Pub Date : 2024-05-01DOI: 10.1016/j.tem.2024.04.007
Nelmari Ruiz-Otero, Jeffery S Tessem, Ronadip R Banerjee
Pancreatic islets, particularly insulin-producing β-cells, are central regulators of glucose homeostasis capable of responding to a variety of metabolic stressors. Pregnancy is a unique physiological stressor, necessitating the islets to adapt to the complex interplay of maternal and fetal-placental factors influencing the metabolic milieu. In this review we highlight studies defining gestational adaptation mechanisms within maternal islets and emerging studies revealing islet adaptations during the early postpartum and lactation periods. These include adaptations in both β and in 'non-β' islet cells. We also discuss insights into how gestational and postpartum adaptation may inform pregnancy-specific and general mechanisms of islet responses to metabolic stress and contribute to investigation of gestational diabetes.
{"title":"Pancreatic islet adaptation in pregnancy and postpartum.","authors":"Nelmari Ruiz-Otero, Jeffery S Tessem, Ronadip R Banerjee","doi":"10.1016/j.tem.2024.04.007","DOIUrl":"https://doi.org/10.1016/j.tem.2024.04.007","url":null,"abstract":"<p><p>Pancreatic islets, particularly insulin-producing β-cells, are central regulators of glucose homeostasis capable of responding to a variety of metabolic stressors. Pregnancy is a unique physiological stressor, necessitating the islets to adapt to the complex interplay of maternal and fetal-placental factors influencing the metabolic milieu. In this review we highlight studies defining gestational adaptation mechanisms within maternal islets and emerging studies revealing islet adaptations during the early postpartum and lactation periods. These include adaptations in both β and in 'non-β' islet cells. We also discuss insights into how gestational and postpartum adaptation may inform pregnancy-specific and general mechanisms of islet responses to metabolic stress and contribute to investigation of gestational diabetes.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140871239","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}
Pub Date : 2024-05-01Epub Date: 2024-02-27DOI: 10.1016/j.tem.2024.02.009
Yan Hu, Hao Huang, Rong Xiang
Mitochondrial dysfunctions predominantly cause encephalomyopathies with muscle atrophy and neurodegeneration. However, their impact on other tissues, particularly the gastrointestinal tract, requires further investigation. In a recent report in Nature, Moschandrea et al. used mice deficient in the mitochondrial aminoacyl-tRNA synthetase DARS2 to investigate the role of enterocytic mitochondria in dietary lipid processing and transport. Their work sheds light on the development of gastrointestinal disorders as a result of mitochondrial dysfunction.
{"title":"Mitochondrial dysfunction in lipid processing and gastrointestinal disorders.","authors":"Yan Hu, Hao Huang, Rong Xiang","doi":"10.1016/j.tem.2024.02.009","DOIUrl":"10.1016/j.tem.2024.02.009","url":null,"abstract":"<p><p>Mitochondrial dysfunctions predominantly cause encephalomyopathies with muscle atrophy and neurodegeneration. However, their impact on other tissues, particularly the gastrointestinal tract, requires further investigation. In a recent report in Nature, Moschandrea et al. used mice deficient in the mitochondrial aminoacyl-tRNA synthetase DARS2 to investigate the role of enterocytic mitochondria in dietary lipid processing and transport. Their work sheds light on the development of gastrointestinal disorders as a result of mitochondrial dysfunction.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139991811","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}
Pub Date : 2024-05-01Epub Date: 2024-02-28DOI: 10.1016/j.tem.2024.02.001
Zara Siu Wa Chui, Qing Shen, Aimin Xu
Recent advances in fibroblast growth factor 21 (FGF21) biology and pharmacology have led to the development of several long-acting FGF21 analogues and antibody-based mimetics now in various phases of clinical trials for the treatment of obesity-related metabolic comorbidities. The efficacy of these FGF21 analogues/mimetics on glycaemic control and weight loss is rather mild and inconsistent; nevertheless, several promising therapeutic benefits have been reproducibly observed in most clinical studies, including amelioration of dyslipidaemia (particularly hypertriglyceridaemia) and hepatic steatosis, reduction of biomarkers of liver fibrosis and injury, and resolution of metabolic dysfunction-associated steatohepatitis (MASH). Evidence is emerging that combination therapy with FGF21 analogues and other hormones (such as glucagon-like peptide 1; GLP-1) can synergise their pharmacological benefits, thus maximising the therapeutic efficacy for obesity and its comorbidities.
{"title":"Current status and future perspectives of FGF21 analogues in clinical trials.","authors":"Zara Siu Wa Chui, Qing Shen, Aimin Xu","doi":"10.1016/j.tem.2024.02.001","DOIUrl":"10.1016/j.tem.2024.02.001","url":null,"abstract":"<p><p>Recent advances in fibroblast growth factor 21 (FGF21) biology and pharmacology have led to the development of several long-acting FGF21 analogues and antibody-based mimetics now in various phases of clinical trials for the treatment of obesity-related metabolic comorbidities. The efficacy of these FGF21 analogues/mimetics on glycaemic control and weight loss is rather mild and inconsistent; nevertheless, several promising therapeutic benefits have been reproducibly observed in most clinical studies, including amelioration of dyslipidaemia (particularly hypertriglyceridaemia) and hepatic steatosis, reduction of biomarkers of liver fibrosis and injury, and resolution of metabolic dysfunction-associated steatohepatitis (MASH). Evidence is emerging that combination therapy with FGF21 analogues and other hormones (such as glucagon-like peptide 1; GLP-1) can synergise their pharmacological benefits, thus maximising the therapeutic efficacy for obesity and its comorbidities.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139998313","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}
Pub Date : 2024-05-01DOI: 10.1016/j.tem.2024.04.008
Christopher J Nolan, Gernot Desoye
Disentangling which of insulin hypersecretion and insulin resistance is upstream in obesity-related type 2 diabetes (T2D) is challenging. Here, we consider the dynamics of insulin secretion and action in the fetuses of mothers with diabetes. We argue that fetal insulin hypersecretion occurs first, with insulin resistance being an adaptive protective response.
{"title":"Disentangling fetal insulin hypersecretion and insulin resistance.","authors":"Christopher J Nolan, Gernot Desoye","doi":"10.1016/j.tem.2024.04.008","DOIUrl":"https://doi.org/10.1016/j.tem.2024.04.008","url":null,"abstract":"<p><p>Disentangling which of insulin hypersecretion and insulin resistance is upstream in obesity-related type 2 diabetes (T2D) is challenging. Here, we consider the dynamics of insulin secretion and action in the fetuses of mothers with diabetes. We argue that fetal insulin hypersecretion occurs first, with insulin resistance being an adaptive protective response.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140856986","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}
Pub Date : 2024-04-29DOI: 10.1016/j.tem.2024.04.005
Jiuzhou Huo, Jeffery D Molkentin
Skeletal muscle has a major impact on total body metabolism and obesity, and is characterized by dynamic regulation of substrate utilization. While it is accepted that acute increases in mitochondrial matrix Ca2+ increase carbohydrate usage to augment ATP production, recent studies in mice with deleted genes for components of the mitochondrial Ca2+ uniporter (MCU) complex have suggested a more complicated regulatory scenario. Indeed, mice with a deleted Mcu gene in muscle, which lack acute mitochondrial Ca2+ uptake, have greater fatty acid oxidation (FAO) and less adiposity. By contrast, mice deleted for the inhibitory Mcub gene in skeletal muscle, which have greater acute mitochondrial Ca2+ uptake, antithetically display reduced FAO and progressive obesity. In this review we discuss the emerging concept that dynamic fluxing of mitochondrial matrix Ca2+ regulates metabolism.
{"title":"MCU genetically altered mice suggest how mitochondrial Ca<sup>2+</sup> regulates metabolism.","authors":"Jiuzhou Huo, Jeffery D Molkentin","doi":"10.1016/j.tem.2024.04.005","DOIUrl":"10.1016/j.tem.2024.04.005","url":null,"abstract":"<p><p>Skeletal muscle has a major impact on total body metabolism and obesity, and is characterized by dynamic regulation of substrate utilization. While it is accepted that acute increases in mitochondrial matrix Ca<sup>2+</sup> increase carbohydrate usage to augment ATP production, recent studies in mice with deleted genes for components of the mitochondrial Ca<sup>2+</sup> uniporter (MCU) complex have suggested a more complicated regulatory scenario. Indeed, mice with a deleted Mcu gene in muscle, which lack acute mitochondrial Ca<sup>2+</sup> uptake, have greater fatty acid oxidation (FAO) and less adiposity. By contrast, mice deleted for the inhibitory Mcub gene in skeletal muscle, which have greater acute mitochondrial Ca<sup>2+</sup> uptake, antithetically display reduced FAO and progressive obesity. In this review we discuss the emerging concept that dynamic fluxing of mitochondrial matrix Ca<sup>2+</sup> regulates metabolism.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140874092","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}
Pub Date : 2024-04-29DOI: 10.1016/j.tem.2024.04.004
Ilja L Kruglikov, Philipp E Scherer
Lipedema is a poorly understood disorder of adipose tissue characterized by abnormal but symmetrical deposition of subcutaneous white adipose tissue (WAT) in proximal extremities. Here, we propose that the underlying cause for lipedema could be triggered by a selective accumulation of bacterial lipopolysaccharides (LPS; also known as endotoxin) in gluteofemoral WAT. Together with a malfunctioning complement system, this induces low-grade inflammation in the depot and raises its uncontrollable expansion. Correspondingly, more attention should be paid in future research to the endotoxemia prevalent in patients with lipedema. We would like to propose that proper management of endotoxemia can reduce the progression and even improve the state of disease in patients with lipedema.
{"title":"Is the endotoxin-complement cascade the major driver in lipedema?","authors":"Ilja L Kruglikov, Philipp E Scherer","doi":"10.1016/j.tem.2024.04.004","DOIUrl":"10.1016/j.tem.2024.04.004","url":null,"abstract":"<p><p>Lipedema is a poorly understood disorder of adipose tissue characterized by abnormal but symmetrical deposition of subcutaneous white adipose tissue (WAT) in proximal extremities. Here, we propose that the underlying cause for lipedema could be triggered by a selective accumulation of bacterial lipopolysaccharides (LPS; also known as endotoxin) in gluteofemoral WAT. Together with a malfunctioning complement system, this induces low-grade inflammation in the depot and raises its uncontrollable expansion. Correspondingly, more attention should be paid in future research to the endotoxemia prevalent in patients with lipedema. We would like to propose that proper management of endotoxemia can reduce the progression and even improve the state of disease in patients with lipedema.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140868822","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}
Pub Date : 2024-04-20DOI: 10.1016/j.tem.2024.03.006
Stephanie Bourgeois, Sophie Coenen, Laure Degroote, Lien Willems, Annelore Van Mulders, Julie Pierreux, Yves Heremans, Nico De Leu, Willem Staels
The pandemic scale of diabetes mellitus is alarming, its complications remain devastating, and current treatments still pose a major burden on those affected and on the healthcare system as a whole. As the disease emanates from the destruction or dysfunction of insulin-producing pancreatic β-cells, a real cure requires their restoration and protection. An attractive strategy is to regenerate β-cells directly within the pancreas; however, while several approaches for β-cell regeneration have been proposed in the past, clinical translation has proven challenging. This review scrutinizes recent findings in β-cell regeneration and discusses their potential clinical implementation. Hereby, we aim to delineate a path for innovative, targeted therapies to help shift from 'caring for' to 'curing' diabetes.
{"title":"Harnessing beta cell regeneration biology for diabetes therapy.","authors":"Stephanie Bourgeois, Sophie Coenen, Laure Degroote, Lien Willems, Annelore Van Mulders, Julie Pierreux, Yves Heremans, Nico De Leu, Willem Staels","doi":"10.1016/j.tem.2024.03.006","DOIUrl":"https://doi.org/10.1016/j.tem.2024.03.006","url":null,"abstract":"<p><p>The pandemic scale of diabetes mellitus is alarming, its complications remain devastating, and current treatments still pose a major burden on those affected and on the healthcare system as a whole. As the disease emanates from the destruction or dysfunction of insulin-producing pancreatic β-cells, a real cure requires their restoration and protection. An attractive strategy is to regenerate β-cells directly within the pancreas; however, while several approaches for β-cell regeneration have been proposed in the past, clinical translation has proven challenging. This review scrutinizes recent findings in β-cell regeneration and discusses their potential clinical implementation. Hereby, we aim to delineate a path for innovative, targeted therapies to help shift from 'caring for' to 'curing' diabetes.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140872999","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}
Immune checkpoint inhibitors (ICIs) are associated with multiple endocrine side effects, including thyroid disfunctions. In addition, the efficacy and safety profiles of ICIs in the pediatric population need clarification. Here, we discuss the main evidence regarding the efficacy and thyroid toxicities of ICIs in children.
{"title":"Pediatric thyroid side effects of immune checkpoint inhibitors.","authors":"Cesare Morgante, Alessandra Fierabracci, Armando Grossi","doi":"10.1016/j.tem.2024.04.002","DOIUrl":"https://doi.org/10.1016/j.tem.2024.04.002","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) are associated with multiple endocrine side effects, including thyroid disfunctions. In addition, the efficacy and safety profiles of ICIs in the pediatric population need clarification. Here, we discuss the main evidence regarding the efficacy and thyroid toxicities of ICIs in children.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140869566","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}
Selenium (Se) is an essential trace element, which is inserted as selenocysteine (Sec) into selenoproteins during biosynthesis, orchestrating their expression and activity. Se is associated with both beneficial and detrimental health effects; deficient supply or uncontrolled supplementation raises concerns. In particular, Se was associated with an increased incidence of type 2 diabetes (T2D) in a secondary analysis of a randomized controlled trial (RCT). In this review, we discuss the intricate relationship between Se and diabetes and the limitations of the available clinical and experimental studies. Recent evidence points to sexual dimorphism and an association of Se deficiency with gestational diabetes mellitus (GDM). We highlight the emerging evidence linking high Se status with improved prognosis in patients with T2D and lower risk of macrovascular complications.
硒(Se)是一种人体必需的微量元素,在生物合成过程中以硒代半胱氨酸(Sec)的形式插入硒蛋白中,协调硒蛋白的表达和活性。硒对健康既有益处也有害处,供应不足或无节制地补充硒会引起人们的担忧。特别是,在一项随机对照试验(RCT)的二次分析中,Se 与 2 型糖尿病(T2D)发病率的增加有关。在本综述中,我们将讨论 Se 与糖尿病之间错综复杂的关系以及现有临床和实验研究的局限性。最近的证据表明,妊娠期糖尿病(GDM)存在性别二形性和 Se 缺乏相关性。我们强调了新出现的证据,即高 Se 状态与改善 T2D 患者预后和降低大血管并发症风险有关。
{"title":"Selenium, diabetes, and their intricate sex-specific relationship.","authors":"Kamil Demircan, Thilo Samson Chillon, Jeyoung Bang, Vadim N Gladyshev, Lutz Schomburg","doi":"10.1016/j.tem.2024.03.004","DOIUrl":"https://doi.org/10.1016/j.tem.2024.03.004","url":null,"abstract":"<p><p>Selenium (Se) is an essential trace element, which is inserted as selenocysteine (Sec) into selenoproteins during biosynthesis, orchestrating their expression and activity. Se is associated with both beneficial and detrimental health effects; deficient supply or uncontrolled supplementation raises concerns. In particular, Se was associated with an increased incidence of type 2 diabetes (T2D) in a secondary analysis of a randomized controlled trial (RCT). In this review, we discuss the intricate relationship between Se and diabetes and the limitations of the available clinical and experimental studies. Recent evidence points to sexual dimorphism and an association of Se deficiency with gestational diabetes mellitus (GDM). We highlight the emerging evidence linking high Se status with improved prognosis in patients with T2D and lower risk of macrovascular complications.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140871931","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}
Pub Date : 2024-04-09DOI: 10.1016/j.tem.2024.03.002
Devesh Bahety, Elvan Böke, Aida Rodríguez-Nuevo
Mitochondria have a crucial role in cellular function and exhibit remarkable plasticity, adjusting both their structure and activity to meet the changing energy demands of a cell. Oocytes, female germ cells that become eggs, undergo unique transformations: the extended dormancy period, followed by substantial increase in cell size and subsequent maturation involving the segregation of genetic material for the next generation, present distinct metabolic challenges necessitating varied mitochondrial adaptations. Recent findings in dormant oocytes challenged the established respiratory complex hierarchies and underscored the extent of mitochondrial plasticity in long-lived oocytes. In this review, we discuss mitochondrial adaptations observed during oocyte development across three vertebrate species (Xenopus, mouse, and human), emphasising current knowledge, acknowledging limitations, and outlining future research directions.
{"title":"Mitochondrial morphology, distribution and activity during oocyte development.","authors":"Devesh Bahety, Elvan Böke, Aida Rodríguez-Nuevo","doi":"10.1016/j.tem.2024.03.002","DOIUrl":"https://doi.org/10.1016/j.tem.2024.03.002","url":null,"abstract":"<p><p>Mitochondria have a crucial role in cellular function and exhibit remarkable plasticity, adjusting both their structure and activity to meet the changing energy demands of a cell. Oocytes, female germ cells that become eggs, undergo unique transformations: the extended dormancy period, followed by substantial increase in cell size and subsequent maturation involving the segregation of genetic material for the next generation, present distinct metabolic challenges necessitating varied mitochondrial adaptations. Recent findings in dormant oocytes challenged the established respiratory complex hierarchies and underscored the extent of mitochondrial plasticity in long-lived oocytes. In this review, we discuss mitochondrial adaptations observed during oocyte development across three vertebrate species (Xenopus, mouse, and human), emphasising current knowledge, acknowledging limitations, and outlining future research directions.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140871444","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}