and memory Tregs in the HC and sibling groups but not in patients with T1D. Baseline memory Treg levels in siblings resembled those of patients with T1D. These findings highlight the existence of an age-independent, disease-specific immune fingerprint that could serve as a minimally invasive biomarker for early diagnosis and personalized immunotherapy. Further studies using functional and single-cells analysis are needed to confirm memory Tregs as a pathogenic trait. Article Highlights There are more memory regulatory T cells (Tregs) in individuals with type 1 diabetes (T1D) and siblings than in healthy control (HC) individuals. Individuals with T1D and their siblings share an immunological profile, with siblings displaying an intermediate phenotype that overlaps with both T1D and HC individuals. Memory Tregs increased with age in HC individuals and siblings but not in individuals with T1D. Diabetic ketoacidosis status had no impact on immune cell populations in patients with T1D.
{"title":"Memory Regulatory T Cells as a Biomarker of Early Type I Diabetes","authors":"Davide Raineri, Silvia Savastio, Simonetta Bellone, Lorenza Scotti, Camilla Barbero-Mazzucca, Giuseppe Cappellano, Flavia Prodam, Erica Pozzi, Ivana Rabbone, Annalisa Chiocchetti","doi":"10.2337/db25-0161","DOIUrl":"https://doi.org/10.2337/db25-0161","url":null,"abstract":"Type 1 diabetes (T1D) is the most common chronic autoimmune disease in children, driven by a breakdown in self-tolerance and T cell–mediated immune attack of pancreatic β-cells. There are no biomarkers to effectively diagnose autoimmunity before disease onset and clinical symptom development. Here, we applied deep multiparametric immunophenotyping to compare immune landscapes in 38 patients with new-onset T1D, 24 siblings, and 18 healthy control participants (HCs). Patients with T1D underwent clinical and metabolic evaluations. Immune populations in fresh whole-blood samples were analyzed using a panel of 26 antibodies, detecting 39 different cell populations. Memory regulatory T cells (memory Tregs) were significantly increased in patients with T1D (P &lt; 0.05) and their siblings (P &lt; 0.01) compared with HCs but not between patients with T1D and siblings. Memory Tregs were associated with disease status and age in multivariable analysis. There was a positive correlation between age and memory Tregs in the HC and sibling groups but not in patients with T1D. Baseline memory Treg levels in siblings resembled those of patients with T1D. These findings highlight the existence of an age-independent, disease-specific immune fingerprint that could serve as a minimally invasive biomarker for early diagnosis and personalized immunotherapy. Further studies using functional and single-cells analysis are needed to confirm memory Tregs as a pathogenic trait. Article Highlights There are more memory regulatory T cells (Tregs) in individuals with type 1 diabetes (T1D) and siblings than in healthy control (HC) individuals. Individuals with T1D and their siblings share an immunological profile, with siblings displaying an intermediate phenotype that overlaps with both T1D and HC individuals. Memory Tregs increased with age in HC individuals and siblings but not in individuals with T1D. Diabetic ketoacidosis status had no impact on immune cell populations in patients with T1D.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"67 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147274321","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}
Jinghan Wang, Yue Jiang, Hong Lv, Di Pi, Xiumei Han, Bo Xu, Xiaoyu Liu, Kun Zhou, Yangqian Jiang, Xiaolin Yang, Xin Xu, Yuanyan Dou, Tao Jiang, Jiangbo Du, Guangfu Jin, Hongxia Ma, Zhibin Hu, Hongbing Shen, Yuan Lin
Gestational diabetes mellitus (GDM) is a heterogeneous condition diagnosed solely through glucose. It is characterized by profound perturbations in the metabolome, with specific metabolic profiles linked to adverse birth outcomes. Metabolomics can reveal population heterogeneity in health and disease. Here, we used nontargeted metabolomics to systematically profile the circulating metabolome in 2,050 pregnant women during midpregnancy, identifying 30 metabolites that define the GDM metabolic signature (mGDM). Participants were stratified into four groups by distinct glycemic and metabolic profiles, namely normoglycemic non-mGDM, hyperglycemic non-mGDM, normoglycemic mGDM, and hyperglycemic mGDM, and associations with subsequent adverse birth outcomes were assessed. Compared with normoglycemic non-mGDM, normoglycemic mGDM demonstrated nearly a twofold increased risk of preterm birth (odds ratio [OR] 1.93, 95% CI 1.02–3.65) and large for gestational age (OR 2.11, 95% CI 1.53–2.92). Conversely, the hyperglycemic non-mGDM group did not show elevated risks in adverse birth outcomes versus the normoglycemic group. The hyperglycemic mGDM profile was associated with higher risks of preterm birth (OR 2.37, 95% CI 1.04–5.39), large for gestational age (OR 2.28, 95% CI 1.50–3.47), congenital malformations (OR 1.87, 95% CI 1.03–3.39), and neonatal intensive care unit (NICU) admissions (OR 1.69, 95% CI 1.09–2.61). We observed a stepwise increase in adverse outcome risk across the four-level metabolic-glycemic categories (P for trend < 0.001 for large for gestational age, 0.013 for preterm birth, and 0.018 for NICU admission). Taken together, our study outlines the metabolic profile of GDM and reveals clinically relevant heterogeneity in adverse pregnancy outcomes by metabolic signature. Integrating blood glucose and metabolomics may improve risk stratification and advance precision maternal care. Article Highlights Women diagnosed with gestational diabetes mellitus (GDM) exhibit variability in symptom presentation and pregnancy outcomes. The heterogeneity in metabolic features beyond a GDM diagnosis and their influences on health outcomes is less studied. We aimed to identify the metabolic signatures of GDM, stratify pregnant women by glycemic and metabolic profiles, and further investigate the intergroup heterogeneity and their respective associations with adverse birth outcomes. Maternal metabolic dysregulation, rather than blood glucose alone, exerts more profound associations with adverse outcomes in pregnant women and their offspring. Targeted risk stratification using metabolomics offers a novel opportunity for precision medicine in GDM, potentially improving health management of pregnant women.
妊娠期糖尿病（GDM）是一种仅通过血糖诊断的异质性疾病。它的特点是代谢组的深刻扰动，具有与不良出生结果相关的特定代谢谱。代谢组学可以揭示健康和疾病的人群异质性。在这里，我们使用非靶向代谢组学系统地分析了2050名妊娠中期孕妇的循环代谢组学，确定了30种定义GDM代谢特征（mGDM）的代谢物。参与者根据不同的血糖和代谢特征分为四组，即正常血糖非mGDM，高血糖非mGDM，正常血糖mGDM和高血糖mGDM，并评估与随后不良出生结局的关联。与血糖正常的非mGDM患者相比，血糖正常的mGDM患者早产的风险增加了近两倍（比值比[OR] 1.93, 95% CI 1.02-3.65），并且与胎龄相关（比值比[OR] 2.11, 95% CI 1.53-2.92）。相反，与血糖正常组相比，高血糖非mgdm组在不良出生结局方面没有显示出更高的风险。高血糖mGDM与早产（OR 2.37, 95% CI 1.04-5.39）、胎龄大（OR 2.28, 95% CI 1.50-3.47）、先天性畸形（OR 1.87, 95% CI 1.03-3.39）和新生儿重症监护病房（NICU）入院（OR 1.69, 95% CI 1.09-2.61）的风险较高相关。我们观察到在四个水平的代谢-血糖类别中，不良结局风险逐步增加（P为趋势，P < 0.001，胎龄大的为0.01，早产的为0.013，新生儿重症监护病房入院的为0.018）。总之，我们的研究概述了GDM的代谢特征，并通过代谢特征揭示了不良妊娠结局的临床相关异质性。整合血糖和代谢组学可能改善风险分层和推进精准产妇护理。诊断为妊娠期糖尿病（GDM）的妇女在症状表现和妊娠结局方面表现出变异性。除了GDM诊断外，代谢特征的异质性及其对健康结果的影响研究较少。我们的目的是确定GDM的代谢特征，根据血糖和代谢特征对孕妇进行分层，并进一步研究组间异质性及其与不良出生结局的相关性。母体代谢失调，而不仅仅是血糖失调，与孕妇及其后代的不良后果有着更深刻的联系。利用代谢组学进行有针对性的风险分层，为GDM的精准医疗提供了新的机会，有可能改善孕妇的健康管理。
{"title":"Metabolic Signature of Gestational Diabetes Mellitus and Risk of Adverse Birth Outcomes: A Prospective Birth Cohort Study","authors":"Jinghan Wang, Yue Jiang, Hong Lv, Di Pi, Xiumei Han, Bo Xu, Xiaoyu Liu, Kun Zhou, Yangqian Jiang, Xiaolin Yang, Xin Xu, Yuanyan Dou, Tao Jiang, Jiangbo Du, Guangfu Jin, Hongxia Ma, Zhibin Hu, Hongbing Shen, Yuan Lin","doi":"10.2337/db25-0920","DOIUrl":"https://doi.org/10.2337/db25-0920","url":null,"abstract":"Gestational diabetes mellitus (GDM) is a heterogeneous condition diagnosed solely through glucose. It is characterized by profound perturbations in the metabolome, with specific metabolic profiles linked to adverse birth outcomes. Metabolomics can reveal population heterogeneity in health and disease. Here, we used nontargeted metabolomics to systematically profile the circulating metabolome in 2,050 pregnant women during midpregnancy, identifying 30 metabolites that define the GDM metabolic signature (mGDM). Participants were stratified into four groups by distinct glycemic and metabolic profiles, namely normoglycemic non-mGDM, hyperglycemic non-mGDM, normoglycemic mGDM, and hyperglycemic mGDM, and associations with subsequent adverse birth outcomes were assessed. Compared with normoglycemic non-mGDM, normoglycemic mGDM demonstrated nearly a twofold increased risk of preterm birth (odds ratio [OR] 1.93, 95% CI 1.02–3.65) and large for gestational age (OR 2.11, 95% CI 1.53–2.92). Conversely, the hyperglycemic non-mGDM group did not show elevated risks in adverse birth outcomes versus the normoglycemic group. The hyperglycemic mGDM profile was associated with higher risks of preterm birth (OR 2.37, 95% CI 1.04–5.39), large for gestational age (OR 2.28, 95% CI 1.50–3.47), congenital malformations (OR 1.87, 95% CI 1.03–3.39), and neonatal intensive care unit (NICU) admissions (OR 1.69, 95% CI 1.09–2.61). We observed a stepwise increase in adverse outcome risk across the four-level metabolic-glycemic categories (P for trend &lt; 0.001 for large for gestational age, 0.013 for preterm birth, and 0.018 for NICU admission). Taken together, our study outlines the metabolic profile of GDM and reveals clinically relevant heterogeneity in adverse pregnancy outcomes by metabolic signature. Integrating blood glucose and metabolomics may improve risk stratification and advance precision maternal care. Article Highlights Women diagnosed with gestational diabetes mellitus (GDM) exhibit variability in symptom presentation and pregnancy outcomes. The heterogeneity in metabolic features beyond a GDM diagnosis and their influences on health outcomes is less studied. We aimed to identify the metabolic signatures of GDM, stratify pregnant women by glycemic and metabolic profiles, and further investigate the intergroup heterogeneity and their respective associations with adverse birth outcomes. Maternal metabolic dysregulation, rather than blood glucose alone, exerts more profound associations with adverse outcomes in pregnant women and their offspring. Targeted risk stratification using metabolomics offers a novel opportunity for precision medicine in GDM, potentially improving health management of pregnant women.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"50 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146230889","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}
Madhura Bose, Muthukumar Mohan, Jun Okabe, Harikrishnan Kaipananickal, Victoria Priori, Carolyn Chhor, Karly C. Sourris, Ramtin Radman, Christos Tikellis, Yvonne Zhang, Assam El-Osta, Eoin Brennan, Patrick J. Guiry, Kevin Gahan, Catherine Tighe, Merlin Thomas, Karin Jandeleit-Dahm, Catherine Godson, Phillip Kantharidis, Mark E. Cooper
Chronic low-grade inflammation underlies many microvascular complications of diabetes, including diabetic kidney disease (DKD). Lipoxins (LXs), an endogenously produced family of lipid mediators, resolve inflammation and protect against renal scarring as occurs in DKD. This study examined the mechanism by which LXs protect against DKD, focusing on the regulation of VCAM-1 and the recruitment of macrophages to the diabetic glomerulus. LXA4 and two fourth-generation mimetics were assessed in diabetic ApoE knockout mice, followed by in vitro studies in the main renal cell populations, including podocytes, proximal tubular, mesangial, and glomerular endothelial cells. LXs attenuated albuminuria, mesangial expansion, and collagen and fibronectin deposition as both a preventive and delayed intervention in experimental DKD. LXs also consistently attenuated the TNF-α–induced expression of VCAM-1 in all the human and mouse renal cell populations examined. Further analysis identified that the renoprotection was in part mediated by an epigenetic modification of the VCAM-1 gene through H3K4 monomethylation, which did not appear to be dependent on NF-κB activation in human glomerular endothelial cells. LXs protect against DKD by modulating glomerular endothelial cell inflammation and via a novel LX-mediated epigenetic mechanism regulating the VCAM-1 promoter in these cells. Article Highlights Lipoxins (LXs) protect against diabetic kidney disease (DKD) by resolving chronic low-grade inflammation, but the exact mechanism by which this occurs is not known. We investigated the effect of LXs on inflammatory markers and the recruitment of macrophages to the diabetic glomerulus by using LXs as both a preventive and delayed interventional treatment in streptozotocin-induced diabetic ApoE knockout mice. Protection against DKD was associated with reduced glomerular macrophage accumulation. LXs also attenuated the expression of VCAM1 in glomerular endothelial cells. LXs protect against DKD in part by a mechanism that reduces VCAM1 gene expression via H3K4 monomethylation on the VCAM1 gene.
{"title":"Epigenetic Regulation of VCAM-1 by Lipoxin A4 Is Renoprotective Against Diabetic Kidney Disease","authors":"Madhura Bose, Muthukumar Mohan, Jun Okabe, Harikrishnan Kaipananickal, Victoria Priori, Carolyn Chhor, Karly C. Sourris, Ramtin Radman, Christos Tikellis, Yvonne Zhang, Assam El-Osta, Eoin Brennan, Patrick J. Guiry, Kevin Gahan, Catherine Tighe, Merlin Thomas, Karin Jandeleit-Dahm, Catherine Godson, Phillip Kantharidis, Mark E. Cooper","doi":"10.2337/db25-0970","DOIUrl":"https://doi.org/10.2337/db25-0970","url":null,"abstract":"Chronic low-grade inflammation underlies many microvascular complications of diabetes, including diabetic kidney disease (DKD). Lipoxins (LXs), an endogenously produced family of lipid mediators, resolve inflammation and protect against renal scarring as occurs in DKD. This study examined the mechanism by which LXs protect against DKD, focusing on the regulation of VCAM-1 and the recruitment of macrophages to the diabetic glomerulus. LXA4 and two fourth-generation mimetics were assessed in diabetic ApoE knockout mice, followed by in vitro studies in the main renal cell populations, including podocytes, proximal tubular, mesangial, and glomerular endothelial cells. LXs attenuated albuminuria, mesangial expansion, and collagen and fibronectin deposition as both a preventive and delayed intervention in experimental DKD. LXs also consistently attenuated the TNF-α–induced expression of VCAM-1 in all the human and mouse renal cell populations examined. Further analysis identified that the renoprotection was in part mediated by an epigenetic modification of the VCAM-1 gene through H3K4 monomethylation, which did not appear to be dependent on NF-κB activation in human glomerular endothelial cells. LXs protect against DKD by modulating glomerular endothelial cell inflammation and via a novel LX-mediated epigenetic mechanism regulating the VCAM-1 promoter in these cells. Article Highlights Lipoxins (LXs) protect against diabetic kidney disease (DKD) by resolving chronic low-grade inflammation, but the exact mechanism by which this occurs is not known. We investigated the effect of LXs on inflammatory markers and the recruitment of macrophages to the diabetic glomerulus by using LXs as both a preventive and delayed interventional treatment in streptozotocin-induced diabetic ApoE knockout mice. Protection against DKD was associated with reduced glomerular macrophage accumulation. LXs also attenuated the expression of VCAM1 in glomerular endothelial cells. LXs protect against DKD in part by a mechanism that reduces VCAM1 gene expression via H3K4 monomethylation on the VCAM1 gene.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"35 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215829","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}
Sangeeta Dhawan, Jing Hughes, Aleksey V. Matveyenko, Vincent Poitout
In response to the lockdowns and travel bans during the coronavirus disease 2019 pandemic, Peter C. Butler at the University of California, Los Angeles (UCLA), started a virtual islet biology seminar series. After the authors of this article joined him as co-organizers, this initiative became the Islet Research Seminar Series (IRSS). Like islets of Langerhans adapt to their changing environment, the islet biology community quickly embraced this new format. The IRSS evolved into a lasting scientific forum that convenes weekly and is attended by islet biologists from the U.S., Canada, Europe, and Israel. The series covers a range of topics in islet biology, with presentations from scientists representing all career stages. It has proven particularly valuable for trainees and early-stage investigators in exposing them to a variety of topics in islet biology without travel required and facilitating more spontaneous interactions with senior scientists than at in-person meetings. While the online format is not meant to replace live scientific conferences, we believe that the IRSS plays a unique role in keeping the islet biology community connected and abreast of the most recent scientific discoveries in our field. The success of this platform stands as a testament to the scientific community to adapt and thrive through challenges. This article is dedicated to Peter C. Butler, UCLA, who initiated the IRSS.
为了应对2019年冠状病毒病大流行期间的封锁和旅行禁令，加州大学洛杉矶分校（UCLA）的彼得·c·巴特勒（Peter C. Butler）发起了一个虚拟岛屿生物学系列研讨会。在这篇文章的作者加入他作为共同组织者之后，这个倡议成为了小岛研究研讨会系列（IRSS）。就像朗格汉斯的小岛适应不断变化的环境一样，小岛生物界很快接受了这种新形式。IRSS逐渐发展成为一个持久的科学论坛，每周召开一次，由来自美国、加拿大、欧洲和以色列的岛屿生物学家参加。该系列涵盖了一系列的主题在胰岛生物学，从科学家代表的所有职业阶段的演讲。事实证明，对于学员和早期研究人员来说，它特别有价值，因为它使他们不必旅行就能接触到各种各样的胰岛生物学主题，并且与资深科学家进行更多的自发互动，而不是面对面的会议。虽然在线形式并不意味着取代现场科学会议，但我们相信，IRSS在保持岛屿生物界的联系和跟上本领域最新科学发现方面发挥着独特的作用。该平台的成功证明了科学界能够适应挑战并在挑战中茁壮成长。本文献给加州大学洛杉矶分校的Peter C. Butler，他是IRSS的发起人。
{"title":"Staying Functional Through Connection and Adaptation: When Islets Inspire Islet Biologists","authors":"Sangeeta Dhawan, Jing Hughes, Aleksey V. Matveyenko, Vincent Poitout","doi":"10.2337/dbi25-0036","DOIUrl":"https://doi.org/10.2337/dbi25-0036","url":null,"abstract":"In response to the lockdowns and travel bans during the coronavirus disease 2019 pandemic, Peter C. Butler at the University of California, Los Angeles (UCLA), started a virtual islet biology seminar series. After the authors of this article joined him as co-organizers, this initiative became the Islet Research Seminar Series (IRSS). Like islets of Langerhans adapt to their changing environment, the islet biology community quickly embraced this new format. The IRSS evolved into a lasting scientific forum that convenes weekly and is attended by islet biologists from the U.S., Canada, Europe, and Israel. The series covers a range of topics in islet biology, with presentations from scientists representing all career stages. It has proven particularly valuable for trainees and early-stage investigators in exposing them to a variety of topics in islet biology without travel required and facilitating more spontaneous interactions with senior scientists than at in-person meetings. While the online format is not meant to replace live scientific conferences, we believe that the IRSS plays a unique role in keeping the islet biology community connected and abreast of the most recent scientific discoveries in our field. The success of this platform stands as a testament to the scientific community to adapt and thrive through challenges. This article is dedicated to Peter C. Butler, UCLA, who initiated the IRSS.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"7 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205059","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}
Zhao Xiang, Liu Zitian, Yang Guangwei, Dong Shuohui, Wang Kexin
Pancreatic β-cells play a central role in type 2 diabetes mellitus (T2DM), yet the interactions between β-cells and stromal components within the islet microenvironment remain poorly defined. We investigated the contribution of pancreatic fibroblasts to β-cell dysfunction and T2DM progression. We used single-cell sequencing technology and in vitro experiments to investigate the mechanisms by which bariatric surgery ameliorates T2DM. We introduce the novel concept of a “metabolic synapse” to describe the interaction between pancreatic fibroblasts and β-cells. Our findings reveal that pancreatic fibroblasts secrete excessive glutamate in the early stages of T2DM. Elevated glutamate concentrations within the islet microenvironment subsequently activate N-methyl-d-aspartic acid receptors (NMDARs), triggering PANoptosis in pancreatic β-cells and accelerating T2DM progression. Consistent with this, significant changes in NMDAR expression were observed in human pancreatic samples from patients with T2DM. These findings uncover a previously unrecognized fibroblast-β-cell communication pathway in the islet niche, provide mechanistic insights into T2DM pathogenesis, and highlight the glutamate–NMDAR axis as a potential therapeutic target for nonsurgical intervention. Article Highlights We identify a fibroblast-β-cell “metabolic synapse” in type 2 diabetes that couples stromal glutamate overflow to β-cell N-methyl-d-aspartic acid receptor (NMDAR) activation. Single-cell maps and coculture assays show diabetogenic stress drives fibroblasts to hypersecrete glutamate, whereas β-cells upregulate NMDARs, triggering PANoptosis. In rodents, pharmacologic NMDAR blockade attenuates β-cell PANoptosis, preserves islet function, and improves glycemic control. Human pancreatic samples cohorts reveal fibrosis regression and stage-wise NMDAR upregulation, highlighting the glutamate–NMDAR axis as a therapeutic target.
{"title":"Activation of the Pancreatic “Metabolic Synapse” Aggravates Type 2 Diabetes Mellitus by Inducing PANoptosis in β-Cells","authors":"Zhao Xiang, Liu Zitian, Yang Guangwei, Dong Shuohui, Wang Kexin","doi":"10.2337/db25-0863","DOIUrl":"https://doi.org/10.2337/db25-0863","url":null,"abstract":"Pancreatic β-cells play a central role in type 2 diabetes mellitus (T2DM), yet the interactions between β-cells and stromal components within the islet microenvironment remain poorly defined. We investigated the contribution of pancreatic fibroblasts to β-cell dysfunction and T2DM progression. We used single-cell sequencing technology and in vitro experiments to investigate the mechanisms by which bariatric surgery ameliorates T2DM. We introduce the novel concept of a “metabolic synapse” to describe the interaction between pancreatic fibroblasts and β-cells. Our findings reveal that pancreatic fibroblasts secrete excessive glutamate in the early stages of T2DM. Elevated glutamate concentrations within the islet microenvironment subsequently activate N-methyl-d-aspartic acid receptors (NMDARs), triggering PANoptosis in pancreatic β-cells and accelerating T2DM progression. Consistent with this, significant changes in NMDAR expression were observed in human pancreatic samples from patients with T2DM. These findings uncover a previously unrecognized fibroblast-β-cell communication pathway in the islet niche, provide mechanistic insights into T2DM pathogenesis, and highlight the glutamate–NMDAR axis as a potential therapeutic target for nonsurgical intervention. Article Highlights We identify a fibroblast-β-cell “metabolic synapse” in type 2 diabetes that couples stromal glutamate overflow to β-cell N-methyl-d-aspartic acid receptor (NMDAR) activation. Single-cell maps and coculture assays show diabetogenic stress drives fibroblasts to hypersecrete glutamate, whereas β-cells upregulate NMDARs, triggering PANoptosis. In rodents, pharmacologic NMDAR blockade attenuates β-cell PANoptosis, preserves islet function, and improves glycemic control. Human pancreatic samples cohorts reveal fibrosis regression and stage-wise NMDAR upregulation, highlighting the glutamate–NMDAR axis as a therapeutic target.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"87 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210348","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}
Jamie N. Garcia, Matthew A. Cottam, Alec S. Rodriguez, Anwar F. Hussein Agha, Heather L. Caslin, Nathan C. Winn, Alyssa H. Hasty
Weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Both obesity itself and weight cycling cause adipose tissue inflammation and metabolic dysfunction. Studies show that even after weight loss, increased numbers of lipid-associated macrophages and memory T cells persist in adipose tissue and become more inflammatory on weight regain. This suggests that the immune system retains an obesogenic memory, which may contribute to the elevated inflammation and metabolic dysfunction associated with weight cycling. We show that blocking the CD70–CD27 axis, critical for the formation of immunologic memory, decreases the number of memory T cells and T-cell clonality within adipose tissue after weight loss and weight cycling. Furthermore, although CD70−/− mice have metabolic responses to stable obesity similar to those of wild-type mice, they are protected from the worsened glucose tolerance associated with weight cycling. Our data are the first to support mitigating the metabolic consequences of weight cycling through an immunomodulatory mechanism. We propose a new avenue of therapeutic intervention targeting memory T cells to minimize the adverse consequences of weight cycling. These findings are timely, given the increasing use of weight-loss drugs, which may lead to more instances of human weight cycling. Article Highlights We aimed to address a critical gap in understanding how persistent immune changes with weight cycling contribute to worsened metabolic health. We wanted to determine whether disrupting immune memory formation could prevent the accumulation and reactivation of memory T cells in adipose tissue and thereby protect against the metabolic dysfunction associated with weight cycling. In targeting the CD70–CD27 axis, thereby inhibiting T-cell memory formation, we were able to mitigate the exacerbated glucose intolerance observed in wild-type weight-cycled mice. This study highlights the potential to address the negative metabolic effects of weight cycling through an immunomodulatory approach, offering a novel therapeutic target by disrupting obesogenic immune memory.
{"title":"Interrupting T-Cell Memory Ameliorates Exaggerated Metabolic Response to Weight Cycling","authors":"Jamie N. Garcia, Matthew A. Cottam, Alec S. Rodriguez, Anwar F. Hussein Agha, Heather L. Caslin, Nathan C. Winn, Alyssa H. Hasty","doi":"10.2337/db25-0605","DOIUrl":"https://doi.org/10.2337/db25-0605","url":null,"abstract":"Weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Both obesity itself and weight cycling cause adipose tissue inflammation and metabolic dysfunction. Studies show that even after weight loss, increased numbers of lipid-associated macrophages and memory T cells persist in adipose tissue and become more inflammatory on weight regain. This suggests that the immune system retains an obesogenic memory, which may contribute to the elevated inflammation and metabolic dysfunction associated with weight cycling. We show that blocking the CD70–CD27 axis, critical for the formation of immunologic memory, decreases the number of memory T cells and T-cell clonality within adipose tissue after weight loss and weight cycling. Furthermore, although CD70−/− mice have metabolic responses to stable obesity similar to those of wild-type mice, they are protected from the worsened glucose tolerance associated with weight cycling. Our data are the first to support mitigating the metabolic consequences of weight cycling through an immunomodulatory mechanism. We propose a new avenue of therapeutic intervention targeting memory T cells to minimize the adverse consequences of weight cycling. These findings are timely, given the increasing use of weight-loss drugs, which may lead to more instances of human weight cycling. Article Highlights We aimed to address a critical gap in understanding how persistent immune changes with weight cycling contribute to worsened metabolic health. We wanted to determine whether disrupting immune memory formation could prevent the accumulation and reactivation of memory T cells in adipose tissue and thereby protect against the metabolic dysfunction associated with weight cycling. In targeting the CD70–CD27 axis, thereby inhibiting T-cell memory formation, we were able to mitigate the exacerbated glucose intolerance observed in wild-type weight-cycled mice. This study highlights the potential to address the negative metabolic effects of weight cycling through an immunomodulatory approach, offering a novel therapeutic target by disrupting obesogenic immune memory.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"59 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210349","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}
Shuhao Lin, Kelli A. Lytle, Nicola Fink, Michael D. Jensen
Adipose tissue (AT) lipolysis insulin resistance results in excess free fatty acid (FFA) release. We tested the hypothesis that the ability of insulin to suppress AT lipolysis is unrelated to the ability of niacin to suppress lipolysis, because niacin acts through a different proximal signaling pathway. Ten volunteers (5 women/5 men) with upper body obesity and/or type 2 diabetes mellitus (T2DM) underwent two study visits with overnight intravenous infusions of niacin (1.4 mg/min) or saline, followed by a hyperinsulinemic-euglycemic clamp. FFA-palmitate Ra was measured using [U-13C] and [2H9]palmitate infusions; abdominal AT biopsies were performed before and during the insulin clamp. The suppression of FFA-palmitate Ra by insulin on the saline control day and by niacin after an overnight infusion were highly correlated (r = −0.93, P < 0.001). Fasting AT Akt (pAktS473/474-to-panAkt ratio, P = 0.01) and perilipin 1 (PLN 1) (pPLN1S552-to-panPLN1 ratio, P = 0.02) phosphorylation were less during niacin than the saline control study. Because the suppression of lipolysis by insulin and niacin are highly correlated within individuals and because niacin and insulin act through different proximal signaling pathways, we propose dysregulated AT lipolysis in obesity/T2DM is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.” Article Highlights We undertook this study to compare adipose tissue lipolysis responses to insulin and niacin in humans. We tested the hypothesis that adipose tissue insulin resistance would be unrelated to adipose tissue niacin resistance. The suppression of lipolysis by insulin and niacin were highly correlated. Dysregulated adipose tissue lipolysis in obesity/type 2 diabetes is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.”
{"title":"Adipose Tissue Resistance to the Antilipolytic Effect of Insulin and Niacin in Humans With Obesity","authors":"Shuhao Lin, Kelli A. Lytle, Nicola Fink, Michael D. Jensen","doi":"10.2337/db25-0979","DOIUrl":"https://doi.org/10.2337/db25-0979","url":null,"abstract":"Adipose tissue (AT) lipolysis insulin resistance results in excess free fatty acid (FFA) release. We tested the hypothesis that the ability of insulin to suppress AT lipolysis is unrelated to the ability of niacin to suppress lipolysis, because niacin acts through a different proximal signaling pathway. Ten volunteers (5 women/5 men) with upper body obesity and/or type 2 diabetes mellitus (T2DM) underwent two study visits with overnight intravenous infusions of niacin (1.4 mg/min) or saline, followed by a hyperinsulinemic-euglycemic clamp. FFA-palmitate Ra was measured using [U-13C] and [2H9]palmitate infusions; abdominal AT biopsies were performed before and during the insulin clamp. The suppression of FFA-palmitate Ra by insulin on the saline control day and by niacin after an overnight infusion were highly correlated (r = −0.93, P &lt; 0.001). Fasting AT Akt (pAktS473/474-to-panAkt ratio, P = 0.01) and perilipin 1 (PLN 1) (pPLN1S552-to-panPLN1 ratio, P = 0.02) phosphorylation were less during niacin than the saline control study. Because the suppression of lipolysis by insulin and niacin are highly correlated within individuals and because niacin and insulin act through different proximal signaling pathways, we propose dysregulated AT lipolysis in obesity/T2DM is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.” Article Highlights We undertook this study to compare adipose tissue lipolysis responses to insulin and niacin in humans. We tested the hypothesis that adipose tissue insulin resistance would be unrelated to adipose tissue niacin resistance. The suppression of lipolysis by insulin and niacin were highly correlated. Dysregulated adipose tissue lipolysis in obesity/type 2 diabetes is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.”","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"17 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210347","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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