Pub Date : 2024-11-04DOI: 10.1038/s41574-024-01045-0
Åke Lernmark, Daniel Agardh, Beena Akolkar, Patricia Gesualdo, William A. Hagopian, Michael J. Haller, Heikki Hyöty, Suzanne Bennett Johnson, Helena Elding Larsson, Edwin Liu, Kristian F. Lynch, Eoin F. McKinney, Richard McIndoe, Jessica Melin, Jill M. Norris, Marian Rewers, Stephen S. Rich, Jorma Toppari, Eric Triplett, Kendra Vehik, Suvi M. Virtanen, Anette-G. Ziegler, Desmond A. Schatz, Jeffrey Krischer
The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed. Recruitment and follow-up (from age 4 months to 15 years) of 8,667 children showed high retention and compliance. End points of the presence of autoantibodies against insulin, GAD65, IA-2 and ZnT8 revealed the HLA-associated early appearance of insulin autoantibodies (1–3 years of age) and the later appearance of GAD65 autoantibodies. Competing autoantibodies against tissue transglutaminase (marking coeliac disease autoimmunity) also appeared early (2–4 years). Genetic and environmental factors, including enterovirus infection and gastroenteritis, support mechanistic differences underlying one phenotype of autoimmunity against insulin and another against GAD65. Infant growth and both probiotics and high protein intake affect the two phenotypes differently, as do serious life events during pregnancy. As the end of the TEDDY sampling phase is approaching, major omics approaches are in progress to further dissect the mechanisms that might explain the two possible endotypes of T1DM. This Review outlines the screening, enrolment and recruitment challenges in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. The key findings related to the first primary end point are discussed, and future directions of study are highlighted.
{"title":"Looking back at the TEDDY study: lessons and future directions","authors":"Åke Lernmark, Daniel Agardh, Beena Akolkar, Patricia Gesualdo, William A. Hagopian, Michael J. Haller, Heikki Hyöty, Suzanne Bennett Johnson, Helena Elding Larsson, Edwin Liu, Kristian F. Lynch, Eoin F. McKinney, Richard McIndoe, Jessica Melin, Jill M. Norris, Marian Rewers, Stephen S. Rich, Jorma Toppari, Eric Triplett, Kendra Vehik, Suvi M. Virtanen, Anette-G. Ziegler, Desmond A. Schatz, Jeffrey Krischer","doi":"10.1038/s41574-024-01045-0","DOIUrl":"10.1038/s41574-024-01045-0","url":null,"abstract":"The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed. Recruitment and follow-up (from age 4 months to 15 years) of 8,667 children showed high retention and compliance. End points of the presence of autoantibodies against insulin, GAD65, IA-2 and ZnT8 revealed the HLA-associated early appearance of insulin autoantibodies (1–3 years of age) and the later appearance of GAD65 autoantibodies. Competing autoantibodies against tissue transglutaminase (marking coeliac disease autoimmunity) also appeared early (2–4 years). Genetic and environmental factors, including enterovirus infection and gastroenteritis, support mechanistic differences underlying one phenotype of autoimmunity against insulin and another against GAD65. Infant growth and both probiotics and high protein intake affect the two phenotypes differently, as do serious life events during pregnancy. As the end of the TEDDY sampling phase is approaching, major omics approaches are in progress to further dissect the mechanisms that might explain the two possible endotypes of T1DM. This Review outlines the screening, enrolment and recruitment challenges in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. The key findings related to the first primary end point are discussed, and future directions of study are highlighted.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 3","pages":"154-165"},"PeriodicalIF":31.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574394","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 : 2024-10-28DOI: 10.1038/s41574-024-01056-x
Morten Dall, Katharina Herzog, Antonia Hufnagel, Daniel B. Ibsen, Benjamin Lebiecka-Johansen, Philip M. M. Ruppert, Jessica M. Preston, Pearlyn J. Y. Toh, Christina Yfanti
Although science is becoming ever more complex, interdisciplinary and open, the scientific publication process has largely remained static, which affects the integrity and impact of articles. At the 2023 Danish Diabetes and Endocrine Academy Postdoc Summit, we identified five aspects of this process that need attention to enable reform.
{"title":"Our future, we decide: five ways to reform the scientific publication process","authors":"Morten Dall, Katharina Herzog, Antonia Hufnagel, Daniel B. Ibsen, Benjamin Lebiecka-Johansen, Philip M. M. Ruppert, Jessica M. Preston, Pearlyn J. Y. Toh, Christina Yfanti","doi":"10.1038/s41574-024-01056-x","DOIUrl":"10.1038/s41574-024-01056-x","url":null,"abstract":"Although science is becoming ever more complex, interdisciplinary and open, the scientific publication process has largely remained static, which affects the integrity and impact of articles. At the 2023 Danish Diabetes and Endocrine Academy Postdoc Summit, we identified five aspects of this process that need attention to enable reform.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 1","pages":"5-6"},"PeriodicalIF":31.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519242","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 : 2024-10-25DOI: 10.1038/s41574-024-01049-w
Taitum Mason, Simon Alesi, Melinda Fernando, Eszter Vanky, Helena J. Teede, Aya Mousa
Metformin is an effective oral hypoglycaemic agent used in the treatment of type 2 diabetes mellitus; however, its use in pregnancy for the treatment of gestational diabetes mellitus (GDM) remains controversial owing to concerns around safety and efficacy. This comprehensive review outlines the physiological metabolic functions of metformin and synthesizes existing literature and key knowledge gaps pertaining to the use of metformin in pregnancy across various end points in women with GDM. On the basis of current evidence, metformin reduces gestational weight gain, neonatal hypoglycaemia and macrosomia and increases insulin sensitivity. However, considerable heterogeneity between existing studies and the grouping of aggregate and often inharmonious data within meta-analyses has led to disparate findings regarding the efficacy of metformin in treating hyperglycaemia in GDM. Innovative analytical approaches with stratification by individual-level characteristics (for example, obesity, ethnicity, GDM severity and so on) and treatment regimens (diagnostic criteria, treatment timing and follow-up duration) are needed to establish efficacy across a range of end points and to identify which, if any, subgroups might benefit from metformin treatment during pregnancy. This Review outlines the complex actions of metformin in metabolic regulation, providing a plausible basis for its benefits in the management of gestational diabetes mellitus. The authors also critically evaluate the safety profile of metformin use during pregnancy in patients with gestational diabetes mellitus.
{"title":"Metformin in gestational diabetes: physiological actions and clinical applications","authors":"Taitum Mason, Simon Alesi, Melinda Fernando, Eszter Vanky, Helena J. Teede, Aya Mousa","doi":"10.1038/s41574-024-01049-w","DOIUrl":"10.1038/s41574-024-01049-w","url":null,"abstract":"Metformin is an effective oral hypoglycaemic agent used in the treatment of type 2 diabetes mellitus; however, its use in pregnancy for the treatment of gestational diabetes mellitus (GDM) remains controversial owing to concerns around safety and efficacy. This comprehensive review outlines the physiological metabolic functions of metformin and synthesizes existing literature and key knowledge gaps pertaining to the use of metformin in pregnancy across various end points in women with GDM. On the basis of current evidence, metformin reduces gestational weight gain, neonatal hypoglycaemia and macrosomia and increases insulin sensitivity. However, considerable heterogeneity between existing studies and the grouping of aggregate and often inharmonious data within meta-analyses has led to disparate findings regarding the efficacy of metformin in treating hyperglycaemia in GDM. Innovative analytical approaches with stratification by individual-level characteristics (for example, obesity, ethnicity, GDM severity and so on) and treatment regimens (diagnostic criteria, treatment timing and follow-up duration) are needed to establish efficacy across a range of end points and to identify which, if any, subgroups might benefit from metformin treatment during pregnancy. This Review outlines the complex actions of metformin in metabolic regulation, providing a plausible basis for its benefits in the management of gestational diabetes mellitus. The authors also critically evaluate the safety profile of metformin use during pregnancy in patients with gestational diabetes mellitus.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 2","pages":"77-91"},"PeriodicalIF":31.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489415","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 : 2024-10-24DOI: 10.1038/s41574-024-01046-z
Dunya Tomic, Jessica L. Harding, Alicia J. Jenkins, Jonathan E. Shaw, Dianna J. Magliano
Although type 1 diabetes mellitus (T1DM) is traditionally viewed as a youth-onset disorder, the number of older adults being diagnosed with this disease is growing. Improvements in the average life expectancy of people with T1DM have also contributed to the growing number of older people living with this disease. We summarize the evidence regarding the epidemiology (incidence, prevalence and excess mortality) of T1DM in older adults (ages ≥60 years) as well as the genetics, immunology and diagnostic challenges. Several studies report an incidence peak of T1DM in older adults of a similar size to or exceeding that in children, and population prevalence generally increases with increasing age. Glutamic acid decarboxylase antibody positivity is frequently observed in adult-onset T1DM. Guidelines for differentiating T1DM from type 2 diabetes mellitus in older adults recommend measuring levels of C-peptide and autoantibodies, including glutamic acid decarboxylase antibodies. However, there is no gold standard for differentiating T1DM from type 2 diabetes mellitus in people aged 60 years and over. As such, the global variation observed in T1DM epidemiology might be in part explained by misclassification, which increases with increasing age of diabetes mellitus onset. With a growing global population of older adults with T1DM, improved genetic and immunological evidence is needed to differentiate diabetes mellitus type at older ages so that a clear epidemiological picture can emerge. This Review discusses the incidence, prevalence and disease burden of type 1 diabetes mellitus in older adults in diverse geographical regions. The challenges involved in defining and diagnosing type 1 diabetes mellitus in this population and the implications of these challenges for epidemiological studies of this disease are also addressed.
{"title":"The epidemiology of type 1 diabetes mellitus in older adults","authors":"Dunya Tomic, Jessica L. Harding, Alicia J. Jenkins, Jonathan E. Shaw, Dianna J. Magliano","doi":"10.1038/s41574-024-01046-z","DOIUrl":"10.1038/s41574-024-01046-z","url":null,"abstract":"Although type 1 diabetes mellitus (T1DM) is traditionally viewed as a youth-onset disorder, the number of older adults being diagnosed with this disease is growing. Improvements in the average life expectancy of people with T1DM have also contributed to the growing number of older people living with this disease. We summarize the evidence regarding the epidemiology (incidence, prevalence and excess mortality) of T1DM in older adults (ages ≥60 years) as well as the genetics, immunology and diagnostic challenges. Several studies report an incidence peak of T1DM in older adults of a similar size to or exceeding that in children, and population prevalence generally increases with increasing age. Glutamic acid decarboxylase antibody positivity is frequently observed in adult-onset T1DM. Guidelines for differentiating T1DM from type 2 diabetes mellitus in older adults recommend measuring levels of C-peptide and autoantibodies, including glutamic acid decarboxylase antibodies. However, there is no gold standard for differentiating T1DM from type 2 diabetes mellitus in people aged 60 years and over. As such, the global variation observed in T1DM epidemiology might be in part explained by misclassification, which increases with increasing age of diabetes mellitus onset. With a growing global population of older adults with T1DM, improved genetic and immunological evidence is needed to differentiate diabetes mellitus type at older ages so that a clear epidemiological picture can emerge. This Review discusses the incidence, prevalence and disease burden of type 1 diabetes mellitus in older adults in diverse geographical regions. The challenges involved in defining and diagnosing type 1 diabetes mellitus in this population and the implications of these challenges for epidemiological studies of this disease are also addressed.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 2","pages":"92-104"},"PeriodicalIF":31.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488608","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 : 2024-10-24DOI: 10.1038/s41574-024-01053-0
David A. Antonetti, Paolo S. Silva, Alan W. Stitt
{"title":"Publisher Correction: Current understanding of the molecular and cellular pathology of diabetic retinopathy","authors":"David A. Antonetti, Paolo S. Silva, Alan W. Stitt","doi":"10.1038/s41574-024-01053-0","DOIUrl":"10.1038/s41574-024-01053-0","url":null,"abstract":"","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 1","pages":"62-62"},"PeriodicalIF":31.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41574-024-01053-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1038/s41574-024-01047-y
Matúš Soták, Madison Clark, Bianca E. Suur, Emma Börgeson
Inflammation is an essential physiological defence mechanism, but prolonged or excessive inflammation can cause disease. Indeed, unresolved systemic and adipose tissue inflammation drives obesity-related cardiovascular disease and type 2 diabetes mellitus. Drugs targeting pro-inflammatory cytokine pathways or inflammasome activation have been approved for clinical use for the past two decades. However, potentially serious adverse effects, such as drug-induced weight gain and increased susceptibility to infections, prevented their wider clinical implementation. Furthermore, these drugs do not modulate the resolution phase of inflammation. This phase is an active process orchestrated by specialized pro-resolving mediators, such as lipoxins, and other endogenous resolution mechanisms. Pro-resolving mediators mitigate inflammation and development of obesity-related disease, for instance, alleviating insulin resistance and atherosclerosis in experimental disease models, so mechanisms to modulate their activity are, therefore, of great therapeutic interest. Here, we review current clinical attempts to either target pro-inflammatory mediators (IL-1β, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, tumour necrosis factor (TNF) and IL-6) or utilize endogenous resolution pathways to reduce obesity-related inflammation and improve cardiometabolic outcomes. A remaining challenge in the field is to establish more precise biomarkers that can differentiate between acute and chronic inflammation and to assess the functionality of individual leukocyte populations. Such advancements would improve the monitoring of drug effects and support personalized treatment strategies that battle obesity-related inflammation and cardiometabolic disease. This Review discusses translational attempts to mitigate the inflammation that drives obesity-related cardiometabolic diseases. The Review also focuses on mechanisms that control inflammatory cascades, either through traditional anti-inflammatory drugs or via the specialized pro-resolving mediators that actively control the resolution of inflammation.
{"title":"Inflammation and resolution in obesity","authors":"Matúš Soták, Madison Clark, Bianca E. Suur, Emma Börgeson","doi":"10.1038/s41574-024-01047-y","DOIUrl":"10.1038/s41574-024-01047-y","url":null,"abstract":"Inflammation is an essential physiological defence mechanism, but prolonged or excessive inflammation can cause disease. Indeed, unresolved systemic and adipose tissue inflammation drives obesity-related cardiovascular disease and type 2 diabetes mellitus. Drugs targeting pro-inflammatory cytokine pathways or inflammasome activation have been approved for clinical use for the past two decades. However, potentially serious adverse effects, such as drug-induced weight gain and increased susceptibility to infections, prevented their wider clinical implementation. Furthermore, these drugs do not modulate the resolution phase of inflammation. This phase is an active process orchestrated by specialized pro-resolving mediators, such as lipoxins, and other endogenous resolution mechanisms. Pro-resolving mediators mitigate inflammation and development of obesity-related disease, for instance, alleviating insulin resistance and atherosclerosis in experimental disease models, so mechanisms to modulate their activity are, therefore, of great therapeutic interest. Here, we review current clinical attempts to either target pro-inflammatory mediators (IL-1β, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, tumour necrosis factor (TNF) and IL-6) or utilize endogenous resolution pathways to reduce obesity-related inflammation and improve cardiometabolic outcomes. A remaining challenge in the field is to establish more precise biomarkers that can differentiate between acute and chronic inflammation and to assess the functionality of individual leukocyte populations. Such advancements would improve the monitoring of drug effects and support personalized treatment strategies that battle obesity-related inflammation and cardiometabolic disease. This Review discusses translational attempts to mitigate the inflammation that drives obesity-related cardiometabolic diseases. The Review also focuses on mechanisms that control inflammatory cascades, either through traditional anti-inflammatory drugs or via the specialized pro-resolving mediators that actively control the resolution of inflammation.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 1","pages":"45-61"},"PeriodicalIF":31.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488981","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 : 2024-10-24DOI: 10.1038/s41574-024-01054-z
Christian Stoess, Ariel E. Feldstein
Having more refined mouse models of metabolic dysfunction-associated steatotic liver disease (MASLD; also known as nonalcoholic fatty liver disease) will help to advance research into this disease. In their study, Jeong and colleagues use streptozotocin together with a high-fat diet for 6–60 weeks to investigate the progression from MASLD to hepatocellular carcinoma.
{"title":"Modelling human liver disease: from steatotic liver disease to MASH-HCC","authors":"Christian Stoess, Ariel E. Feldstein","doi":"10.1038/s41574-024-01054-z","DOIUrl":"10.1038/s41574-024-01054-z","url":null,"abstract":"Having more refined mouse models of metabolic dysfunction-associated steatotic liver disease (MASLD; also known as nonalcoholic fatty liver disease) will help to advance research into this disease. In their study, Jeong and colleagues use streptozotocin together with a high-fat diet for 6–60 weeks to investigate the progression from MASLD to hepatocellular carcinoma.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 1","pages":"10-11"},"PeriodicalIF":31.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488379","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 : 2024-10-24DOI: 10.1038/s41574-024-01055-y
Laszlo Hegedüs, Endre Vezekenyi Nagy, Enrico Papini, Petros Perros
Liothyronine treatment for some patients with hypothyroidism has preoccupied academics, clinicians and patients for decades, and is a controversial topic in thyroidology. Persistent symptoms are at the heart of this discourse and, contrary to scientific evidence, liothyronine use is increasingly common. Aetiologies and interventions beyond thyroid dysregulation and pharmacological approaches must be pursued.
{"title":"Limiting the use and misuse of liothyronine in hypothyroidism","authors":"Laszlo Hegedüs, Endre Vezekenyi Nagy, Enrico Papini, Petros Perros","doi":"10.1038/s41574-024-01055-y","DOIUrl":"10.1038/s41574-024-01055-y","url":null,"abstract":"Liothyronine treatment for some patients with hypothyroidism has preoccupied academics, clinicians and patients for decades, and is a controversial topic in thyroidology. Persistent symptoms are at the heart of this discourse and, contrary to scientific evidence, liothyronine use is increasingly common. Aetiologies and interventions beyond thyroid dysregulation and pharmacological approaches must be pursued.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 1","pages":"3-4"},"PeriodicalIF":31.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488378","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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