Pub Date : 2024-06-01DOI: 10.1016/j.tem.2023.10.009
Giovanni Solinas, Barbara Becattini
The current paradigm for the insulin system focuses on the phenomenon of glucose-stimulated insulin secretion and insulin action on blood glucose control. This historical glucose-centric perspective may have introduced a conceptual bias in our understanding of insulin regulation. A body of evidence demonstrating that in vivo variations in blood glucose and insulin secretion can be largely dissociated motivated us to reconsider the fundamental design of the insulin system as a control system for metabolic homeostasis. Here, we propose that a minimal glucose-centric model does not accurately describe the physiological behavior of the insulin system and propose a new paradigm focusing on the effects of incretins, arguing that under fasting conditions, insulin is regulated by an adipoincretin effect.
{"title":"An adipoincretin effect links adipostasis with insulin secretion.","authors":"Giovanni Solinas, Barbara Becattini","doi":"10.1016/j.tem.2023.10.009","DOIUrl":"https://doi.org/10.1016/j.tem.2023.10.009","url":null,"abstract":"<p><p>The current paradigm for the insulin system focuses on the phenomenon of glucose-stimulated insulin secretion and insulin action on blood glucose control. This historical glucose-centric perspective may have introduced a conceptual bias in our understanding of insulin regulation. A body of evidence demonstrating that in vivo variations in blood glucose and insulin secretion can be largely dissociated motivated us to reconsider the fundamental design of the insulin system as a control system for metabolic homeostasis. Here, we propose that a minimal glucose-centric model does not accurately describe the physiological behavior of the insulin system and propose a new paradigm focusing on the effects of incretins, arguing that under fasting conditions, insulin is regulated by an adipoincretin effect.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141307437","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 : 2024-06-01Epub Date: 2024-04-09DOI: 10.1016/j.tem.2024.04.001
Gabriel O de Souza, Willian O Dos Santos, Jose Donato
Obesity is associated with dysfunctions in hypothalamic neurons that regulate metabolism, including agouti-related protein (AgRP)-expressing neurons. In a recent article, Zhang et al. demonstrated that either diet- or genetically induced obesity promoted iron accumulation specifically in AgRP neurons. Preventing iron overload in AgRP neurons mitigated diet-induced obesity and related comorbidities in male mice.
{"title":"Ironing out obesity.","authors":"Gabriel O de Souza, Willian O Dos Santos, Jose Donato","doi":"10.1016/j.tem.2024.04.001","DOIUrl":"10.1016/j.tem.2024.04.001","url":null,"abstract":"<p><p>Obesity is associated with dysfunctions in hypothalamic neurons that regulate metabolism, including agouti-related protein (AgRP)-expressing neurons. In a recent article, Zhang et al. demonstrated that either diet- or genetically induced obesity promoted iron accumulation specifically in AgRP neurons. Preventing iron overload in AgRP neurons mitigated diet-induced obesity and related comorbidities in male mice.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140869016","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 : 2024-06-01Epub Date: 2024-03-23DOI: 10.1016/j.tem.2024.02.016
Ren Zhang, Kezhong Zhang
The regulation of triglyceride (TG) tissue distribution, storage, and utilization, a fundamental process of energy homeostasis, critically depends on lipoprotein lipase (LPL). We review the intricate mechanisms by which LPL activity is regulated by angiopoietin-like proteins (ANGPTL3, 4, 8), apolipoproteins (APOA5, APOC3, APOC2), and the cAMP-responsive element-binding protein H (CREBH). ANGPTL8 functions as a molecular switch, through complex formation, activating ANGPTL3 while deactivating ANGPTL4 in their LPL inhibition. The ANGPTL3-4-8 model integrates the roles of the aforementioned proteins in TG partitioning between white adipose tissue (WAT) and oxidative tissues (heart and skeletal muscles) during the feed/fast cycle. This model offers a unified perspective on LPL regulation, providing insights into TG metabolism, metabolic diseases, and therapeutics.
{"title":"A unified model for regulating lipoprotein lipase activity.","authors":"Ren Zhang, Kezhong Zhang","doi":"10.1016/j.tem.2024.02.016","DOIUrl":"10.1016/j.tem.2024.02.016","url":null,"abstract":"<p><p>The regulation of triglyceride (TG) tissue distribution, storage, and utilization, a fundamental process of energy homeostasis, critically depends on lipoprotein lipase (LPL). We review the intricate mechanisms by which LPL activity is regulated by angiopoietin-like proteins (ANGPTL3, 4, 8), apolipoproteins (APOA5, APOC3, APOC2), and the cAMP-responsive element-binding protein H (CREBH). ANGPTL8 functions as a molecular switch, through complex formation, activating ANGPTL3 while deactivating ANGPTL4 in their LPL inhibition. The ANGPTL3-4-8 model integrates the roles of the aforementioned proteins in TG partitioning between white adipose tissue (WAT) and oxidative tissues (heart and skeletal muscles) during the feed/fast cycle. This model offers a unified perspective on LPL regulation, providing insights into TG metabolism, metabolic diseases, and therapeutics.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140195109","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 : 2024-06-01Epub Date: 2024-04-03DOI: 10.1016/j.tem.2024.03.001
Masaki Kimura, Takanori Takebe
En masse phenotyping technology, using massively mosaic donor-derived cells and organoids, can offer enriched insights for cellotype-phenotype association in a cell-type-specific regulatory context. This emerging approach will help to discover biomarkers, inform genetic-epigenetic interactions and identify personalized therapeutic targets, offering hope for precision medicine against highly heterogeneous metabolic diseases.
{"title":"Cellotype-phenotype associations using 'organoid villages'.","authors":"Masaki Kimura, Takanori Takebe","doi":"10.1016/j.tem.2024.03.001","DOIUrl":"10.1016/j.tem.2024.03.001","url":null,"abstract":"<p><p>En masse phenotyping technology, using massively mosaic donor-derived cells and organoids, can offer enriched insights for cellotype-phenotype association in a cell-type-specific regulatory context. This emerging approach will help to discover biomarkers, inform genetic-epigenetic interactions and identify personalized therapeutic targets, offering hope for precision medicine against highly heterogeneous metabolic diseases.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140864451","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 : 2024-06-01Epub Date: 2024-05-13DOI: 10.1016/j.tem.2024.04.019
Clara Mosquera-Lopez, Peter G Jacobs
Digital twin technology is emerging as a transformative paradigm for personalized medicine in the management of chronic conditions. In this article, we explore the concept and key characteristics of a digital twin and its applications in chronic non-communicable metabolic disease management, with a focus on diabetes case studies. We cover various types of digital twin models, including mechanistic models based on ODEs, data-driven ML algorithms, and hybrid modeling strategies that combine the strengths of both approaches. We present successful case studies demonstrating the potential of digital twins in improving glucose outcomes for individuals with T1D and T2D, and discuss the benefits and challenges of translating digital twin research applications to clinical practice.
数字孪生技术正在成为慢性病管理中个性化医疗的变革范例。在本文中,我们将探讨数字孪生的概念和关键特征及其在慢性非传染性代谢性疾病管理中的应用,重点是糖尿病案例研究。我们介绍了各种类型的数字孪生模型,包括基于 ODE 的机理模型、数据驱动的 ML 算法以及结合两种方法优势的混合建模策略。我们介绍了成功的案例研究,展示了数字孪生子在改善 T1D 和 T2D 患者血糖结果方面的潜力,并讨论了将数字孪生子研究应用转化为临床实践的益处和挑战。
{"title":"Digital twins and artificial intelligence in metabolic disease research.","authors":"Clara Mosquera-Lopez, Peter G Jacobs","doi":"10.1016/j.tem.2024.04.019","DOIUrl":"10.1016/j.tem.2024.04.019","url":null,"abstract":"<p><p>Digital twin technology is emerging as a transformative paradigm for personalized medicine in the management of chronic conditions. In this article, we explore the concept and key characteristics of a digital twin and its applications in chronic non-communicable metabolic disease management, with a focus on diabetes case studies. We cover various types of digital twin models, including mechanistic models based on ODEs, data-driven ML algorithms, and hybrid modeling strategies that combine the strengths of both approaches. We present successful case studies demonstrating the potential of digital twins in improving glucose outcomes for individuals with T1D and T2D, and discuss the benefits and challenges of translating digital twin research applications to clinical practice.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140924000","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 : 2024-06-01Epub Date: 2024-04-09DOI: 10.1016/j.tem.2024.03.005
Aysim Gunes, Jennifer L Estall
Lack of preclinical model translation is often blamed for failed drug development. Here we discuss mouse models within the context of human steatotic liver disease (SLD). Variables such as aging and non-food hepatic stressors are often ignored but could explain challenges in reproducing the human disease in a laboratory.
{"title":"Is MASLD lost in translation in mice?","authors":"Aysim Gunes, Jennifer L Estall","doi":"10.1016/j.tem.2024.03.005","DOIUrl":"10.1016/j.tem.2024.03.005","url":null,"abstract":"<p><p>Lack of preclinical model translation is often blamed for failed drug development. Here we discuss mouse models within the context of human steatotic liver disease (SLD). Variables such as aging and non-food hepatic stressors are often ignored but could explain challenges in reproducing the human disease in a laboratory.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140861519","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 : 2024-05-31DOI: 10.1016/j.tem.2024.04.018
Shiyu Zhao, Frank Qian, Zhenzhen Wan, Xue Chen, An Pan, Gang Liu
Numerous observational studies have demonstrated a significant inverse association between vitamin D status and the risk of major chronic disease, including type 2 diabetes (T2D), cardiovascular disease (CVD), and cancer. However, findings from Mendelian randomization (MR) studies and randomized controlled trials (RCTs) suggest minimal or no benefit of increased vitamin D levels. We provide an overview of recent literature linking vitamin D to major chronic diseases. Because emerging evidence indicates a potential threshold effect of vitamin D, future well-designed studies focused on diverse populations with vitamin D deficiency or insufficiency are warranted for a more comprehensive understanding of the effect of maintaining sufficient vitamin D status on the prevention of major chronic diseases.
大量观察性研究表明,维生素 D 状态与主要慢性疾病(包括 2 型糖尿病(T2D)、心血管疾病(CVD)和癌症)风险之间存在显著的反向关系。然而,孟德尔随机化(MR)研究和随机对照试验(RCT)的结果表明,提高维生素 D 水平的益处很小或没有益处。我们概述了维生素 D 与主要慢性疾病相关的最新文献。由于新出现的证据表明维生素 D 具有潜在的阈值效应,因此今后有必要对维生素 D 缺乏或不足的不同人群进行精心设计的研究,以便更全面地了解保持足够的维生素 D 状态对预防主要慢性疾病的影响。
{"title":"Vitamin D and major chronic diseases.","authors":"Shiyu Zhao, Frank Qian, Zhenzhen Wan, Xue Chen, An Pan, Gang Liu","doi":"10.1016/j.tem.2024.04.018","DOIUrl":"https://doi.org/10.1016/j.tem.2024.04.018","url":null,"abstract":"<p><p>Numerous observational studies have demonstrated a significant inverse association between vitamin D status and the risk of major chronic disease, including type 2 diabetes (T2D), cardiovascular disease (CVD), and cancer. However, findings from Mendelian randomization (MR) studies and randomized controlled trials (RCTs) suggest minimal or no benefit of increased vitamin D levels. We provide an overview of recent literature linking vitamin D to major chronic diseases. Because emerging evidence indicates a potential threshold effect of vitamin D, future well-designed studies focused on diverse populations with vitamin D deficiency or insufficiency are warranted for a more comprehensive understanding of the effect of maintaining sufficient vitamin D status on the prevention of major chronic diseases.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141187024","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 : 2024-05-30DOI: 10.1016/j.tem.2024.05.002
Tim Gruber, Franziska Lechner, Jean-Philippe Krieger, Cristina García-Cáceres
The past decades have witnessed the rise and fall of several, largely unsuccessful, therapeutic attempts to bring the escalating obesity pandemic to a halt. Looking back to look ahead, the field has now put its highest hopes in translating insights from how the gastrointestinal (GI) tract communicates with the brain to calibrate behavior, physiology, and metabolism. A major focus of this review is to summarize the latest advances in comprehending the neuroendocrine aspects of this so-called 'gut-brain axis' and to explore novel concepts, cutting-edge technologies, and recent paradigm-shifting experiments. These exciting insights continue to refine our understanding of gut-brain crosstalk and are poised to promote the development of additional therapeutic avenues at the dawn of a new era of antiobesity therapeutics.
{"title":"Neuroendocrine gut-brain signaling in obesity.","authors":"Tim Gruber, Franziska Lechner, Jean-Philippe Krieger, Cristina García-Cáceres","doi":"10.1016/j.tem.2024.05.002","DOIUrl":"https://doi.org/10.1016/j.tem.2024.05.002","url":null,"abstract":"<p><p>The past decades have witnessed the rise and fall of several, largely unsuccessful, therapeutic attempts to bring the escalating obesity pandemic to a halt. Looking back to look ahead, the field has now put its highest hopes in translating insights from how the gastrointestinal (GI) tract communicates with the brain to calibrate behavior, physiology, and metabolism. A major focus of this review is to summarize the latest advances in comprehending the neuroendocrine aspects of this so-called 'gut-brain axis' and to explore novel concepts, cutting-edge technologies, and recent paradigm-shifting experiments. These exciting insights continue to refine our understanding of gut-brain crosstalk and are poised to promote the development of additional therapeutic avenues at the dawn of a new era of antiobesity therapeutics.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184966","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 : 2024-05-29DOI: 10.1016/j.tem.2024.05.006
Emma Barroso, Javier Jurado-Aguilar, Walter Wahli, Xavier Palomer, Manuel Vázquez-Carrera
Abnormally increased hepatic gluconeogenesis is a significant contributor to hyperglycemia in the fasting state in patients with type 2 diabetes mellitus (T2DM) due to insulin resistance. Metformin, the most prescribed drug for the treatment of T2DM, is believed to exert its effect mainly by reducing hepatic gluconeogenesis. Here, we discuss how increased hepatic gluconeogenesis contributes to T2DM and we review newly revealed mechanisms underlying the attenuation of gluconeogenesis by metformin. In addition, we analyze the recent findings on new determinants involved in the regulation of gluconeogenesis, which might ultimately lead to the identification of novel and targeted treatment strategies for T2DM.
{"title":"Increased hepatic gluconeogenesis and type 2 diabetes mellitus.","authors":"Emma Barroso, Javier Jurado-Aguilar, Walter Wahli, Xavier Palomer, Manuel Vázquez-Carrera","doi":"10.1016/j.tem.2024.05.006","DOIUrl":"https://doi.org/10.1016/j.tem.2024.05.006","url":null,"abstract":"<p><p>Abnormally increased hepatic gluconeogenesis is a significant contributor to hyperglycemia in the fasting state in patients with type 2 diabetes mellitus (T2DM) due to insulin resistance. Metformin, the most prescribed drug for the treatment of T2DM, is believed to exert its effect mainly by reducing hepatic gluconeogenesis. Here, we discuss how increased hepatic gluconeogenesis contributes to T2DM and we review newly revealed mechanisms underlying the attenuation of gluconeogenesis by metformin. In addition, we analyze the recent findings on new determinants involved in the regulation of gluconeogenesis, which might ultimately lead to the identification of novel and targeted treatment strategies for T2DM.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141181380","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 : 2024-05-27DOI: 10.1016/j.tem.2024.05.001
Ana Vela-Sebastián, Pilar Bayona-Bafaluy, David Pacheu-Grau
Mitochondrial genetic defects caused by whole-body mutations typically affect different tissues in different ways. Elucidating the molecular determinants that cause certain cell types to be primarily affected has become a critical research target within the field. We propose a differential activation of the integrated stress response as a potential contributor to this tissue specificity.
{"title":"ISR pathway contribution to tissue specificity of mitochondrial diseases.","authors":"Ana Vela-Sebastián, Pilar Bayona-Bafaluy, David Pacheu-Grau","doi":"10.1016/j.tem.2024.05.001","DOIUrl":"https://doi.org/10.1016/j.tem.2024.05.001","url":null,"abstract":"<p><p>Mitochondrial genetic defects caused by whole-body mutations typically affect different tissues in different ways. Elucidating the molecular determinants that cause certain cell types to be primarily affected has become a critical research target within the field. We propose a differential activation of the integrated stress response as a potential contributor to this tissue specificity.</p>","PeriodicalId":54415,"journal":{"name":"Trends in Endocrinology and Metabolism","volume":null,"pages":null},"PeriodicalIF":10.9,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162016","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}