Yue Sun, Jinfu Zhang, Yuanyuan Su, Tiancheng Wu, Jiaqi Chen, Nan Yang, Xiao Han, Haiyan Lin, Ye Yin
Chronic overnutrition promotes excessive hepatic triglyceride accumulation, subsequently leading to insulin resistance and systemic metabolic dysfunction. Inorganic pyrophosphatase 1 (PPA1), an enzyme that hydrolyzes inorganic pyrophosphate, plays a key role in driving synthetic biochemical reactions. Here, we identified PPA1 as a novel regulator of systemic energy expenditure that functions by controlling hepatic production of fibroblast growth factor 21 (FGF21). FGF21 is a hormone predominantly secreted by the liver that protects against obesity by enhancing whole-body energy expenditure. Although nutritional states and various transcription factors are known to regulate hepatic FGF21 expression, the underlying mechanisms remain elusive. In this study, we demonstrate that hepatic-specific deletion of PPA1 effectively attenuates high-fat diet–induced obesity, reduces hepatic lipid deposition, and improves systemic insulin sensitivity in vivo. PPA1 ablation in the liver significantly elevates circulating FGF21 levels and increases whole-body energy expenditure by promoting adipose tissue browning and thermogenesis. Knockdown of hepatic FGF21 expression partially counteracts the protective effect conferred by PPA1 deficiency. Mechanistically, hepatic PPA1 deficiency elevates FGF21 through the GCN2/eIF2α/ATF4 pathway, a process that is dependent on the loss of its enzymatic activity. Our findings not only establish PPA1 as a critical regulator of systemic energy metabolism but also identify it as a novel modulator of FGF21, highlighting its potential as a therapeutic target for obesity and related metabolic disorders. ARTICLE HIGHLIGHTS Pyrophosphatase 1 (PPA1) is upregulated in livers of high-fat diet–induced obese mice and metabolic dysfunction–associated steatotic liver disease patients. Hepatic PPA1 deletion protects mice against high-fat diet–induced obesity and related metabolic disorders by promoting whole-body energy expenditure. Deficiency of hepatic PPA1 expression facilitates fibroblast growth factor 21 production by activating the GCN2/eIF2α/ATF4 signaling pathway.
{"title":"Down-Regulation of Hepatic PPA1 Protects Against Obesity by Elevating FGF21 Production via eIF2α Phosphorylation","authors":"Yue Sun, Jinfu Zhang, Yuanyuan Su, Tiancheng Wu, Jiaqi Chen, Nan Yang, Xiao Han, Haiyan Lin, Ye Yin","doi":"10.2337/db25-0655","DOIUrl":"https://doi.org/10.2337/db25-0655","url":null,"abstract":"Chronic overnutrition promotes excessive hepatic triglyceride accumulation, subsequently leading to insulin resistance and systemic metabolic dysfunction. Inorganic pyrophosphatase 1 (PPA1), an enzyme that hydrolyzes inorganic pyrophosphate, plays a key role in driving synthetic biochemical reactions. Here, we identified PPA1 as a novel regulator of systemic energy expenditure that functions by controlling hepatic production of fibroblast growth factor 21 (FGF21). FGF21 is a hormone predominantly secreted by the liver that protects against obesity by enhancing whole-body energy expenditure. Although nutritional states and various transcription factors are known to regulate hepatic FGF21 expression, the underlying mechanisms remain elusive. In this study, we demonstrate that hepatic-specific deletion of PPA1 effectively attenuates high-fat diet–induced obesity, reduces hepatic lipid deposition, and improves systemic insulin sensitivity in vivo. PPA1 ablation in the liver significantly elevates circulating FGF21 levels and increases whole-body energy expenditure by promoting adipose tissue browning and thermogenesis. Knockdown of hepatic FGF21 expression partially counteracts the protective effect conferred by PPA1 deficiency. Mechanistically, hepatic PPA1 deficiency elevates FGF21 through the GCN2/eIF2α/ATF4 pathway, a process that is dependent on the loss of its enzymatic activity. Our findings not only establish PPA1 as a critical regulator of systemic energy metabolism but also identify it as a novel modulator of FGF21, highlighting its potential as a therapeutic target for obesity and related metabolic disorders. ARTICLE HIGHLIGHTS Pyrophosphatase 1 (PPA1) is upregulated in livers of high-fat diet–induced obese mice and metabolic dysfunction–associated steatotic liver disease patients. Hepatic PPA1 deletion protects mice against high-fat diet–induced obesity and related metabolic disorders by promoting whole-body energy expenditure. Deficiency of hepatic PPA1 expression facilitates fibroblast growth factor 21 production by activating the GCN2/eIF2α/ATF4 signaling pathway.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"5 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972254","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}
Eftychia Kontidou, Aida Collado, Rawan Humoud, Kesavan Manickam, John Tengbom, Tong Jiao, Michael Alvarsson, Jiangning Yang, Linda Mellbin, Ali Mahdi, John Pernow, Zhichao Zhou
Type 2 diabetes increases cardiovascular risk, with endothelial dysfunction playing a key role. Prolonged disease duration exacerbates cardiovascular risk, but the underlying mechanisms remain unclear. We previously demonstrated that red blood cells (RBCs) from individuals with type 2 diabetes impair endothelial function via reduced miRNA (miR)-210-3p. We investigated whether disease duration influences RBC-induced endothelial dysfunction and its link to miR-210-3p. RBCs were isolated from diabetic db/db mice of various ages and from humans with newly diagnosed (<1 year) or long-lasting type 2 diabetes (>7 years). Endothelial-dependent relaxation (EDR), miR-210-3p levels, its target protein glycerol-3-phosphate dehydrogenase 2 (GPD2), and oxidative stress marker 4-hydroxynonenal (4-HNE) were assessed. RBCs from 14- and 22-week-old, but not 7-week-old, db/db mice impaired EDR. These RBCs showed similarly reduced miR-210-3p levels and increased vascular GPD2 and 4-HNE expression. RBCs from individuals with long-lasting type 2 diabetes, but not from the newly diagnosed group, impaired EDR. After ≥7 years, RBCs from initially newly diagnosed individuals impaired EDR, which was rescued by miR-210-3p mimic transfection. In contrast, RBCs from healthy subjects did not impair EDR after follow-up. These findings underscore the pivotal role of disease duration for RBC-mediated vascular dysfunction, linked to miR-210-3p downregulation. RBC miR-210-3p may serve as a biomarker for diabetes-related vascular disease. Article Highlights Red blood cells (RBCs) from older (representing longer duration of diabetes) but not young diabetic mice induce endothelial dysfunction. Protective miRNA-210-3p levels in RBCs are reduced in older diabetic mice compared with young ones. RBCs from individuals with long-lasting (>7 years) but not newly diagnosed type 2 diabetes (<1 year) induce endothelial dysfunction. RBCs from individuals with newly diagnosed type 2 diabetes induce endothelial dysfunction at a >7-year follow up, which is rescued by miRNA-210-3p mimic.
{"title":"Long Duration of Type 2 Diabetes Drives Erythrocyte-Induced Vascular Endothelial Dysfunction: A Link to miRNA-210-3p","authors":"Eftychia Kontidou, Aida Collado, Rawan Humoud, Kesavan Manickam, John Tengbom, Tong Jiao, Michael Alvarsson, Jiangning Yang, Linda Mellbin, Ali Mahdi, John Pernow, Zhichao Zhou","doi":"10.2337/db25-0463","DOIUrl":"https://doi.org/10.2337/db25-0463","url":null,"abstract":"Type 2 diabetes increases cardiovascular risk, with endothelial dysfunction playing a key role. Prolonged disease duration exacerbates cardiovascular risk, but the underlying mechanisms remain unclear. We previously demonstrated that red blood cells (RBCs) from individuals with type 2 diabetes impair endothelial function via reduced miRNA (miR)-210-3p. We investigated whether disease duration influences RBC-induced endothelial dysfunction and its link to miR-210-3p. RBCs were isolated from diabetic db/db mice of various ages and from humans with newly diagnosed (&lt;1 year) or long-lasting type 2 diabetes (&gt;7 years). Endothelial-dependent relaxation (EDR), miR-210-3p levels, its target protein glycerol-3-phosphate dehydrogenase 2 (GPD2), and oxidative stress marker 4-hydroxynonenal (4-HNE) were assessed. RBCs from 14- and 22-week-old, but not 7-week-old, db/db mice impaired EDR. These RBCs showed similarly reduced miR-210-3p levels and increased vascular GPD2 and 4-HNE expression. RBCs from individuals with long-lasting type 2 diabetes, but not from the newly diagnosed group, impaired EDR. After ≥7 years, RBCs from initially newly diagnosed individuals impaired EDR, which was rescued by miR-210-3p mimic transfection. In contrast, RBCs from healthy subjects did not impair EDR after follow-up. These findings underscore the pivotal role of disease duration for RBC-mediated vascular dysfunction, linked to miR-210-3p downregulation. RBC miR-210-3p may serve as a biomarker for diabetes-related vascular disease. Article Highlights Red blood cells (RBCs) from older (representing longer duration of diabetes) but not young diabetic mice induce endothelial dysfunction. Protective miRNA-210-3p levels in RBCs are reduced in older diabetic mice compared with young ones. RBCs from individuals with long-lasting (&gt;7 years) but not newly diagnosed type 2 diabetes (&lt;1 year) induce endothelial dysfunction. RBCs from individuals with newly diagnosed type 2 diabetes induce endothelial dysfunction at a &gt;7-year follow up, which is rescued by miRNA-210-3p mimic.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"76 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920332","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}
Noah J. Levi, Alejandro Tamayo Garcia, Madina Sokolov, Rene Barro-Soria, Alejandro Caicedo
The parasympathetic nervous system modulates hormone and digestive enzyme secretion from the pancreas. However, the mechanisms of neuroeffector transmission within the final parasympathetic pathway in the pancreas have not been elucidated. Here, we demonstrate that intrapancreatic cholinergic neurons are bona fide postganglionic neurons that functionally couple vagal input to target cells in the pancreas. In living pancreatic slices from various mice expressing genetically encoded sensors and actuators, we found that intrapancreatic neurons responded to cholinergic input via nicotinic and muscarinic M1 acetylcholine receptors. However, only muscarinic receptor signaling was necessary and sufficient to elicit responses in exocrine and endocrine target cells. We established that muscarinic receptor signaling in intrapancreatic neurons is linked to the potassium M-current, thus producing the sustained reverberating activity required to efficiently modulate insulin and glucagon secretion and elicit oscillatory responses in acinar cells. Whereas intrapancreatic neurons triggered responses in acinar cells without additional stimulation, they only primed and amplified hormone secretion already stimulated by changes in glucose levels. This mechanistic insight into how intrapancreatic neurons regulate pancreas function challenges canonical models of parasympathetic neurotransmission and is critical to understanding autonomic control of the pancreas. Article Highlights Neurotransmission mechanisms at the final parasympathetic pathway in the pancreas have not been elucidated. We manipulated and recorded neuronal and target cell responses in living pancreatic slices to assess how intrapancreatic neurons affect pancreatic cell function. Activating muscarinic receptor signaling in intrapancreatic neurons was required to trigger exocrine cell activity and modulate endocrine cell secretion. Our findings revise conventional models of parasympathetic neuronal control of pancreatic function.
{"title":"Activating Muscarinic Receptor Signaling in Intrapancreatic Neurons Is Required for Parasympathetic Cholinergic Control of Pancreatic Cell Function","authors":"Noah J. Levi, Alejandro Tamayo Garcia, Madina Sokolov, Rene Barro-Soria, Alejandro Caicedo","doi":"10.2337/db25-0604","DOIUrl":"https://doi.org/10.2337/db25-0604","url":null,"abstract":"The parasympathetic nervous system modulates hormone and digestive enzyme secretion from the pancreas. However, the mechanisms of neuroeffector transmission within the final parasympathetic pathway in the pancreas have not been elucidated. Here, we demonstrate that intrapancreatic cholinergic neurons are bona fide postganglionic neurons that functionally couple vagal input to target cells in the pancreas. In living pancreatic slices from various mice expressing genetically encoded sensors and actuators, we found that intrapancreatic neurons responded to cholinergic input via nicotinic and muscarinic M1 acetylcholine receptors. However, only muscarinic receptor signaling was necessary and sufficient to elicit responses in exocrine and endocrine target cells. We established that muscarinic receptor signaling in intrapancreatic neurons is linked to the potassium M-current, thus producing the sustained reverberating activity required to efficiently modulate insulin and glucagon secretion and elicit oscillatory responses in acinar cells. Whereas intrapancreatic neurons triggered responses in acinar cells without additional stimulation, they only primed and amplified hormone secretion already stimulated by changes in glucose levels. This mechanistic insight into how intrapancreatic neurons regulate pancreas function challenges canonical models of parasympathetic neurotransmission and is critical to understanding autonomic control of the pancreas. Article Highlights Neurotransmission mechanisms at the final parasympathetic pathway in the pancreas have not been elucidated. We manipulated and recorded neuronal and target cell responses in living pancreatic slices to assess how intrapancreatic neurons affect pancreatic cell function. Activating muscarinic receptor signaling in intrapancreatic neurons was required to trigger exocrine cell activity and modulate endocrine cell secretion. Our findings revise conventional models of parasympathetic neuronal control of pancreatic function.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"11 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903708","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}
Angiotensin II (AngII) activation, a key driver of diabetes pathogenesis and associated complications, induces kidney injury by promoting oxidative stress and inflammation. Ferroptosis is an iron-dependent regulated cell death, playing a crucial role in kidney injury. This study aimed to explore the contribution of ferroptosis to AngII-induced kidney injury and its regulatory mechanisms. Our findings reveal that chronic AngII stimulation leads to renal dysfunction, characterized by elevated serum creatinine levels, increased urinary protein-to-creatinine ratio, and tubular injury. These changes are associated with ferroptosis in renal tubular epithelial cells (TECs) and a marked upregulation of dipeptidase 1 (DPEP1) expression. Notably, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reversed ferroptosis in TECs, restored tubular integrity, and improved renal function. DPEP1 gene silencing and the DPEP1 inhibitor cilastatin significantly inhibited AngII-induced ferroptosis in TECs. Mechanistically, AngII upregulated DPEP1 expression via the transcription factor SP1. Elevated DPEP1 enhanced ubiquitination of SLC3A2, a key cystine/glutathione transporter. Furthermore, inhibiting DPEP1 with cilastatin in a mouse model effectively reversed ferroptosis and alleviated kidney injury. These findings highlight ferroptosis’ key role in AngII-induced kidney injury and suggest DPEP1 targeting as a therapeutic strategy against AngII-driven renal damage. Article Highlights This study investigated the role of ferroptosis in angiotensin II (AngII)-induced kidney injury, addressing a critical gap in understanding AngII-mediated nephropathy mechanisms. We asked whether dipeptidase 1 (DPEP1)-mediated SLC3A2 degradation drives ferroptosis and renal damage under AngII activation. AngII upregulates DPEP1 via SP1, promoting SLC3A2 ubiquitination and glutathione depletion, ultimately triggering tubular ferroptosis. DPEP1 inhibition rescues renal function. Targeting the SP1-DPEP1-SLC3A2 axis offers a novel therapeutic strategy against ferroptosis-dependent kidney injury in hypertension and metabolic disorders.
{"title":"Angiotensin II–Induced Ferroptosis in Epithelial Cells Contributes to Kidney Injury via SP1-DPEP1–Mediated SLC3A2 Degradation","authors":"Yuan Tian, Ge Yang, Qihe Zhang, Chao Dong, Yanru Li, Shuang Lv, Shuang Li, Haiying Zhang, Xin Jiang, Ying Xin","doi":"10.2337/db25-0619","DOIUrl":"https://doi.org/10.2337/db25-0619","url":null,"abstract":"Angiotensin II (AngII) activation, a key driver of diabetes pathogenesis and associated complications, induces kidney injury by promoting oxidative stress and inflammation. Ferroptosis is an iron-dependent regulated cell death, playing a crucial role in kidney injury. This study aimed to explore the contribution of ferroptosis to AngII-induced kidney injury and its regulatory mechanisms. Our findings reveal that chronic AngII stimulation leads to renal dysfunction, characterized by elevated serum creatinine levels, increased urinary protein-to-creatinine ratio, and tubular injury. These changes are associated with ferroptosis in renal tubular epithelial cells (TECs) and a marked upregulation of dipeptidase 1 (DPEP1) expression. Notably, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reversed ferroptosis in TECs, restored tubular integrity, and improved renal function. DPEP1 gene silencing and the DPEP1 inhibitor cilastatin significantly inhibited AngII-induced ferroptosis in TECs. Mechanistically, AngII upregulated DPEP1 expression via the transcription factor SP1. Elevated DPEP1 enhanced ubiquitination of SLC3A2, a key cystine/glutathione transporter. Furthermore, inhibiting DPEP1 with cilastatin in a mouse model effectively reversed ferroptosis and alleviated kidney injury. These findings highlight ferroptosis’ key role in AngII-induced kidney injury and suggest DPEP1 targeting as a therapeutic strategy against AngII-driven renal damage. Article Highlights This study investigated the role of ferroptosis in angiotensin II (AngII)-induced kidney injury, addressing a critical gap in understanding AngII-mediated nephropathy mechanisms. We asked whether dipeptidase 1 (DPEP1)-mediated SLC3A2 degradation drives ferroptosis and renal damage under AngII activation. AngII upregulates DPEP1 via SP1, promoting SLC3A2 ubiquitination and glutathione depletion, ultimately triggering tubular ferroptosis. DPEP1 inhibition rescues renal function. Targeting the SP1-DPEP1-SLC3A2 axis offers a novel therapeutic strategy against ferroptosis-dependent kidney injury in hypertension and metabolic disorders.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"177 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903705","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}
Yoichi Ono, Simone Kennard, Benjamin T. Wall, Jing Ma, Eric J. Belin de Chantemèle
Although control of metabolism by leptin is primarily viewed as centrally mediated, leptin has also been shown to directly regulate adipocyte function. However, the impact of the peripheral effects of leptin on systemic metabolism, especially in the context of obesity, remains unclear. To address this question, we selectively restored adipocyte leptin receptor (LEPR) expression in obese male and female LEPR–conditional knockout mice. Adipocyte LEPR restoration did not affect body weight but selectively increased brown adipose tissue (BAT) mass in male mice. This was associated with increased energy expenditure, smaller BAT adipocytes, lower triglycerides content, and increased markers of browning and lipolysis exclusively in males. Additionally, adipocyte LEPR restoration enhanced the expression of markers of endothelial cells and angiogenesis in male mouse BAT, supporting increased local vascularization. Improved BAT function in males was also associated with lower HbA1c, better insulin sensitivity, reduced systolic blood pressure, decreased arterial stiffness, and improved endothelial function. Lastly, adipocyte LEPR restoration lowered circulating proinflammatory cytokines and reduced tissue inflammation in the aorta and heart, again in males only. These findings reveal a critical role for adipocyte leptin signaling in regulating BAT function and emphasize its importance in maintaining glycemic and cardiovascular health in males with obesity. Article Highlights Leptin is known to enhance brown adipose tissue (BAT) activity through sympathetic stimulation. However, in vitro studies suggest leptin could also act directly on adipocytes to promote lipolysis. Whether these peripheral effects of leptin are relevant to systemic metabolic control in obesity remains unclear. We addressed this question by selectively restoring leptin receptor (LEPR) expression in adipocytes of obese LEPR–conditional knockout mice. LEPR restoration selectively enhanced BAT activity in male mice, which led to improved glycemic control and cardiovascular function. These findings reveal a crucial role for BAT leptin signaling in regulating energy expenditure and glycemic and cardiovascular health, primarily in males.
{"title":"Adipocyte Leptin Signaling Regulates Glycemia and Cardiovascular Function by Enhancing Brown Adipose Tissue Thermogenesis in Obese Male Mice","authors":"Yoichi Ono, Simone Kennard, Benjamin T. Wall, Jing Ma, Eric J. Belin de Chantemèle","doi":"10.2337/db25-0388","DOIUrl":"https://doi.org/10.2337/db25-0388","url":null,"abstract":"Although control of metabolism by leptin is primarily viewed as centrally mediated, leptin has also been shown to directly regulate adipocyte function. However, the impact of the peripheral effects of leptin on systemic metabolism, especially in the context of obesity, remains unclear. To address this question, we selectively restored adipocyte leptin receptor (LEPR) expression in obese male and female LEPR–conditional knockout mice. Adipocyte LEPR restoration did not affect body weight but selectively increased brown adipose tissue (BAT) mass in male mice. This was associated with increased energy expenditure, smaller BAT adipocytes, lower triglycerides content, and increased markers of browning and lipolysis exclusively in males. Additionally, adipocyte LEPR restoration enhanced the expression of markers of endothelial cells and angiogenesis in male mouse BAT, supporting increased local vascularization. Improved BAT function in males was also associated with lower HbA1c, better insulin sensitivity, reduced systolic blood pressure, decreased arterial stiffness, and improved endothelial function. Lastly, adipocyte LEPR restoration lowered circulating proinflammatory cytokines and reduced tissue inflammation in the aorta and heart, again in males only. These findings reveal a critical role for adipocyte leptin signaling in regulating BAT function and emphasize its importance in maintaining glycemic and cardiovascular health in males with obesity. Article Highlights Leptin is known to enhance brown adipose tissue (BAT) activity through sympathetic stimulation. However, in vitro studies suggest leptin could also act directly on adipocytes to promote lipolysis. Whether these peripheral effects of leptin are relevant to systemic metabolic control in obesity remains unclear. We addressed this question by selectively restoring leptin receptor (LEPR) expression in adipocytes of obese LEPR–conditional knockout mice. LEPR restoration selectively enhanced BAT activity in male mice, which led to improved glycemic control and cardiovascular function. These findings reveal a crucial role for BAT leptin signaling in regulating energy expenditure and glycemic and cardiovascular health, primarily in males.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"36 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903707","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}
Current imaging technologies cannot detect diabetic retinopathy until there has been significant permanent damage to patients’ vision. We hypothesized that hyperglycemia causes retinal hypoxia, and hypoxia may lead to apoptosis of retinal cells. We performed experiments using a mouse model of streptozotocin (STZ)-induced diabetes to investigate the role of hyperglycemia in diabetic eye disease. Our experimental results indicate that diabetic retinas are significantly hypoxic compared with nondiabetic controls. Retinal hypoxia can be detected using HYPOX-4, an early-detection imaging probe, potentially before any detectable changes in the diabetic retina. In the early stages of diabetes, we did not observe any detectable changes in electroretinography response, vascular permeability in fluorescein angiography, or retinal thickness in optical coherence tomographic imaging. In addition, increased HYPOX-4 fluorescence in the diabetic retina was not associated with focal ischemia; rather, increased levels of HYPOX-4 fluorescence were observed throughout the entire diabetic retina. Moreover, hypoxia profiles in STZ-induced diabetic retinas were colocalized with TUNEL-positive apoptotic cells. To confirm the role of hyperglycemia in the diabetic retina, human retinal cells were treated under hyperglycemic conditions, and hypoxia was monitored using the pimonidazole-adduct immunostaining method. Surprisingly, retinal cells became hypoxic under hyperglycemic conditions within the first few hours. We conclude that the diabetic retina becomes hypoxic as a result of hyperglycemia in the early stage of diabetes, which could lead to the degeneration of retinal cells at later stages of the disease. In addition, HYPOX-4 could be used as a powerful early diagnostic imaging method to detect retinal hypoxia in the diabetic retina before any detectable retinopathy. ARTICLE HIGHLIGHTS Hyperglycemia causes retinal hypoxia. Hypoxia may lead to apoptosis of retinal cells. Retinal hypoxia can be detected before any detectable changes in the diabetic retina. HYPOX-4 is a powerful early diagnostic imaging method to detect hypoxia in the diabetic retinas of living patients.
{"title":"Imaging Hypoxia in the Diabetic Retina: A Potential Early-Detection Imaging Biomarker Before Detectable Retinopathy in Diabetes","authors":"MD Imam Uddin, Blake Dieckmann, David E. Burgos","doi":"10.2337/db25-0394","DOIUrl":"https://doi.org/10.2337/db25-0394","url":null,"abstract":"Current imaging technologies cannot detect diabetic retinopathy until there has been significant permanent damage to patients’ vision. We hypothesized that hyperglycemia causes retinal hypoxia, and hypoxia may lead to apoptosis of retinal cells. We performed experiments using a mouse model of streptozotocin (STZ)-induced diabetes to investigate the role of hyperglycemia in diabetic eye disease. Our experimental results indicate that diabetic retinas are significantly hypoxic compared with nondiabetic controls. Retinal hypoxia can be detected using HYPOX-4, an early-detection imaging probe, potentially before any detectable changes in the diabetic retina. In the early stages of diabetes, we did not observe any detectable changes in electroretinography response, vascular permeability in fluorescein angiography, or retinal thickness in optical coherence tomographic imaging. In addition, increased HYPOX-4 fluorescence in the diabetic retina was not associated with focal ischemia; rather, increased levels of HYPOX-4 fluorescence were observed throughout the entire diabetic retina. Moreover, hypoxia profiles in STZ-induced diabetic retinas were colocalized with TUNEL-positive apoptotic cells. To confirm the role of hyperglycemia in the diabetic retina, human retinal cells were treated under hyperglycemic conditions, and hypoxia was monitored using the pimonidazole-adduct immunostaining method. Surprisingly, retinal cells became hypoxic under hyperglycemic conditions within the first few hours. We conclude that the diabetic retina becomes hypoxic as a result of hyperglycemia in the early stage of diabetes, which could lead to the degeneration of retinal cells at later stages of the disease. In addition, HYPOX-4 could be used as a powerful early diagnostic imaging method to detect retinal hypoxia in the diabetic retina before any detectable retinopathy. ARTICLE HIGHLIGHTS Hyperglycemia causes retinal hypoxia. Hypoxia may lead to apoptosis of retinal cells. Retinal hypoxia can be detected before any detectable changes in the diabetic retina. HYPOX-4 is a powerful early diagnostic imaging method to detect hypoxia in the diabetic retinas of living patients.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"29 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777593","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}
Fibroblasts play a pivotal role in wound healing, particularly during the proliferative and remodeling phase, where they migrate to the injury site, proliferate, and synthesize essential extracellular matrix (ECM) components such as collagen and fibronectin (FN). However, fibroblast functionality is compromised because of factors such as vascular dysfunction and oxidative stress in diabetic wounds, leading to chronic inflammation and delayed healing. This study investigates the role of mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), a key enzyme in energy metabolism, in regulating fibroblast function during diabetic wound healing. We demonstrate that mGPDH is overexpressed in diabetic wounds and in fibroblasts cultured under high-glucose conditions, contributing to impaired ECM repair. Importantly, the inhibition of mGPDH restores fibroblast functionality by enhancing ECM synthesis, increasing the levels of collagen IV and α-smooth muscle actin (α-SMA) proteins, and accelerating wound healing. Mechanistically, mGPDH deficiency activates the SIRT1–c-Myc–TGF-β1 signaling axis, resulting in reduced c-Myc protein stability, alleviation of its inhibitory effects on TGF-β1 signaling, and subsequent activation of ECM synthesis pathways. This study highlights the role of mGPDH in regulating fibroblast migration and ECM secretion, without affecting apoptosis or proliferation, thereby underscoring its selective regulatory role in wound healing. These findings establish mGPDH as a pivotal regulatory node in fibroblast function during diabetic wound healing, providing a foundation for the development of localized therapeutic strategies aimed at restoring fibroblast activity and improving wound healing outcomes in patients with diabetes. ARTICLE HIGHLIGHTS Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is elevated in diabetic wounds; its inhibition enhances extracellular matrix production and wound closure. mGPDH deficiency activates SIRT1, deacetylating c-Myc to boost TGF-β1 and extracellular matrix production synthesis genes. Targeted mGPDH inhibition can restore fibroblast function and accelerate wound healing in diabetes.
{"title":"Mitochondrial mGPDH Modulates Fibroblast Function in Diabetic Wound Healing via the SIRT1–c-Myc–TGF-β1 Axis","authors":"Ling Zhou, Yue Hong, Xing Li, Yuling Zhang, Linlin Zhang, Guiliang Peng, Hua Qu, Xiaoyu Liao, Mingyu Liao, Yongliang Yang, Liqing Cheng, Weiling Leng, Yanling Zheng, Yanlin Zhang, Hongting Zheng, Min Long","doi":"10.2337/db25-0539","DOIUrl":"https://doi.org/10.2337/db25-0539","url":null,"abstract":"Fibroblasts play a pivotal role in wound healing, particularly during the proliferative and remodeling phase, where they migrate to the injury site, proliferate, and synthesize essential extracellular matrix (ECM) components such as collagen and fibronectin (FN). However, fibroblast functionality is compromised because of factors such as vascular dysfunction and oxidative stress in diabetic wounds, leading to chronic inflammation and delayed healing. This study investigates the role of mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), a key enzyme in energy metabolism, in regulating fibroblast function during diabetic wound healing. We demonstrate that mGPDH is overexpressed in diabetic wounds and in fibroblasts cultured under high-glucose conditions, contributing to impaired ECM repair. Importantly, the inhibition of mGPDH restores fibroblast functionality by enhancing ECM synthesis, increasing the levels of collagen IV and α-smooth muscle actin (α-SMA) proteins, and accelerating wound healing. Mechanistically, mGPDH deficiency activates the SIRT1–c-Myc–TGF-β1 signaling axis, resulting in reduced c-Myc protein stability, alleviation of its inhibitory effects on TGF-β1 signaling, and subsequent activation of ECM synthesis pathways. This study highlights the role of mGPDH in regulating fibroblast migration and ECM secretion, without affecting apoptosis or proliferation, thereby underscoring its selective regulatory role in wound healing. These findings establish mGPDH as a pivotal regulatory node in fibroblast function during diabetic wound healing, providing a foundation for the development of localized therapeutic strategies aimed at restoring fibroblast activity and improving wound healing outcomes in patients with diabetes. ARTICLE HIGHLIGHTS Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is elevated in diabetic wounds; its inhibition enhances extracellular matrix production and wound closure. mGPDH deficiency activates SIRT1, deacetylating c-Myc to boost TGF-β1 and extracellular matrix production synthesis genes. Targeted mGPDH inhibition can restore fibroblast function and accelerate wound healing in diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"4 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765336","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 browning of white adipose tissue (WAT) enhances thermogenesis and represents a promising approach for combating obesity and metabolic disorders. miRNA-494 (miR-494) acts as a suppressor of browning in cultured adipocytes via regulation of peroxisome proliferator–activated receptor γ coactivator 1α, and its inhibition is expected to promote browning and thereby improve obesity and metabolic disorders. To assess its in vivo role and therapeutic potential, we generated miR-494–knockout (KO) mice using CRISPR/Cas9. KO mice showed increased browning of WAT and resistance to high-fat diet–induced obesity. Notably, they also exhibited improved glucose tolerance, even under normal chow feeding conditions without weight loss. Ex vivo analysis revealed enhanced β-adrenergic–stimulated oxidative phosphorylation directly induced by miR-494 deletion. Metabolomic and Seahorse analyses further suggested accelerated glucose metabolism independent of insulin secretion or sensitivity. Analysis of human adipose tissue transcriptomic data supported the association between low miR-494 expression and better glucose tolerance without weight differences. These findings suggest that suppression of miR-494 improves glucose metabolism through both insulin-dependent and insulin-independent mechanisms, independently of changes in body weight. Targeting miR-494 could represent a potential therapeutic strategy for obesity and various forms of diabetes. Article Highlights Browning of white adipose tissue enhances energy expenditure and may improve metabolic health; however, it remains unclear whether inhibition of its suppressor, miRNA-494 (miR-494), can exert therapeutic effects in vivo. We investigated whether genetic deletion of miR-494 expression in vivo promotes adipocyte browning, exerts antiobesity effects, and improves glucose tolerance. miR-494–knockout mice showed resistance to high-fat diet–induced obesity and improved glucose tolerance, even under normal chow feeding conditions. miR-494 inhibition may offer a therapeutic strategy for improving glycemic control through both insulin-dependent and insulin-independent mechanisms, independently of changes in body weight.
{"title":"miR-494 Deletion Improves Glucose Metabolism Independently of Obesity in Mice","authors":"Lucia Sugawara, Katsutaro Morino, Hirotaka Iwasaki, Natsuko Ohashi, Shogo Ida, Koichiro Murata, Tsuyoshi Yanagimachi, Itsuko Miyazawa, Mengistu Lemecha, Takeshi Imamura, Satoshi Ugi, Seiya Mizuno, Satoru Takahashi, Yukihiro Fujita, Hiroshi Maegawa, Shinji Kume","doi":"10.2337/db25-0355","DOIUrl":"https://doi.org/10.2337/db25-0355","url":null,"abstract":"The browning of white adipose tissue (WAT) enhances thermogenesis and represents a promising approach for combating obesity and metabolic disorders. miRNA-494 (miR-494) acts as a suppressor of browning in cultured adipocytes via regulation of peroxisome proliferator–activated receptor γ coactivator 1α, and its inhibition is expected to promote browning and thereby improve obesity and metabolic disorders. To assess its in vivo role and therapeutic potential, we generated miR-494–knockout (KO) mice using CRISPR/Cas9. KO mice showed increased browning of WAT and resistance to high-fat diet–induced obesity. Notably, they also exhibited improved glucose tolerance, even under normal chow feeding conditions without weight loss. Ex vivo analysis revealed enhanced β-adrenergic–stimulated oxidative phosphorylation directly induced by miR-494 deletion. Metabolomic and Seahorse analyses further suggested accelerated glucose metabolism independent of insulin secretion or sensitivity. Analysis of human adipose tissue transcriptomic data supported the association between low miR-494 expression and better glucose tolerance without weight differences. These findings suggest that suppression of miR-494 improves glucose metabolism through both insulin-dependent and insulin-independent mechanisms, independently of changes in body weight. Targeting miR-494 could represent a potential therapeutic strategy for obesity and various forms of diabetes. Article Highlights Browning of white adipose tissue enhances energy expenditure and may improve metabolic health; however, it remains unclear whether inhibition of its suppressor, miRNA-494 (miR-494), can exert therapeutic effects in vivo. We investigated whether genetic deletion of miR-494 expression in vivo promotes adipocyte browning, exerts antiobesity effects, and improves glucose tolerance. miR-494–knockout mice showed resistance to high-fat diet–induced obesity and improved glucose tolerance, even under normal chow feeding conditions. miR-494 inhibition may offer a therapeutic strategy for improving glycemic control through both insulin-dependent and insulin-independent mechanisms, independently of changes in body weight.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"10 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728706","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}
Sharmeen Islam, Xinrui Li, M.D. Nazmul Hossain, Zhongyun Kou, Li-Wei Chen, Jeanene Marie Deavila, Mei-Jun Zhu, Min Du
Forty-two percent of American women of childbearing age are obese, impacting offspring muscle and metabolism. The insulin-like growth factor 2 (IGF2) pathway is vital for muscle growth, but its regulation by maternal obesity (MO) remains unclear. H19, a long noncoding RNA, is reciprocally regulated with Igf2, which has multiple promoters (P0–P3). H19 interacts with EZH2, the catalytic subunit of polycomb repressive complex 2 depositing H3K27me3. We found that MO increased fetal H19 expression and investigated how H19 epigenetically regulates Igf2 in offspring muscle. C57BL/6J female mice were fed a control (10% fat) or high-fat diet (45% fat) to induce obesity before mating, continuing through pregnancy and lactation. Neonates were sampled for biochemical analysis, and 3-month-old offspring were used for assessing muscle function and metabolism. MO increased H19 expression, enhancing H19-EZH2 interaction and H3K27me3-mediated repression of Igf2 in the P3 promoter, leading to hypermethylation and impaired muscle function in offspring. In addition, offspring with myogenic cell-specific H19 overexpression were also used. Weaning offspring with H19 overexpression showed reduced muscle mass, strength, and endurance and altered structure. Primary myogenic cells from H19 overexpressing neonates showed suppressed Igf2 expression, promoter activity, and myotube formation, which were recovered upon IGF2 treatment. In C2C12 and human skeletal myoblast cells, H19 overexpression disrupted IGF2 signaling, increased EZH2 recruitment, and reduced myotube formation, while its knockdown had opposite effects. Additionally, EZH2 inhibition reduced H3K27me3 deposition and methylation in the Igf2 P3 promoter. These data show that MO impairs muscle development by disrupting IGF2 signaling through H19-EZH2 interaction, affecting offspring muscle function. Article Highlights H19-mediated epigenetic modifications alter Igf2 promoter activity, leading to persistent Igf2 suppression in maternal obesity (MO) offspring, causing long-term muscle dysfunction. MO increases H19 expression and enhances EZH2 recruitment and H3K27me3 deposition in the Igf2 P3 promoter, leading to higher DNA methylation. H19-EZH2 axis provides a potential therapeutic target for mitigating MO-induced muscle dysfunction and improving offspring metabolic health.
{"title":"Maternal Obesity Leads to Muscle Dysfunction via H19 -Mediated Programming of Insulin-Like Growth Factor 2 Signaling","authors":"Sharmeen Islam, Xinrui Li, M.D. Nazmul Hossain, Zhongyun Kou, Li-Wei Chen, Jeanene Marie Deavila, Mei-Jun Zhu, Min Du","doi":"10.2337/db25-0271","DOIUrl":"https://doi.org/10.2337/db25-0271","url":null,"abstract":"Forty-two percent of American women of childbearing age are obese, impacting offspring muscle and metabolism. The insulin-like growth factor 2 (IGF2) pathway is vital for muscle growth, but its regulation by maternal obesity (MO) remains unclear. H19, a long noncoding RNA, is reciprocally regulated with Igf2, which has multiple promoters (P0–P3). H19 interacts with EZH2, the catalytic subunit of polycomb repressive complex 2 depositing H3K27me3. We found that MO increased fetal H19 expression and investigated how H19 epigenetically regulates Igf2 in offspring muscle. C57BL/6J female mice were fed a control (10% fat) or high-fat diet (45% fat) to induce obesity before mating, continuing through pregnancy and lactation. Neonates were sampled for biochemical analysis, and 3-month-old offspring were used for assessing muscle function and metabolism. MO increased H19 expression, enhancing H19-EZH2 interaction and H3K27me3-mediated repression of Igf2 in the P3 promoter, leading to hypermethylation and impaired muscle function in offspring. In addition, offspring with myogenic cell-specific H19 overexpression were also used. Weaning offspring with H19 overexpression showed reduced muscle mass, strength, and endurance and altered structure. Primary myogenic cells from H19 overexpressing neonates showed suppressed Igf2 expression, promoter activity, and myotube formation, which were recovered upon IGF2 treatment. In C2C12 and human skeletal myoblast cells, H19 overexpression disrupted IGF2 signaling, increased EZH2 recruitment, and reduced myotube formation, while its knockdown had opposite effects. Additionally, EZH2 inhibition reduced H3K27me3 deposition and methylation in the Igf2 P3 promoter. These data show that MO impairs muscle development by disrupting IGF2 signaling through H19-EZH2 interaction, affecting offspring muscle function. Article Highlights H19-mediated epigenetic modifications alter Igf2 promoter activity, leading to persistent Igf2 suppression in maternal obesity (MO) offspring, causing long-term muscle dysfunction. MO increases H19 expression and enhances EZH2 recruitment and H3K27me3 deposition in the Igf2 P3 promoter, leading to higher DNA methylation. H19-EZH2 axis provides a potential therapeutic target for mitigating MO-induced muscle dysfunction and improving offspring metabolic health.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"3 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lue Ping Zhao, George K. Papadopoulos, Jay S. Skyler, Hemang M. Parikh, William W. Kwok, Terry P. Lybrand, George P. Bondinas, Antonis K. Moustakas, Ruihan Wang, Chul-Woo Pyo, Wyatt C. Nelson, Daniel E. Geraghty, Åke Lernmark
The primary objective of this study was to investigate whether ligand-receptor interactions (LRIs) between IGHG and FCGR gene products are associated with progression to type 1 diabetes (T1D). Using two completed clinical trials (DPT-1 and TN07), we applied next-generation targeted sequencing to genotype IGHG and FCGR genes in a cohort of 1,214 individuals and assessed LRI associations with disease progression. A Cox regression model was used to quantify LRI associations. IGHG or FCGR alone was found to have weak and sporadic associations with progression. Multiple LRIs between IGHG and FCGR gene products were found to be associated with progression, especially LRIs of IGHG2 with multiple FCGR receptors that accelerate progression and those of IGHG4 with multiple FCGR receptors (some overlapping) that delay progression. Furthermore, as several crystal structures of FcγRs complexed with distinct IgG molecules are known, application of this knowledge here was hampered by the absence of any information on the subclass distribution of each of the several T1D-related autoantibodies. It cannot be excluded that their respective state of glycosylation may influence binding affinity to various FcγRs and the function of thus-formed complexes. Our findings suggest that LRIs of the IGHG and FCGR gene products probably influence progression, shedding new insights into some of the immunological mechanisms involved in progression to T1D. Our findings potentially facilitate the search for new immunotherapeutic treatment through intervening at key steps in the progression. Article Highlights This study investigated ligand-receptor interactions (LRIs) between IGHG and FCGR gene products in type 1 diabetes progression. Genes of 1,214 participants from the DPT-1 and TN07 trials were sequenced using next-generation targeted sequencing technology, and LRI associations with the progression time to type 1 diabetes were analyzed using Cox regression modeling. Weak associations were found for IGHG or FCGR variants individually, but multiple LRIs significantly impacted progression. Several IGHG2-FCGR interactions accelerated progression, while a few other IGHG4-FCGR interactions delayed it. The results may provide insights into certain immunogenetic mechanisms of T1D and suggest therapeutic potential of targeting specific LRIs.
{"title":"Profiling Associations Between IGHG-FCGR Ligand-Receptor Interactions and Disease Progression From Stage 1 and 2 to Stage 3 Type 1 Diabetes","authors":"Lue Ping Zhao, George K. Papadopoulos, Jay S. Skyler, Hemang M. Parikh, William W. Kwok, Terry P. Lybrand, George P. Bondinas, Antonis K. Moustakas, Ruihan Wang, Chul-Woo Pyo, Wyatt C. Nelson, Daniel E. Geraghty, Åke Lernmark","doi":"10.2337/db25-0610","DOIUrl":"https://doi.org/10.2337/db25-0610","url":null,"abstract":"The primary objective of this study was to investigate whether ligand-receptor interactions (LRIs) between IGHG and FCGR gene products are associated with progression to type 1 diabetes (T1D). Using two completed clinical trials (DPT-1 and TN07), we applied next-generation targeted sequencing to genotype IGHG and FCGR genes in a cohort of 1,214 individuals and assessed LRI associations with disease progression. A Cox regression model was used to quantify LRI associations. IGHG or FCGR alone was found to have weak and sporadic associations with progression. Multiple LRIs between IGHG and FCGR gene products were found to be associated with progression, especially LRIs of IGHG2 with multiple FCGR receptors that accelerate progression and those of IGHG4 with multiple FCGR receptors (some overlapping) that delay progression. Furthermore, as several crystal structures of FcγRs complexed with distinct IgG molecules are known, application of this knowledge here was hampered by the absence of any information on the subclass distribution of each of the several T1D-related autoantibodies. It cannot be excluded that their respective state of glycosylation may influence binding affinity to various FcγRs and the function of thus-formed complexes. Our findings suggest that LRIs of the IGHG and FCGR gene products probably influence progression, shedding new insights into some of the immunological mechanisms involved in progression to T1D. Our findings potentially facilitate the search for new immunotherapeutic treatment through intervening at key steps in the progression. Article Highlights This study investigated ligand-receptor interactions (LRIs) between IGHG and FCGR gene products in type 1 diabetes progression. Genes of 1,214 participants from the DPT-1 and TN07 trials were sequenced using next-generation targeted sequencing technology, and LRI associations with the progression time to type 1 diabetes were analyzed using Cox regression modeling. Weak associations were found for IGHG or FCGR variants individually, but multiple LRIs significantly impacted progression. Several IGHG2-FCGR interactions accelerated progression, while a few other IGHG4-FCGR interactions delayed it. The results may provide insights into certain immunogenetic mechanisms of T1D and suggest therapeutic potential of targeting specific LRIs.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"169 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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