Pub Date : 2025-09-24DOI: 10.1038/s41574-025-01185-x
Greta Lyons, Julia Priestley
{"title":"Why the science on T3 and genomics is not settled","authors":"Greta Lyons, Julia Priestley","doi":"10.1038/s41574-025-01185-x","DOIUrl":"10.1038/s41574-025-01185-x","url":null,"abstract":"","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 12","pages":"799-799"},"PeriodicalIF":40.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133988","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 : 2025-09-22DOI: 10.1038/s41574-025-01184-y
Roger R. Fan, John D. Beckham, Kartik N. Rajagopalan
The response to infection is an energy-demanding process that bolsters cell division and protein synthesis to overcome a rapidly dividing and invasive pathogen. Paradoxically, anorexia, a conserved behavioural response to infection, sharply limits food intake during this period of high energy demand. Leptin, the release of which from adipocytes is coordinated with the immune response, signals to the hypothalamus to balance energy availability and expenditure with respect to various physiological processes. Congenital deficiency of leptin or its receptor in humans predisposes to infection. Moreover, low serum levels of leptin are associated with poor outcomes in sepsis. Leptin activates pro-opiomelanocortin neurons, which produce melanocortins, a family of peptide hormones that has diverse roles. The melanocortins have targets in many organ systems and their functions include suppressing inflammation and upregulating sympathetic tone. Here, we discuss what is known about leptin and melanocortin signalling in the response to infection, with evidence from preclinical research and human studies. We close by offering insights into how study of these pathways might be translated into therapies for infectious disease as well as new avenues for exploration. In this Review, the authors cover how leptin and melanocortin signalling affect the response to infection by regulating immune cells and the nervous system. The authors also discuss how these signalling pathways might be targeted to improve this response and the potential adverse effects that should be considered as these treatments are investigated.
{"title":"Leptin and melanocortin signalling in the response to infection","authors":"Roger R. Fan, John D. Beckham, Kartik N. Rajagopalan","doi":"10.1038/s41574-025-01184-y","DOIUrl":"10.1038/s41574-025-01184-y","url":null,"abstract":"The response to infection is an energy-demanding process that bolsters cell division and protein synthesis to overcome a rapidly dividing and invasive pathogen. Paradoxically, anorexia, a conserved behavioural response to infection, sharply limits food intake during this period of high energy demand. Leptin, the release of which from adipocytes is coordinated with the immune response, signals to the hypothalamus to balance energy availability and expenditure with respect to various physiological processes. Congenital deficiency of leptin or its receptor in humans predisposes to infection. Moreover, low serum levels of leptin are associated with poor outcomes in sepsis. Leptin activates pro-opiomelanocortin neurons, which produce melanocortins, a family of peptide hormones that has diverse roles. The melanocortins have targets in many organ systems and their functions include suppressing inflammation and upregulating sympathetic tone. Here, we discuss what is known about leptin and melanocortin signalling in the response to infection, with evidence from preclinical research and human studies. We close by offering insights into how study of these pathways might be translated into therapies for infectious disease as well as new avenues for exploration. In this Review, the authors cover how leptin and melanocortin signalling affect the response to infection by regulating immune cells and the nervous system. The authors also discuss how these signalling pathways might be targeted to improve this response and the potential adverse effects that should be considered as these treatments are investigated.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"22 2","pages":"92-101"},"PeriodicalIF":40.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117164","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 : 2025-09-17DOI: 10.1038/s41574-025-01176-y
Blake J. Cochran, Thomas W. King, Kevin Chemello, Shane R. Thomas, Kerry-Anne Rye
Epidemiological studies have identified an inverse association of high-density lipoprotein (HDL) cholesterol with cardiovascular risk. Preclinical studies have shown that HDLs also exhibit cardioprotective functions in cultured cells and animal models. However, large, randomized, placebo-controlled clinical trials of HDL-raising agents have failed to reduce cardiovascular events in humans. Despite this negative outcome, glycaemic control was considerably improved in the patients with type 2 diabetes mellitus who were recruited into these trials. This finding indicated that HDLs might have anti-diabetic functions. This was shown to be the case in cell studies and animal studies, which have established that HDLs and apolipoprotein A1, the main HDL apolipoprotein, improve pancreatic β-cell function and increase insulin sensitivity. On the other hand, diabetes mellitus adversely affects the structure, anti-diabetic functions and cardioprotective functions of HDLs. These complex, closely linked relationships, which are undoubtedly worthy of further investigation, form the focus of this Review. This Review describes the metabolic functions of high-density lipoproteins (HDLs) and the structural and functional changes that they undergo in diabetes mellitus. The authors discuss how diabetes mellitus reduces the ability of HDLs to act as antioxidants, control inflammation and reduce the risk of cardiovascular disease.
{"title":"HDL metabolism and function in diabetes mellitus","authors":"Blake J. Cochran, Thomas W. King, Kevin Chemello, Shane R. Thomas, Kerry-Anne Rye","doi":"10.1038/s41574-025-01176-y","DOIUrl":"10.1038/s41574-025-01176-y","url":null,"abstract":"Epidemiological studies have identified an inverse association of high-density lipoprotein (HDL) cholesterol with cardiovascular risk. Preclinical studies have shown that HDLs also exhibit cardioprotective functions in cultured cells and animal models. However, large, randomized, placebo-controlled clinical trials of HDL-raising agents have failed to reduce cardiovascular events in humans. Despite this negative outcome, glycaemic control was considerably improved in the patients with type 2 diabetes mellitus who were recruited into these trials. This finding indicated that HDLs might have anti-diabetic functions. This was shown to be the case in cell studies and animal studies, which have established that HDLs and apolipoprotein A1, the main HDL apolipoprotein, improve pancreatic β-cell function and increase insulin sensitivity. On the other hand, diabetes mellitus adversely affects the structure, anti-diabetic functions and cardioprotective functions of HDLs. These complex, closely linked relationships, which are undoubtedly worthy of further investigation, form the focus of this Review. This Review describes the metabolic functions of high-density lipoproteins (HDLs) and the structural and functional changes that they undergo in diabetes mellitus. The authors discuss how diabetes mellitus reduces the ability of HDLs to act as antioxidants, control inflammation and reduce the risk of cardiovascular disease.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"22 1","pages":"36-49"},"PeriodicalIF":40.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077733","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 : 2025-09-11DOI: 10.1038/s41574-025-01170-4
Yong-ho Lee, Soo Lim, Melanie J. Davies
The therapeutic scope of sodium–glucose cotransporter 2 (SGLT2) inhibitors has expanded beyond glycaemic regulation in the management of diabetes mellitus. Studies published in the past few years highlight their substantial effect on cardiovascular outcomes, notably in decreasing mortality and the need for heart failure-related hospitalization. These agents also lead to pronounced improvements in a range of renal outcomes. The primary actions of SGLT2 inhibition, glycosuria and natriuresis, are pivotal in enhancing glucose control, promoting weight loss and lowering blood pressure. These effects initiate a series of beneficial mechanisms: facilitating haemodynamic improvement by reducing interstitial volume, enhancing cardiac function, boosting energy efficiency through altered ketone body metabolism and mitigating inflammation and oxidative stress. Additional effects include heightened erythropoiesis, reduced hyperuricaemia and increased levels of angiotensin-converting enzyme 2 and angiotensin (1–7). SGLT2 inhibitors also attenuate sympathetic overactivity by modulating neurohumoral activation and renal afferent signalling, contributing to their cardioprotective and renoprotective profiles. This Review provides a comprehensive overview of the diverse mechanisms underpinning the cardiometabolic and renal effects of SGLT2 inhibitors, emphasizing their clinical relevance and therapeutic potential. In the past decade, the therapeutic scope of sodium–glucose cotransporter 2 (SGLT2) inhibitors has expanded beyond glycaemic regulation in the management of type 2 diabetes mellitus. In this Review, Lim et al. discuss data from clinical studies of SGLT2 inhibitors, demonstrating their multifaceted cardiovascular, metabolic and renal effects, and elucidate the diverse mechanisms underpinning these benefits.
{"title":"Cardiometabolic and renal benefits of sodium–glucose cotransporter 2 inhibitors","authors":"Yong-ho Lee, Soo Lim, Melanie J. Davies","doi":"10.1038/s41574-025-01170-4","DOIUrl":"10.1038/s41574-025-01170-4","url":null,"abstract":"The therapeutic scope of sodium–glucose cotransporter 2 (SGLT2) inhibitors has expanded beyond glycaemic regulation in the management of diabetes mellitus. Studies published in the past few years highlight their substantial effect on cardiovascular outcomes, notably in decreasing mortality and the need for heart failure-related hospitalization. These agents also lead to pronounced improvements in a range of renal outcomes. The primary actions of SGLT2 inhibition, glycosuria and natriuresis, are pivotal in enhancing glucose control, promoting weight loss and lowering blood pressure. These effects initiate a series of beneficial mechanisms: facilitating haemodynamic improvement by reducing interstitial volume, enhancing cardiac function, boosting energy efficiency through altered ketone body metabolism and mitigating inflammation and oxidative stress. Additional effects include heightened erythropoiesis, reduced hyperuricaemia and increased levels of angiotensin-converting enzyme 2 and angiotensin (1–7). SGLT2 inhibitors also attenuate sympathetic overactivity by modulating neurohumoral activation and renal afferent signalling, contributing to their cardioprotective and renoprotective profiles. This Review provides a comprehensive overview of the diverse mechanisms underpinning the cardiometabolic and renal effects of SGLT2 inhibitors, emphasizing their clinical relevance and therapeutic potential. In the past decade, the therapeutic scope of sodium–glucose cotransporter 2 (SGLT2) inhibitors has expanded beyond glycaemic regulation in the management of type 2 diabetes mellitus. In this Review, Lim et al. discuss data from clinical studies of SGLT2 inhibitors, demonstrating their multifaceted cardiovascular, metabolic and renal effects, and elucidate the diverse mechanisms underpinning these benefits.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 12","pages":"783-798"},"PeriodicalIF":40.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031775","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 : 2025-09-11DOI: 10.1038/s41574-025-01171-3
Victor Martinez Leon, Rachel Hilburg, Katalin Susztak
Kidney disease is one of the leading causes of mortality in persons with diabetes mellitus. Diabetic kidney disease (DKD) typically presents with a reduced estimated glomerular filtration rate and, in many but not all cases, with marked proteinuria. Strict glycaemic control and blood pressure control remain foundational in managing DKD, and advances in the understanding of disease mechanisms have redefined the therapeutic landscape. Large outcome trials, such as EMPA-KIDNEY, DAPA-CKD and CREDENCE, have demonstrated that sodium–glucose cotransporter 2 inhibitors slow chronic kidney disease progression and improve cardiovascular outcomes. Glucagon-like peptide 1 receptor agonists reduce albuminuria and preserve estimated glomerular filtration rate, as shown most recently in the FLOW trial. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, lowered renal and cardiovascular risk in the FIDELIO-DKD and FIGARO-DKD trials. Combination approaches (for example, sodium–glucose cotransporter 2 inhibition plus endothelin receptor type A blockade in ZENITH-CKD), aldosterone synthase inhibition, and targeted anti-inflammatory or complement-modifying agents offer additional promise. We summarize the key pathophysiological drivers (glomerular hyperfiltration, podocyte injury, tubulointerstitial inflammation and fibrosis), review established treatments and highlight emerging strategies to prevent or halt DKD. In this Review, the authors discuss the mechanisms by which diabetes mellitus can lead to kidney damage and describe the clinical characteristics of diabetic kidney disease. The Review also covers current treatments for diabetic kidney disease and new therapies that are being developed.
{"title":"Mechanisms of diabetic kidney disease and established and emerging treatments","authors":"Victor Martinez Leon, Rachel Hilburg, Katalin Susztak","doi":"10.1038/s41574-025-01171-3","DOIUrl":"10.1038/s41574-025-01171-3","url":null,"abstract":"Kidney disease is one of the leading causes of mortality in persons with diabetes mellitus. Diabetic kidney disease (DKD) typically presents with a reduced estimated glomerular filtration rate and, in many but not all cases, with marked proteinuria. Strict glycaemic control and blood pressure control remain foundational in managing DKD, and advances in the understanding of disease mechanisms have redefined the therapeutic landscape. Large outcome trials, such as EMPA-KIDNEY, DAPA-CKD and CREDENCE, have demonstrated that sodium–glucose cotransporter 2 inhibitors slow chronic kidney disease progression and improve cardiovascular outcomes. Glucagon-like peptide 1 receptor agonists reduce albuminuria and preserve estimated glomerular filtration rate, as shown most recently in the FLOW trial. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, lowered renal and cardiovascular risk in the FIDELIO-DKD and FIGARO-DKD trials. Combination approaches (for example, sodium–glucose cotransporter 2 inhibition plus endothelin receptor type A blockade in ZENITH-CKD), aldosterone synthase inhibition, and targeted anti-inflammatory or complement-modifying agents offer additional promise. We summarize the key pathophysiological drivers (glomerular hyperfiltration, podocyte injury, tubulointerstitial inflammation and fibrosis), review established treatments and highlight emerging strategies to prevent or halt DKD. In this Review, the authors discuss the mechanisms by which diabetes mellitus can lead to kidney damage and describe the clinical characteristics of diabetic kidney disease. The Review also covers current treatments for diabetic kidney disease and new therapies that are being developed.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"22 1","pages":"21-35"},"PeriodicalIF":40.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031776","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 : 2025-09-11DOI: 10.1038/s41574-025-01177-x
Thomas W. H. Kay, Jennifer J. Couper
Future treatment targets for type 1 diabetes mellitus will be truly normal blood levels of glucose with a minimum of exogenous insulin and no hypoglycaemia. Here, we present some of the landmark trials from the past 20 years that are driving progress to that goal.
{"title":"Twenty years of progress in type 1 diabetes mellitus","authors":"Thomas W. H. Kay, Jennifer J. Couper","doi":"10.1038/s41574-025-01177-x","DOIUrl":"10.1038/s41574-025-01177-x","url":null,"abstract":"Future treatment targets for type 1 diabetes mellitus will be truly normal blood levels of glucose with a minimum of exogenous insulin and no hypoglycaemia. Here, we present some of the landmark trials from the past 20 years that are driving progress to that goal.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 11","pages":"662-663"},"PeriodicalIF":40.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031777","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 : 2025-09-11DOI: 10.1038/s41574-025-01183-z
Carlota Arenillas, Rodrigo A. Toledo
FDA approval of the selective HIF2α inhibitor belzutifan for advanced phaeochromocytoma and paraganglioma (PPGL) is an important milestone in precision oncology. This achievement underscores the power of scientific collaboration in establishing HIF2α as a central driver of PPGL pathogenesis and offers hope for a historically underserved group of patients.
{"title":"FDA fast-track approval of belzutifan is a milestone in rare cancer therapy","authors":"Carlota Arenillas, Rodrigo A. Toledo","doi":"10.1038/s41574-025-01183-z","DOIUrl":"10.1038/s41574-025-01183-z","url":null,"abstract":"FDA approval of the selective HIF2α inhibitor belzutifan for advanced phaeochromocytoma and paraganglioma (PPGL) is an important milestone in precision oncology. This achievement underscores the power of scientific collaboration in establishing HIF2α as a central driver of PPGL pathogenesis and offers hope for a historically underserved group of patients.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 12","pages":"739-740"},"PeriodicalIF":40.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031725","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 : 2025-09-09DOI: 10.1038/s41574-025-01181-1
John A. Hawley, Nolan J. Hoffman
Molecular biology and omics-based approaches over the past 20 years have rapidly advanced the discipline of exercise metabolism. Here, we examine three innovative human metabolic studies that have increased our understanding of exercise’s complex molecular landscape in skeletal muscle and beyond, and highlight key future directions.
{"title":"Twenty years of progress in human exercise metabolism research","authors":"John A. Hawley, Nolan J. Hoffman","doi":"10.1038/s41574-025-01181-1","DOIUrl":"10.1038/s41574-025-01181-1","url":null,"abstract":"Molecular biology and omics-based approaches over the past 20 years have rapidly advanced the discipline of exercise metabolism. Here, we examine three innovative human metabolic studies that have increased our understanding of exercise’s complex molecular landscape in skeletal muscle and beyond, and highlight key future directions.","PeriodicalId":18916,"journal":{"name":"Nature Reviews Endocrinology","volume":"21 11","pages":"658-659"},"PeriodicalIF":40.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017620","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：