Marjana Marinac, Michael R. Rickels, Jason L. Gaglia, Philip J. O’Connell, Paul R. Johnson, Lorenzo Piemonti, Bruce S. Schneider, Julia L. Greenstein, Sanjoy Dutta, Esther Latres
Type 1 diabetes results from the immune-mediated loss of insulin-producing pancreatic islet β-cells, rendering those affected dependent on exogenous insulin to survive. Despite the array of choices available for insulin delivery, treatment to maintain near-normal glucose metabolism while avoiding hypo- and hyperglycemia remains a challenge. After two decades of clinical trials across four continents, the transplantation of islets isolated from deceased donor pancreases has been shown to be both safe and efficacious in patients experiencing severe hypoglycemia (level 3) or already requiring immunosuppression to support a kidney transplant, offering a distinct set of advantages to appropriate candidates. We are entering a phase of clinical development where islet β-cell replacement approaches should be recognized and studied as more than just a rescue therapy for those with severe hypoglycemia and could be expanded to all individuals with type 1 diabetes. Our aim is to expedite translation of cellular therapy for all individuals living with type 1 diabetes by focusing on new emerging islet β-cell replacement approaches and proposing clinical trial designs that accelerate their development. As we support expansion of the population to be included in the investigation of novel therapies, this perspective presents a road map and clinical trial considerations to guide the development of the next generations of islet β-cell replacement therapies that address the unmet needs of the broader type 1 diabetes community. ARTICLE HIGHLIGHTS Current research and development are ushering in a new era of novel islet β-cell replacement therapies that can no longer be considered solely a rescue treatment for those with unstable glucose management. Clinical trial design must ensure that the application of islet β-cell replacement is broadened beyond the indication of severe hypoglycemia given the potential for establishing insulin-independent normoglycemia. It is imperative that people with type 1 diabetes and their clinicians are at the center of the risk-benefit equipoise as evidence for the safety of cellular products, transplant sites, and immune protection strategies accumulates and an increasing number of options for intervention become available.
{"title":"Future Directions and Clinical Trial Considerations for Novel Islet β-Cell Replacement Therapies for Type 1 Diabetes","authors":"Marjana Marinac, Michael R. Rickels, Jason L. Gaglia, Philip J. O’Connell, Paul R. Johnson, Lorenzo Piemonti, Bruce S. Schneider, Julia L. Greenstein, Sanjoy Dutta, Esther Latres","doi":"10.2337/dbi24-0037","DOIUrl":"https://doi.org/10.2337/dbi24-0037","url":null,"abstract":"Type 1 diabetes results from the immune-mediated loss of insulin-producing pancreatic islet β-cells, rendering those affected dependent on exogenous insulin to survive. Despite the array of choices available for insulin delivery, treatment to maintain near-normal glucose metabolism while avoiding hypo- and hyperglycemia remains a challenge. After two decades of clinical trials across four continents, the transplantation of islets isolated from deceased donor pancreases has been shown to be both safe and efficacious in patients experiencing severe hypoglycemia (level 3) or already requiring immunosuppression to support a kidney transplant, offering a distinct set of advantages to appropriate candidates. We are entering a phase of clinical development where islet β-cell replacement approaches should be recognized and studied as more than just a rescue therapy for those with severe hypoglycemia and could be expanded to all individuals with type 1 diabetes. Our aim is to expedite translation of cellular therapy for all individuals living with type 1 diabetes by focusing on new emerging islet β-cell replacement approaches and proposing clinical trial designs that accelerate their development. As we support expansion of the population to be included in the investigation of novel therapies, this perspective presents a road map and clinical trial considerations to guide the development of the next generations of islet β-cell replacement therapies that address the unmet needs of the broader type 1 diabetes community. ARTICLE HIGHLIGHTS Current research and development are ushering in a new era of novel islet β-cell replacement therapies that can no longer be considered solely a rescue treatment for those with unstable glucose management. Clinical trial design must ensure that the application of islet β-cell replacement is broadened beyond the indication of severe hypoglycemia given the potential for establishing insulin-independent normoglycemia. It is imperative that people with type 1 diabetes and their clinicians are at the center of the risk-benefit equipoise as evidence for the safety of cellular products, transplant sites, and immune protection strategies accumulates and an increasing number of options for intervention become available.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"108 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639854","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}
Obesity is a major risk factor for the development of type 2 diabetes (T2D). While the connection between these two disease entities is still incompletely understood, even modest weight loss can greatly reduce the risk of developing T2D and its sequelae. With the recent success of antiobesity pharmacotherapies, which appear to exert their effects largely through the brainstem, there has been a resurgent interest in understanding the neural mechanisms governing food intake and body weight. Over the past decade or so, my laboratory has sought to understand the neural control mechanism underlying energy homeostasis, through the lens of a small region in the brainstem, known as the dorsal raphe nucleus (DRN). The DRN is a molecularly heterogeneous structure in the dorsal midbrain, which we have found contains multiple cell types that are capable of regulating food intake and energy expenditure, and consequently, body weight. Here, I detail progress made by our laboratory and others over the past decade in our understanding of the DRN at the molecular, cellular, and circuit levels, with a particular emphasis on the integrative regulation of feeding. This line of research has established the DRN as an important regulator of energy balance and opens up exciting new lines of inquiry into the neural control mechanism governing food intake and body weight. This article is part of a series of perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program. ARTICLE HIGHLIGHTS The dorsal raphe nucleus (DRN) is a key regulator of food intake and body weight. The DRN has historically been associated with feeding, as it houses the single largest population of serotonergic neurons in the mammalian brain. Few studies have demonstrated a direct role for DRN serotonergic neurons in regulating feeding; none of these studies have demonstrated effects near those elicited by serotonin, itself. There are many nonserotonergic cell types in the DRN that play an integral role in feeding. These DRN cell types play important roles in both hunger and satiation.
{"title":"The Dorsal Raphe Nucleus and the Integrative Control of Feeding: A Report on Research Supported by Pathway to Stop Diabetes","authors":"Alexander R. Nectow","doi":"10.2337/dbi24-0015","DOIUrl":"https://doi.org/10.2337/dbi24-0015","url":null,"abstract":"Obesity is a major risk factor for the development of type 2 diabetes (T2D). While the connection between these two disease entities is still incompletely understood, even modest weight loss can greatly reduce the risk of developing T2D and its sequelae. With the recent success of antiobesity pharmacotherapies, which appear to exert their effects largely through the brainstem, there has been a resurgent interest in understanding the neural mechanisms governing food intake and body weight. Over the past decade or so, my laboratory has sought to understand the neural control mechanism underlying energy homeostasis, through the lens of a small region in the brainstem, known as the dorsal raphe nucleus (DRN). The DRN is a molecularly heterogeneous structure in the dorsal midbrain, which we have found contains multiple cell types that are capable of regulating food intake and energy expenditure, and consequently, body weight. Here, I detail progress made by our laboratory and others over the past decade in our understanding of the DRN at the molecular, cellular, and circuit levels, with a particular emphasis on the integrative regulation of feeding. This line of research has established the DRN as an important regulator of energy balance and opens up exciting new lines of inquiry into the neural control mechanism governing food intake and body weight. This article is part of a series of perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program. ARTICLE HIGHLIGHTS The dorsal raphe nucleus (DRN) is a key regulator of food intake and body weight. The DRN has historically been associated with feeding, as it houses the single largest population of serotonergic neurons in the mammalian brain. Few studies have demonstrated a direct role for DRN serotonergic neurons in regulating feeding; none of these studies have demonstrated effects near those elicited by serotonin, itself. There are many nonserotonergic cell types in the DRN that play an integral role in feeding. These DRN cell types play important roles in both hunger and satiation.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"3 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639869","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}
Until recently, the prevalence of endogenous Cushing syndrome has been considered to be low. However, improved diagnostic strategies and increased awareness have broadened our understanding of hypercortisolism and its role in the pathophysiology of type 2 diabetes, obesity, hypertension, and cardiovascular disease. Recent studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with difficult-to-control type 2 diabetes, despite treatment with multiple glucose-lowering agents, have hypercortisolism as a causative factor in their poorly managed diabetes. In this review, we examine the pathophysiologic mechanisms via which excess cortisol contributes to the impairment in glucose homeostasis and recommend that hypercortisolism be added to the Ominous Octet to form the Noxious Nine as the pathophysiologic foundation for the development of type 2 diabetes. ARTICLE HIGHLIGHTS Hypercortisolism as a causative factor in the development of type 2 diabetes has received scant attention. Studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with poorly managed type 2 diabetes, despite treatment with multiple glucose-lowering agents, have endogenous hypersecretion of cortisol as a causative factor for their hyperglycemia. In vivo and in vitro studies in animals and humans have demonstrated that excess exposure to glucocorticoids can promote insulin resistance in muscle, liver, and adipocytes and impair insulin secretion. We propose a reverberating cycle in which hypercortisolism disrupts the normal circadian rhythm causing insulin resistance and hyperinsulinemia, which in turn further disrupts the hypothalamic-pituitary-adrenal axis.
{"title":"Cushing Syndrome, Hypercortisolism, and Glucose Homeostasis: A Review","authors":"Ralph A. DeFronzo, Richard J. Auchus","doi":"10.2337/db25-0120","DOIUrl":"https://doi.org/10.2337/db25-0120","url":null,"abstract":"Until recently, the prevalence of endogenous Cushing syndrome has been considered to be low. However, improved diagnostic strategies and increased awareness have broadened our understanding of hypercortisolism and its role in the pathophysiology of type 2 diabetes, obesity, hypertension, and cardiovascular disease. Recent studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with difficult-to-control type 2 diabetes, despite treatment with multiple glucose-lowering agents, have hypercortisolism as a causative factor in their poorly managed diabetes. In this review, we examine the pathophysiologic mechanisms via which excess cortisol contributes to the impairment in glucose homeostasis and recommend that hypercortisolism be added to the Ominous Octet to form the Noxious Nine as the pathophysiologic foundation for the development of type 2 diabetes. ARTICLE HIGHLIGHTS Hypercortisolism as a causative factor in the development of type 2 diabetes has received scant attention. Studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with poorly managed type 2 diabetes, despite treatment with multiple glucose-lowering agents, have endogenous hypersecretion of cortisol as a causative factor for their hyperglycemia. In vivo and in vitro studies in animals and humans have demonstrated that excess exposure to glucocorticoids can promote insulin resistance in muscle, liver, and adipocytes and impair insulin secretion. We propose a reverberating cycle in which hypercortisolism disrupts the normal circadian rhythm causing insulin resistance and hyperinsulinemia, which in turn further disrupts the hypothalamic-pituitary-adrenal axis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"2 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639860","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}
Sarcopenic obesity, a subtype of obesity, is marked by reduced skeletal muscle mass and function, or sarcopenia, and poses a significant health challenge to older adults as it affects an estimated 28.3% of people aged >60 years. This subtype is unique to older adults as aging exacerbates sarcopenia and obesity due to changes in energy metabolism, hormones and inflammatory markers, and lifestyle factors. Traditional treatments for sarcopenic obesity have been focused on exercise and dietary modifications to reduce fat while maintaining muscle mass. Newer glucagon-like peptide 1 receptor agonists (GLP-1RA) and dual gastric inhibitory polypeptide/GLP-1 receptor agonists (GIP/GLP-1RAs), including liraglutide, semaglutide, and tirzepatide, have shown great promise to reduce weight, treat obesity-related complications, improve physical function, and improve quality of life, in younger clinical trial populations. However, the use of GLP-1RAs and GIP/GLP-1RAs has not been exhaustively evaluated in older adults with sarcopenic obesity. These medications come with the risk of loss of muscle mass and an increased rate of adverse events. Thus, clinicians should use them cautiously by weighing the potential benefits against their risks. Herein, we discuss a possible approach to using GLP-1RAs and GIP/GLP-1RAs in patients with sarcopenic obesity, including considerations for patient identification, monitoring, maintenance, and discontinuation. In this article we also discuss the emerging treatments that will be available, which may include activin type II receptor antibodies and selective androgen receptor agonists. We conclude by highlighting the advancement of geroscience as a promising field for individualizing treatments in the future. Article Highlights Sarcopenic obesity, reduced muscle mass and strength coupled with obesity, poses significant health risks to older adults. Aging exacerbates sarcopenia and obesity due to metabolic, hormonal, inflammatory, and lifestyle changes. Traditional interventions emphasize exercise and diet to reduce fat mass while preserving muscle mass. Incretin therapies show promise in weight reduction and physical improvement in younger populations but are minimally studied in older adults. These medications can be used to treat several obesity-related complications, which older adults with sarcopenic obesity are prone to developing. These medications need to be used cautiously among older adults, considering potential muscle mass loss and adverse events.
{"title":"Treating Sarcopenic Obesity in the Era of Incretin Therapies: Perspectives and Challenges","authors":"Alissa S. Chen, John A. Batsis","doi":"10.2337/dbi25-0004","DOIUrl":"https://doi.org/10.2337/dbi25-0004","url":null,"abstract":"Sarcopenic obesity, a subtype of obesity, is marked by reduced skeletal muscle mass and function, or sarcopenia, and poses a significant health challenge to older adults as it affects an estimated 28.3% of people aged >60 years. This subtype is unique to older adults as aging exacerbates sarcopenia and obesity due to changes in energy metabolism, hormones and inflammatory markers, and lifestyle factors. Traditional treatments for sarcopenic obesity have been focused on exercise and dietary modifications to reduce fat while maintaining muscle mass. Newer glucagon-like peptide 1 receptor agonists (GLP-1RA) and dual gastric inhibitory polypeptide/GLP-1 receptor agonists (GIP/GLP-1RAs), including liraglutide, semaglutide, and tirzepatide, have shown great promise to reduce weight, treat obesity-related complications, improve physical function, and improve quality of life, in younger clinical trial populations. However, the use of GLP-1RAs and GIP/GLP-1RAs has not been exhaustively evaluated in older adults with sarcopenic obesity. These medications come with the risk of loss of muscle mass and an increased rate of adverse events. Thus, clinicians should use them cautiously by weighing the potential benefits against their risks. Herein, we discuss a possible approach to using GLP-1RAs and GIP/GLP-1RAs in patients with sarcopenic obesity, including considerations for patient identification, monitoring, maintenance, and discontinuation. In this article we also discuss the emerging treatments that will be available, which may include activin type II receptor antibodies and selective androgen receptor agonists. We conclude by highlighting the advancement of geroscience as a promising field for individualizing treatments in the future. Article Highlights Sarcopenic obesity, reduced muscle mass and strength coupled with obesity, poses significant health risks to older adults. Aging exacerbates sarcopenia and obesity due to metabolic, hormonal, inflammatory, and lifestyle changes. Traditional interventions emphasize exercise and diet to reduce fat mass while preserving muscle mass. Incretin therapies show promise in weight reduction and physical improvement in younger populations but are minimally studied in older adults. These medications can be used to treat several obesity-related complications, which older adults with sarcopenic obesity are prone to developing. These medications need to be used cautiously among older adults, considering potential muscle mass loss and adverse events.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"12 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611138","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 prevalence of prediabetes is increasing globally, driven by rising obesity rates. Prediabetes increases the risk of neurodegenerative diseases, which are linked by neuroinflammation. Protein tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. However, the role and underlying mechanisms of PTP1B in prediabetes-induced cognitive impairment remain poorly understood. Here, we observed elevated levels of PTP1B in the serum of individuals with obesity and prediabetes. In mouse model of obesity and prediabetes induced by a high-fat, high-sugar diet (HFHSD), the PTP1B level was significantly increased in the hippocampus, correlating with cognitive decline, microglial activation, and inflammatory response. In a series of mouse models with selective PTP1B deletion, the loss of PTP1B in the hippocampus, hippocampal neurons, and leptin receptor–expressing cells reversed impairments of hippocampal leptin synaptic signaling, synaptic ultrastructure and associated proteins, and cognitive function in HFHSD-fed prediabetic mice. In a palmitic acid-induced, prediabetic, hippocampal neuronal model, genetic knockout or pharmacological inhibition of PTP1B effectively restored synaptic signaling and neurite outgrowth. These findings underscore the critical role of hippocampal neuronal PTP1B in mediating impairments of synaptic signaling leading to cognitive decline in prediabetes and suggest its significant therapeutic potential in addressing neurodegeneration. Article Highlights The present study reveals a previously unknown molecular mechanism linking prediabetes to neurodegeneration, addressing a critical gap in understanding metabolic-neurological interplay. We investigated whether PTP1B mediates prediabetes-induced cognitive impairment. PTP1B impaired synaptic signaling and synaptic ultrastructure in hippocampal neurons, contributing to cognitive decline in prediabetes. PTP1B is a novel therapeutic target for prediabetes-associated neurodegeneration.
{"title":"Reducing PTP1B in the Hippocampus Protects Against Cognitive Decline in Prediabetes","authors":"Menglu Zhou, Xiaoying Yang, Xing Ge, Jiajia Chen, Wanyun Wu, Mingxuan Zheng, Xiaocheng Zhu, Xiaoying Cui, Renxian Tang, Kuiyang Zheng, Xu-Feng Huang, Libin Yao, Yinghua Yu","doi":"10.2337/db24-1167","DOIUrl":"https://doi.org/10.2337/db24-1167","url":null,"abstract":"The prevalence of prediabetes is increasing globally, driven by rising obesity rates. Prediabetes increases the risk of neurodegenerative diseases, which are linked by neuroinflammation. Protein tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. However, the role and underlying mechanisms of PTP1B in prediabetes-induced cognitive impairment remain poorly understood. Here, we observed elevated levels of PTP1B in the serum of individuals with obesity and prediabetes. In mouse model of obesity and prediabetes induced by a high-fat, high-sugar diet (HFHSD), the PTP1B level was significantly increased in the hippocampus, correlating with cognitive decline, microglial activation, and inflammatory response. In a series of mouse models with selective PTP1B deletion, the loss of PTP1B in the hippocampus, hippocampal neurons, and leptin receptor–expressing cells reversed impairments of hippocampal leptin synaptic signaling, synaptic ultrastructure and associated proteins, and cognitive function in HFHSD-fed prediabetic mice. In a palmitic acid-induced, prediabetic, hippocampal neuronal model, genetic knockout or pharmacological inhibition of PTP1B effectively restored synaptic signaling and neurite outgrowth. These findings underscore the critical role of hippocampal neuronal PTP1B in mediating impairments of synaptic signaling leading to cognitive decline in prediabetes and suggest its significant therapeutic potential in addressing neurodegeneration. Article Highlights The present study reveals a previously unknown molecular mechanism linking prediabetes to neurodegeneration, addressing a critical gap in understanding metabolic-neurological interplay. We investigated whether PTP1B mediates prediabetes-induced cognitive impairment. PTP1B impaired synaptic signaling and synaptic ultrastructure in hippocampal neurons, contributing to cognitive decline in prediabetes. PTP1B is a novel therapeutic target for prediabetes-associated neurodegeneration.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"35 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602898","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}
Ryota Inoue, Takahiro Tsuno, Takashi Nishimura, Setsuko Fukushima, Sayaka Hirai, Masayuki Shimoda, Yuto Yoshinari, Chisato Sakai, Tatsuya Kin, Euodia X. I. Hui Lim, Adrian Kee Keong Teo, Shinichi Matsumoto, A. M. James Shapiro, Jun Shirakawa
Imeglimin, a drug for type 2 diabetes, reportedly promotes β-cell proliferation and increases β-cell survival; however, the detailed underlying molecular mechanism remains unclear. Here, we investigated metabolites in pancreatic islets after imeglimin treatment via liquid chromatography with tandem mass spectrometry. Treatment with imeglimin for 1 h significantly altered the levels of 17 metabolites at 5.6 mmol/L glucose and 11 metabolites at 11.1 mmol/L glucose. After 24 h of treatment, imeglimin changed the levels of 12 metabolites at 5.6 mmol/L glucose and 28 metabolites at 11.1 mmol/L glucose. The metabolites altered by imeglimin under high-glucose conditions were involved in NAD synthesis, amino acid metabolism, and nucleic acid metabolism. Adenylosuccinate (S-AMP), produced by adenylosuccinate synthase (ADSS) from inosine monophosphate (IMP) and aspartate, increased 2.98-fold after treatment with imeglimin. The levels of IMP and aspartate and both the mRNA and protein levels of ADSS were elevated following imeglimin treatment in islets. Alanosine, an inhibitor of ADSS, suppressed imeglimin-induced β-cell proliferation and survival in mouse islets, human islets, human pluripotent stem cell–derived β-cells, and porcine islets. Taken together, these findings suggest that chronic treatment with imeglimin promotes β-cell proliferation and survival partly through an increase in S-AMP production. Article Highlights Although imeglimin promotes β-cell proliferation and ameliorates β-cell apoptosis, the detailed metabolic changes induced by imeglimin in β-cells are unknown. Imeglimin increases adenylosuccinate (S-AMP), which is produced by adenylosuccinate synthase (ADSS) from inosine monophosphate and aspartate, and imeglimin also increases amino acid content, including aspartate, in mouse islets. Inhibition of S-AMP production by an ADSS inhibitor reduces the ability of imeglimin to increase β-cell proliferation and ameliorate β-cell apoptosis in mouse islets, human islets, porcine islets, and human pluripotent stem cell–derived β-cells. Imeglimin increases S-AMP to promote β-cell proliferation and ameliorate β-cell apoptosis.
{"title":"Adenylosuccinate Mediates Imeglimin-Induced Proliferative and Antiapoptotic Effects in β-Cells","authors":"Ryota Inoue, Takahiro Tsuno, Takashi Nishimura, Setsuko Fukushima, Sayaka Hirai, Masayuki Shimoda, Yuto Yoshinari, Chisato Sakai, Tatsuya Kin, Euodia X. I. Hui Lim, Adrian Kee Keong Teo, Shinichi Matsumoto, A. M. James Shapiro, Jun Shirakawa","doi":"10.2337/db24-1090","DOIUrl":"https://doi.org/10.2337/db24-1090","url":null,"abstract":"Imeglimin, a drug for type 2 diabetes, reportedly promotes β-cell proliferation and increases β-cell survival; however, the detailed underlying molecular mechanism remains unclear. Here, we investigated metabolites in pancreatic islets after imeglimin treatment via liquid chromatography with tandem mass spectrometry. Treatment with imeglimin for 1 h significantly altered the levels of 17 metabolites at 5.6 mmol/L glucose and 11 metabolites at 11.1 mmol/L glucose. After 24 h of treatment, imeglimin changed the levels of 12 metabolites at 5.6 mmol/L glucose and 28 metabolites at 11.1 mmol/L glucose. The metabolites altered by imeglimin under high-glucose conditions were involved in NAD synthesis, amino acid metabolism, and nucleic acid metabolism. Adenylosuccinate (S-AMP), produced by adenylosuccinate synthase (ADSS) from inosine monophosphate (IMP) and aspartate, increased 2.98-fold after treatment with imeglimin. The levels of IMP and aspartate and both the mRNA and protein levels of ADSS were elevated following imeglimin treatment in islets. Alanosine, an inhibitor of ADSS, suppressed imeglimin-induced β-cell proliferation and survival in mouse islets, human islets, human pluripotent stem cell–derived β-cells, and porcine islets. Taken together, these findings suggest that chronic treatment with imeglimin promotes β-cell proliferation and survival partly through an increase in S-AMP production. Article Highlights Although imeglimin promotes β-cell proliferation and ameliorates β-cell apoptosis, the detailed metabolic changes induced by imeglimin in β-cells are unknown. Imeglimin increases adenylosuccinate (S-AMP), which is produced by adenylosuccinate synthase (ADSS) from inosine monophosphate and aspartate, and imeglimin also increases amino acid content, including aspartate, in mouse islets. Inhibition of S-AMP production by an ADSS inhibitor reduces the ability of imeglimin to increase β-cell proliferation and ameliorate β-cell apoptosis in mouse islets, human islets, porcine islets, and human pluripotent stem cell–derived β-cells. Imeglimin increases S-AMP to promote β-cell proliferation and ameliorate β-cell apoptosis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"22 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603078","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}
Xuan Ren, Gaobo Zhang, Boqian Zhou, Wenting Gu, Xue Jiang, Hongen Liao, Meng-Xing Tang, Xin Liu
Microvasculature and hemodynamic changes in the cerebrovascular system are valuable indicators for the investigation of diabetic cerebrovascular disease. However, it is challenging for conventional imaging techniques to capture these minute features, meaning that the specific effects of diabetes on the brain vasculature and its potential disruption of brain function remain inadequately investigated. Ultrasound localization microscopy, with its unprecedented subdiffraction resolution and microvascular sensitivity, enables previously unobserved subtle variations to be revealed. Here, we aimed to leverage this advanced imaging technology to explore the alterations of brain in a diabetic rodent model in vivo. Parallel comparisons were made between diabetic rats and age-matched controls, and longitudinal assessments were performed before and after development of diabetes. In parallel comparisons, we found that rats with diabetes had significantly reduced vascular density in several key brain regions, including the striatum (13.70%), basal forebrain (8.48%), thalamus (12.20%), hypothalamus (20.85%), and hippocampus (8.73%). These findings were further supported by vascular staining and high-field MRI results. In addition, we demonstrated that a slowing of blood flow could be observed in the above brain regions. These results pave the way to understanding the effects of diabetes on the cerebral vasculature and may enable the future development of therapeutic and intervention strategies for diabetic cerebrovascular lesions. ARTICLE HIGHLIGHTS Cerebral microvascular disease can be triggered in people with diabetes who have chronic hyperglycemia. The aim of our study was to understand what effect diabetes has on the cerebral vasculature. In a rodent model, diabetes caused varying degrees of reduced cerebral vascular density and slowed cerebral blood flow in the brain striatum, basal forebrain, thalamus, hypothalamus, and hippocampus. There is a correlation between vessel density and blood flow velocity and the correlation changes in the diabetic state.
{"title":"Revealing Cerebral Microvascular Changes in Diabetic Rodents With Ultrasound Localization Microscopy","authors":"Xuan Ren, Gaobo Zhang, Boqian Zhou, Wenting Gu, Xue Jiang, Hongen Liao, Meng-Xing Tang, Xin Liu","doi":"10.2337/db25-0007","DOIUrl":"https://doi.org/10.2337/db25-0007","url":null,"abstract":"Microvasculature and hemodynamic changes in the cerebrovascular system are valuable indicators for the investigation of diabetic cerebrovascular disease. However, it is challenging for conventional imaging techniques to capture these minute features, meaning that the specific effects of diabetes on the brain vasculature and its potential disruption of brain function remain inadequately investigated. Ultrasound localization microscopy, with its unprecedented subdiffraction resolution and microvascular sensitivity, enables previously unobserved subtle variations to be revealed. Here, we aimed to leverage this advanced imaging technology to explore the alterations of brain in a diabetic rodent model in vivo. Parallel comparisons were made between diabetic rats and age-matched controls, and longitudinal assessments were performed before and after development of diabetes. In parallel comparisons, we found that rats with diabetes had significantly reduced vascular density in several key brain regions, including the striatum (13.70%), basal forebrain (8.48%), thalamus (12.20%), hypothalamus (20.85%), and hippocampus (8.73%). These findings were further supported by vascular staining and high-field MRI results. In addition, we demonstrated that a slowing of blood flow could be observed in the above brain regions. These results pave the way to understanding the effects of diabetes on the cerebral vasculature and may enable the future development of therapeutic and intervention strategies for diabetic cerebrovascular lesions. ARTICLE HIGHLIGHTS Cerebral microvascular disease can be triggered in people with diabetes who have chronic hyperglycemia. The aim of our study was to understand what effect diabetes has on the cerebral vasculature. In a rodent model, diabetes caused varying degrees of reduced cerebral vascular density and slowed cerebral blood flow in the brain striatum, basal forebrain, thalamus, hypothalamus, and hippocampus. There is a correlation between vessel density and blood flow velocity and the correlation changes in the diabetic state.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"153 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593908","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}
Ewan R. Pearson, Stefano Del Prato, Imre Pavo, Denise R. Franco, Junyuan Zheng, Claudia Nicolay, Andrea Hemmingway, Russell J. Wiese, Steven E. Kahn
This post hoc analysis assessed sustainability of lowered glycated hemoglobin (HbA1c) and weight with tirzepatide in people with type 2 diabetes and increased cardiovascular risk. Participants achieving HbA1c ≤48 mmol/mol (6.5%) or weight loss ≥10% at 52 weeks were evaluated for sustained glycemic or weight control and predictors of initial and sustained efficacy. For tirzepatide-treated participants achieving HbA1c ≤48 mmol/mol (6.5%) at 52 weeks, 75–84% sustained this until study end (median 81 weeks). Factors predicting achievement were higher tirzepatide dose, shorter diabetes duration, and lower HbA1c, higher HOMA of β-cell function (HOMA-B), metformin alone, and absence of albuminuria at baseline. Factors predicting sustained glycemic control were greater weight loss, smaller fasting glucose decrease, no sulfonylurea, and higher HOMA-B at 52 weeks. For participants achieving ≥10% weight loss at 52 weeks, 79–82% maintained weight loss. Factors predicting achievement were higher tirzepatide dose, female sex, no cardiovascular disease history, and lower baseline HbA1c, estimated glomerular filtration rate, and triglycerides. Greater decrease in LDL-cholesterol to 52 weeks predicted maintained weight loss. Greater weight loss and better β-cell function achieved with tirzepatide were the main predictors for sustained glycemic control in this post hoc analysis; no clinically meaningful predictor was identified for sustained weight control. Article Highlights We aimed to explore sustainability of lowered glycated hemoglobin (HbA1c) and weight with tirzepatide in a post hoc analysis. The question we wanted to answer was what predicted achieving and sustaining HbA1c and weight reduction in A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4). We found greater weight loss and improved β-cell function were the main predictors for sustained glycemic control with tirzepatide therapy. No clinically relevant predictor was identified for sustained weight loss. Simple clinical measures may predict initial and sustained glycemic control and initial weight loss with tirzepatide.
{"title":"Predictors of Initial and Sustained Glycemic and Weight Response to Tirzepatide: A Post Hoc Analysis of SURPASS-4","authors":"Ewan R. Pearson, Stefano Del Prato, Imre Pavo, Denise R. Franco, Junyuan Zheng, Claudia Nicolay, Andrea Hemmingway, Russell J. Wiese, Steven E. Kahn","doi":"10.2337/db25-0276","DOIUrl":"https://doi.org/10.2337/db25-0276","url":null,"abstract":"This post hoc analysis assessed sustainability of lowered glycated hemoglobin (HbA1c) and weight with tirzepatide in people with type 2 diabetes and increased cardiovascular risk. Participants achieving HbA1c ≤48 mmol/mol (6.5%) or weight loss ≥10% at 52 weeks were evaluated for sustained glycemic or weight control and predictors of initial and sustained efficacy. For tirzepatide-treated participants achieving HbA1c ≤48 mmol/mol (6.5%) at 52 weeks, 75–84% sustained this until study end (median 81 weeks). Factors predicting achievement were higher tirzepatide dose, shorter diabetes duration, and lower HbA1c, higher HOMA of β-cell function (HOMA-B), metformin alone, and absence of albuminuria at baseline. Factors predicting sustained glycemic control were greater weight loss, smaller fasting glucose decrease, no sulfonylurea, and higher HOMA-B at 52 weeks. For participants achieving ≥10% weight loss at 52 weeks, 79–82% maintained weight loss. Factors predicting achievement were higher tirzepatide dose, female sex, no cardiovascular disease history, and lower baseline HbA1c, estimated glomerular filtration rate, and triglycerides. Greater decrease in LDL-cholesterol to 52 weeks predicted maintained weight loss. Greater weight loss and better β-cell function achieved with tirzepatide were the main predictors for sustained glycemic control in this post hoc analysis; no clinically meaningful predictor was identified for sustained weight control. Article Highlights We aimed to explore sustainability of lowered glycated hemoglobin (HbA1c) and weight with tirzepatide in a post hoc analysis. The question we wanted to answer was what predicted achieving and sustaining HbA1c and weight reduction in A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4). We found greater weight loss and improved β-cell function were the main predictors for sustained glycemic control with tirzepatide therapy. No clinically relevant predictor was identified for sustained weight loss. Simple clinical measures may predict initial and sustained glycemic control and initial weight loss with tirzepatide.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"11 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593906","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}
Stephanie K. Holm, Valdemar B. I. Johansen, Pablo Ranea-Robles, Charlotte Svendsen, Christoffer Merrild, Rebecca Rohlfs, Mauro Lo Conte, Wouter F. J. Hogendorf, Myrte Merkestein, Alexander N. Zaykov, Andreas M. Fritzen, Bharath K. Mani, Christoffer Clemmensen
The recent identification of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous antagonist and inverse agonist of the growth hormone secretagogue receptor (GHSR) has revived interest in targeting the ghrelin-GHSR pathway for obesity treatment. Here, we assessed the preclinical efficacy of treatment with a long-acting LEAP2 (LA-LEAP2) analog for weight loss and explored its potential as an adjunct to semaglutide to enhance weight reduction and mitigate weight regain. We found that LA-LEAP2 lowered body weight in obese mice, which was reflected in reduced energy intake and preserved energy expenditure. While not uniformly observed across all experiments, some studies demonstrated superior weight reduction with the combination of LA-LEAP2 and semaglutide compared with semaglutide monotherapy. Notably, the combination also attenuated weight regain more effectively than semaglutide alone. Importantly, no signs of discomfort or behavioral aversion were detected following LA-LEAP2 administration. Collectively, these data indicate that LEAP2 analogs have the potential to enhance the efficacy of glucagon-like peptide 1 receptor agonism and support durable weight loss. ARTICLE HIGHLIGHTS Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous ghrelin receptor (GHSR) antagonist and inverse agonist, and represents a novel strategy to modulate the GHSR system for treatment of cardiometabolic disease. A long-acting LEAP2 (LA-LEAP2) analog induces significant weight reduction in rodent models without causing aversion. LA-LEAP2–mediated weight loss is driven by decreased energy intake alongside preservation of energy expenditure during weight loss. Combined LA-LEAP2 and semaglutide therapy supports durable weight loss, addressing a critical gap in obesity treatment.
{"title":"Sustained Weight Loss With Combined LEAP2 and Semaglutide Treatment in Mice","authors":"Stephanie K. Holm, Valdemar B. I. Johansen, Pablo Ranea-Robles, Charlotte Svendsen, Christoffer Merrild, Rebecca Rohlfs, Mauro Lo Conte, Wouter F. J. Hogendorf, Myrte Merkestein, Alexander N. Zaykov, Andreas M. Fritzen, Bharath K. Mani, Christoffer Clemmensen","doi":"10.2337/db24-1056","DOIUrl":"https://doi.org/10.2337/db24-1056","url":null,"abstract":"The recent identification of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous antagonist and inverse agonist of the growth hormone secretagogue receptor (GHSR) has revived interest in targeting the ghrelin-GHSR pathway for obesity treatment. Here, we assessed the preclinical efficacy of treatment with a long-acting LEAP2 (LA-LEAP2) analog for weight loss and explored its potential as an adjunct to semaglutide to enhance weight reduction and mitigate weight regain. We found that LA-LEAP2 lowered body weight in obese mice, which was reflected in reduced energy intake and preserved energy expenditure. While not uniformly observed across all experiments, some studies demonstrated superior weight reduction with the combination of LA-LEAP2 and semaglutide compared with semaglutide monotherapy. Notably, the combination also attenuated weight regain more effectively than semaglutide alone. Importantly, no signs of discomfort or behavioral aversion were detected following LA-LEAP2 administration. Collectively, these data indicate that LEAP2 analogs have the potential to enhance the efficacy of glucagon-like peptide 1 receptor agonism and support durable weight loss. ARTICLE HIGHLIGHTS Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous ghrelin receptor (GHSR) antagonist and inverse agonist, and represents a novel strategy to modulate the GHSR system for treatment of cardiometabolic disease. A long-acting LEAP2 (LA-LEAP2) analog induces significant weight reduction in rodent models without causing aversion. LA-LEAP2–mediated weight loss is driven by decreased energy intake alongside preservation of energy expenditure during weight loss. Combined LA-LEAP2 and semaglutide therapy supports durable weight loss, addressing a critical gap in obesity treatment.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"66 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533064","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}
Nicole Sheanon, Shana O. Warner, Yufei Dai, Nat H. Whitsett, Shahriar Arbabi, Blair Hoeting, Shailendra B. Patel, Diana Lindquist, Jason J. Winnick
Short-term fasting (<24 h) is common in individuals with type 1 diabetes (T1D), but it is associated with increased risk of hypoglycemia. Current strategies to mitigate this risk include changing the timing and/or dose of insulin; however, it is unclear whether counterregulatory hormone secretion is diminished, which would also contribute to this elevated risk. The current experiments were conducted to determine whether short-term fasting affects the hormonal and hepatic responses to insulin-induced hypoglycemia in those with T1D. Nine C-peptide–negative individuals with T1D gave their informed consent to participate in a randomly assigned crossover-design metabolic trial. In one study, participants ate an isocaloric breakfast and lunch before undergoing a hyperinsulinemic/hypoglycemic metabolic challenge in the evening (FED); in the other, they fasted before the hypoglycemic challenge (FAST). Immediately before insulin-induced hypoglycemia, glucagon concentrations were 43% lower in FAST compared with FED (31 ± 5 and 54 ± 6 pg/mL, respectively; P < 0.001), and endogenous glucose production (EGP) was 28% lower (3.4 ± 0.2 and 4.6 ± 0.3 mg/kg/min, respectively; P < 0.01). During insulin-induced hypoglycemia, the area under the curve for glucagon remained lower by 42% in FAST compared with FED (1,598 ± 229 and 2,768 ± 422 pg/mL ∗ 60 min, respectively; P < 0.01), as did EGP (41 ± 4 and 78 ± 12 mg/kg ∗ 60 min, respectively; P = 0.01). These data demonstrate that fasting lowers glucagon concentrations and EGP under euglycemic/normoinsulinemic metabolic conditions and during insulin-induced hypoglycemia. This reduction in metabolic flexibility, in addition to hyperinsulinemia, enhances susceptibility to fasting-induced low blood glucose in individuals with T1D and should be considered when developing strategies to avoid hypoglycemia. Article Highlights Fasting is associated with increased risk of hypoglycemia in patients with type 1 diabetes (T1D); however, little is known about how the counterregulatory responses to low blood sugar are affected under these metabolic conditions. During insulin-induced hypoglycemia, fasting (compared with eating normal meals for breakfast and lunch) glucagon concentrations were lower by 42% and endogenous glucose production by 47% in individuals with T1D. The secretion of other counterregulatory hormones during hypoglycemia was not affected by fasting (e.g., epinephrine, norepinephrine, cortisol). Fasting diminishes glucagon levels under hypoglycemic conditions in those with T1D, which may increase their susceptibility to hypoglycemia.
{"title":"Fasting Lowers Glucagon Levels Under Basal Conditions and During Insulin-Induced Hypoglycemia in Individuals With Type 1 Diabetes","authors":"Nicole Sheanon, Shana O. Warner, Yufei Dai, Nat H. Whitsett, Shahriar Arbabi, Blair Hoeting, Shailendra B. Patel, Diana Lindquist, Jason J. Winnick","doi":"10.2337/db25-0251","DOIUrl":"https://doi.org/10.2337/db25-0251","url":null,"abstract":"Short-term fasting (&lt;24 h) is common in individuals with type 1 diabetes (T1D), but it is associated with increased risk of hypoglycemia. Current strategies to mitigate this risk include changing the timing and/or dose of insulin; however, it is unclear whether counterregulatory hormone secretion is diminished, which would also contribute to this elevated risk. The current experiments were conducted to determine whether short-term fasting affects the hormonal and hepatic responses to insulin-induced hypoglycemia in those with T1D. Nine C-peptide–negative individuals with T1D gave their informed consent to participate in a randomly assigned crossover-design metabolic trial. In one study, participants ate an isocaloric breakfast and lunch before undergoing a hyperinsulinemic/hypoglycemic metabolic challenge in the evening (FED); in the other, they fasted before the hypoglycemic challenge (FAST). Immediately before insulin-induced hypoglycemia, glucagon concentrations were 43% lower in FAST compared with FED (31 ± 5 and 54 ± 6 pg/mL, respectively; P &lt; 0.001), and endogenous glucose production (EGP) was 28% lower (3.4 ± 0.2 and 4.6 ± 0.3 mg/kg/min, respectively; P &lt; 0.01). During insulin-induced hypoglycemia, the area under the curve for glucagon remained lower by 42% in FAST compared with FED (1,598 ± 229 and 2,768 ± 422 pg/mL ∗ 60 min, respectively; P &lt; 0.01), as did EGP (41 ± 4 and 78 ± 12 mg/kg ∗ 60 min, respectively; P = 0.01). These data demonstrate that fasting lowers glucagon concentrations and EGP under euglycemic/normoinsulinemic metabolic conditions and during insulin-induced hypoglycemia. This reduction in metabolic flexibility, in addition to hyperinsulinemia, enhances susceptibility to fasting-induced low blood glucose in individuals with T1D and should be considered when developing strategies to avoid hypoglycemia. Article Highlights Fasting is associated with increased risk of hypoglycemia in patients with type 1 diabetes (T1D); however, little is known about how the counterregulatory responses to low blood sugar are affected under these metabolic conditions. During insulin-induced hypoglycemia, fasting (compared with eating normal meals for breakfast and lunch) glucagon concentrations were lower by 42% and endogenous glucose production by 47% in individuals with T1D. The secretion of other counterregulatory hormones during hypoglycemia was not affected by fasting (e.g., epinephrine, norepinephrine, cortisol). Fasting diminishes glucagon levels under hypoglycemic conditions in those with T1D, which may increase their susceptibility to hypoglycemia.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"635 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520338","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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