Diabetes最新文献

{"title":"DNA Methylation Biomarkers Predict Offspring Metabolic Risk From Mothers With Hyperglycemia in Pregnancy","authors":"Johnny Assaf, Ishant Khurana, Ram Abou Zaki, Claudia H.T. Tam, Ilana Correa, Scott Maxwell, Julie Kinnberg, Malou Christiansen, Caroline Frørup, Heung Man Lee, Harikrishnan Kaipananickal, Jun Okabe, Safiya Naina Marikar, Kwun Kiu Wong, Cadmon K.P. Lim, Lai Yuk Yuen, Xilin Yang, Chi Chiu Wang, Juliana C.N. Chan, Kevin Y.L. Yip, William L. Lowe, Wing Hung Tam, Ronald C.W. Ma, Assam El-Osta","doi":"10.2337/db25-0105","DOIUrl":"https://doi.org/10.2337/db25-0105","url":null,"abstract":"Gestational diabetes mellitus affects almost 18 million pregnancies worldwide, increasing by >70% in the past 20 years. DNA methylation has been associated with maternal hyperglycemia and type 2 diabetes risk in offspring. This study hypothesized that hyperglycemia during pregnancy influences DNA methylation changes at birth that mediate metabolic risk in offspring. Cord blood samples (n = 112) were obtained from women with normal (n = 43), impaired (n = 31), and low (n = 38) glucose tolerance enrolled in the Hong Kong field center of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. Differentially methylated regions (DMRs) were identified using methylation sequencing and evaluated for their association with offspring metabolic dysfunction. Receiver operating characteristic curve analysis assessed the predictive value of DMRs for the classification of maternal glycemic status. These DMRs were assessed in human β-cells and pancreatic ductal epithelial cells in response to hyperglycemic stimuli. Methylation sequencing identified 19 methylation biomarkers in cord blood associated with maternal hyperglycemia, which correlated with offspring metabolic abnormalities. Incorporating the 19 DMRs improved the prediction of offspring β-cell dysfunction at 7, 11, and 18 years of age from area under the curve (AUC) scores ranging from 0.53 to 0.68 using clinical factors alone to AUC scores ranging from 0.71 to 0.95. Validation in human cell models confirmed that hyperglycemia influences methylation-dependent gene expression. This study demonstrates that DNA methylation biomarkers in cord blood predict offspring metabolic dysfunction, highlighting their potential as early indicators of diabetes risk. The findings align with methylation-mediated regulation in human pancreatic cells. ARTICLE HIGHLIGHTS Maternal hyperglycemia is linked to 19 cord blood DNA methylation biomarkers that predict offspring metabolic dysfunction. These methylation changes, associated with maternal glycemic status, improved the prediction of β-cell dysfunction at 7, 11, and 18 years of age compared with clinical factors alone. Validation in human β-cells and pancreatic ductal epithelial cells confirmed that hyperglycemia influences methylation-dependent gene expression. These findings highlight the role of epigenetic modifications at birth as early indicators of diabetes risk, suggesting that in utero hyperglycemic exposure may mediate long-term metabolic outcomes in offspring.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"70 1","pages":"1695-1707"},"PeriodicalIF":7.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898112","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}

{"title":"Erratum. Liraglutide Treatment Reverses Unconventional Cellular Defects in Induced Pluripotent Stem Cell–Derived β-Cells Harboring a Partially Functional WFS1 Variant. Diabetes 2025;74:1273–1288","authors":"Silvia Torchio, Gabriel Siracusano, Federica Cuozzo, Valentina Zamarian, Silvia Pellegrini, Fabio Manenti, Riccardo Bonfanti, Giulio Frontino, Valeria Sordi, Raniero Chimienti, Lorenzo Piemonti","doi":"10.2337/db25-er10a","DOIUrl":"https://doi.org/10.2337/db25-er10a","url":null,"abstract":"In the article cited above, TG was incorrectly introduced as transforming secretory granules in the main text. The correct term is thapsigargin. The editors apologize for the error. The online version of the article (https://doi.org/10.2337/db24-0720) has been updated to correct the error.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"29 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786535","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}

{"title":"ALY688 Attenuates Iron-Induced ER Stress and Insulin Resistance via Activation of ER-Phagy","authors":"Khang Nguyen, Jialing Tang, Damian Gatica, Ryan C. Russell, Hye Kyoung Sung, Gary Sweeney","doi":"10.2337/db25-0405","DOIUrl":"https://doi.org/10.2337/db25-0405","url":null,"abstract":"Iron overload (IO) is a common contributing factor to aspects of the metabolic syndrome (MetS), including insulin resistance. Mechanisms of IO-induced insulin resistance include elevated oxidative stress, endoplasmic reticulum (ER) stress and impaired autophagy. Using an Akt biosensor L6 skeletal muscle cell line, we found that the adiponectin receptor agonist ALY688 prevented impaired insulin signaling in response to IO. Mechanistically, ALY688 counteracted IO-dependent effects on ER stress, the unfolded protein response (UPR), and autophagic flux. Importantly, we found that ALY688 induced FAM134B-dependent ER-phagy (reticulophagy) to ameliorate ER stress. The beneficial effects of ALY688 were attenuated in cells lacking Atg7 or FAM134B, highlighting the importance of selective autophagy of the ER by FAM134B in mitigating IO-induced impaired insulin signaling. These findings translated to a mouse model of IO in which ALY688 improved glucose tolerance, insulin sensitivity, UPR activation, FAM134B expression, and autophagy flux. Collectively, our results demonstrate that ALY688 effectively attenuated IO-induced ER stress and insulin resistance in both mice and cellular skeletal muscle models via stimulation of the UPR and ER-phagy. Article Highlights This study adds mechanistic insight to the association between excess iron and insulin resistance and identifies an effective intervention strategy. Using a cellular skeletal muscle cell model and a preclinical animal model, we show that iron elicits endoplasmic reticulum (ER) stress and impairs insulin signaling. The adiponectin receptor agonist peptide ALY688 counteracts iron-induced ER stress and maintains insulin sensitivity. Loss-of-function approaches indicated that ALY688 acts via an autophagy-dependent, and specifically ER-phagy–dependent, mechanism.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"12 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778512","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}

{"title":"The Islet-1 Interaction Partner Rnf20 Regulates Glucose Homeostasis and Pancreatic β-Cell Identity","authors":"Tanya H. Pierre, Maigen M. Bethea, Kristen Coutinho, Yanping Liu, Jin-Hua Liu, Min Guo, Sahil Chada, Sylvia M. Evans, Wei Li, Sushant Bhatnagar, Roland W. Stein, Chad S. Hunter","doi":"10.2337/db25-0167","DOIUrl":"https://doi.org/10.2337/db25-0167","url":null,"abstract":"Diabetes is characterized by a loss of functional β-cell mass; therefore, identifying factors involved in establishing and preserving β-cells is critical to combat rising diabetes incidence. While transcription factors are crucial β-cell regulators, knowledge of coregulators facilitating gene expression is limited. Previously, we demonstrated that the islet-1 (Isl1) transcription factor forms complexes with ubiquitin ligases ring finger 20 (Rnf20) and Rnf40 to regulate β-cells in vitro. Here, we investigated whether Rnf20-mediated complexes are required for β-cell function in adult islets by characterizing a novel β-cell–enriched Rnf20 knockout mouse model. Tamoxifen induction of Rnf20 recombination prompted a robust loss of histone 2B monoubiquitination, imparted severe hyperglycemia and glucose intolerance, and elicited an overall reduction in insulin content. Expression of mRNAs and proteins involved in glucose-stimulated insulin secretion and β-cell identity were also dysregulated in Rnf20Δβ-cell mice. Comparative analyses of the loss of either Rnf20 or Isl1 yielded similar changes in the β-cell regulome, supporting that Isl1::Rnf20 complexes are critical regulators of β-cell identity and function. Isl1::Rnf20 complexes are maintained in human tissues wherein they regulate insulin expression, secretion, and content. These findings increase our understanding of key players in β-cell maintenance, which is crucial for the advancement of β-cell derivation diabetes therapeutics. Article Highlights Transcription factor Islet-1 (Isl1) and ubiquitin ligase Ring Finger 20 (Rnf20) complexes regulate insulin secretion and β-cell gene expression in vitro. Loss of Rnf20 in adult β-cells disrupts β-cell identity and insulin processing, production, and secretion. In complex with Isl1, Rnf20 influences the β-cell regulome and supports proper glucose homeostasis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"3 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755838","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}

{"title":"Empagliflozin Enhances Hepatic Glucose Production and Reduces Total-Body Norepinephrine Turnover Rate: A Randomized Trial","authors":"Siham Abdelgani, Ahmed Khattab, John M. Adams, Fahd Al-Mulla, Mohamed Abu-Farha, Gozde Baskoy, Jehad Abubaker, Aurora Merovci, Ralph A. DeFronzo, Renata Belfort De Aguiar, Muhammad Abdul-Ghani","doi":"10.2337/db25-0210","DOIUrl":"https://doi.org/10.2337/db25-0210","url":null,"abstract":"The current study examined the effect of empagliflozin on hepatic glucose production (HGP) and total-body norepinephrine (NE) turnover in individuals with and without type 2 diabetes (T2D). The study randomized 36 individuals with T2D and 36 individuals without T2D to receive in a double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks. HGP and NE turnover were measured with [3-3H]glucose and [3H]NE infusion, respectively, at baseline and at day 1 and 12 weeks after starting therapy with empagliflozin or placebo. Empagliflozin increased HGP by 22% in individuals with T2D and by 19% in those without T2D, and the increase in HGP persisted at week 12. Total-body NE turnover significantly decreased in both groups at 1 day after empagliflozin administration, and the decrease in NE turnover persisted for 12 weeks. The decrease in NE turnover strongly and inversely correlated with the increase in HGP at week 12 (r = 0.64, P < 0.001), but not with the increase in HGP on day 1 of empagliflozin administration (r = 0.09, P = ns). These results demonstrate that empagliflozin causes a long-term reduction in NE turnover and that the decrease in NE turnover was strongly correlated with the increase in HGP. Regulation of sympathetic activity by sodium–glucose cotransporter 2 inhibitors (SGLT2i) can explain some of the systemic actions of SGLT2i, but cannot explain the long-term SGLT2i-induced rise in HGP. ARTICLE HIGHLIGHTS Sodium–glucose cotransporter 2 inhibitors (SGLT2i) cause an increase in hepatic glucose production (HGP). We previously showed that SGLT2i cause a rapid (within 4 hours) increase in the total-body norepinephrine (NE) turnover rate, which could explain the increase in HGP. Because the increase in HGP caused by SGLT2i is long-lasting, we examined the long-term effect of SGLT2i on the NE turnover rate. Empagliflozin caused a decrease in total-body NE turnover at 1 day and at 12 weeks after starting therapy, despite an increase in glucose production, and the magnitude of decrease in NE turnover inversely correlated with the increase in HGP caused by empagliflozin.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"10 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645584","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}

{"title":"The GLP-1 Receptor Agonist Dulaglutide Attenuates Hepatic Steatosis in Obesity via a Weight-Independent Mechanism","authors":"Dharti Shantaram, Xilal Y. Rima, David Bradley, Joey Z. Liu, Valerie P. Wright, Anastasiia Amari, Anahita Jalilvand, Joseph Rottinghaus, Jaden M. Fernandes, Alan J. Smith, Dana Middendorf, Martha Yearsley, Debasish Roy, Willa A. Hsueh","doi":"10.2337/db24-0861","DOIUrl":"https://doi.org/10.2337/db24-0861","url":null,"abstract":"Recent clinical trials testing glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrated improved outcomes in obesity-associated complications, including cardiovascular events and hepatic steatosis. Despite their positive effects, whether the benefits of GLP-1 RAs are due to weight loss or are a direct therapeutic effect remains unclear. Therefore, we pair fed middle-aged low-density lipoprotein receptor knockout (Ldlr−/−) mice a western high-fat diet to model complex atherosclerosis and metabolic dysfunction–associated fatty liver disease (MAFLD) and then administered dulaglutide or placebo twice a week for 6 weeks. Older compared with younger Ldlr−/− mice develop accelerated atherosclerosis resembling human lesions, and advanced MAFLD. Dulaglutide improved glucose tolerance and MAFLD independent of weight but had no effects on insulin sensitivity or atherosclerosis compared with weight-matched placebo-treated mice. The diminished hepatic steatosis was attributed to both decreased de novo lipogenesis and reduced adipose tissue lipolysis. These changes were associated with amelioration of inflammation and oxidative stress with a marked attenuation in M1-like macrophages in the liver. Therefore, dulaglutide has therapeutic effects on the liver that may further synergize with GLP-1 RA–mediated weight loss to reduce hepatic steatosis and inflammation, a major complication of obesity. ARTICLE HIGHLIGHTS Glucagon-like peptide-1 receptor agonists are promising therapies in treating various obesity-associated diseases; however, the mechanisms are convoluted with the benefits of weight loss. Dulaglutide has weight-independent therapeutic effects on the liver, reducing hepatic steatosis and improving liver function. Dulaglutide reduces de novo lipogenesis, lipid droplet stability, inflammation, and oxidative stress in the liver and lipolysis in adipose tissue. Weight loss may play an important role in glucagon-like peptide-1 receptor agonists’ effect on decreasing coronary vascular disease risk.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"2 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639848","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}

{"title":"Future Directions and Clinical Trial Considerations for Novel Islet β-Cell Replacement Therapies for Type 1 Diabetes","authors":"Marjana Marinac, Michael R. Rickels, Jason L. Gaglia, Philip J. O’Connell, Paul R. Johnson, Lorenzo Piemonti, Bruce S. Schneider, Julia L. Greenstein, Sanjoy Dutta, Esther Latres","doi":"10.2337/dbi24-0037","DOIUrl":"https://doi.org/10.2337/dbi24-0037","url":null,"abstract":"Type 1 diabetes results from the immune-mediated loss of insulin-producing pancreatic islet β-cells, rendering those affected dependent on exogenous insulin to survive. Despite the array of choices available for insulin delivery, treatment to maintain near-normal glucose metabolism while avoiding hypo- and hyperglycemia remains a challenge. After two decades of clinical trials across four continents, the transplantation of islets isolated from deceased donor pancreases has been shown to be both safe and efficacious in patients experiencing severe hypoglycemia (level 3) or already requiring immunosuppression to support a kidney transplant, offering a distinct set of advantages to appropriate candidates. We are entering a phase of clinical development where islet β-cell replacement approaches should be recognized and studied as more than just a rescue therapy for those with severe hypoglycemia and could be expanded to all individuals with type 1 diabetes. Our aim is to expedite translation of cellular therapy for all individuals living with type 1 diabetes by focusing on new emerging islet β-cell replacement approaches and proposing clinical trial designs that accelerate their development. As we support expansion of the population to be included in the investigation of novel therapies, this perspective presents a road map and clinical trial considerations to guide the development of the next generations of islet β-cell replacement therapies that address the unmet needs of the broader type 1 diabetes community. ARTICLE HIGHLIGHTS Current research and development are ushering in a new era of novel islet β-cell replacement therapies that can no longer be considered solely a rescue treatment for those with unstable glucose management. Clinical trial design must ensure that the application of islet β-cell replacement is broadened beyond the indication of severe hypoglycemia given the potential for establishing insulin-independent normoglycemia. It is imperative that people with type 1 diabetes and their clinicians are at the center of the risk-benefit equipoise as evidence for the safety of cellular products, transplant sites, and immune protection strategies accumulates and an increasing number of options for intervention become available.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"108 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Dorsal Raphe Nucleus and the Integrative Control of Feeding: A Report on Research Supported by Pathway to Stop Diabetes","authors":"Alexander R. Nectow","doi":"10.2337/dbi24-0015","DOIUrl":"https://doi.org/10.2337/dbi24-0015","url":null,"abstract":"Obesity is a major risk factor for the development of type 2 diabetes (T2D). While the connection between these two disease entities is still incompletely understood, even modest weight loss can greatly reduce the risk of developing T2D and its sequelae. With the recent success of antiobesity pharmacotherapies, which appear to exert their effects largely through the brainstem, there has been a resurgent interest in understanding the neural mechanisms governing food intake and body weight. Over the past decade or so, my laboratory has sought to understand the neural control mechanism underlying energy homeostasis, through the lens of a small region in the brainstem, known as the dorsal raphe nucleus (DRN). The DRN is a molecularly heterogeneous structure in the dorsal midbrain, which we have found contains multiple cell types that are capable of regulating food intake and energy expenditure, and consequently, body weight. Here, I detail progress made by our laboratory and others over the past decade in our understanding of the DRN at the molecular, cellular, and circuit levels, with a particular emphasis on the integrative regulation of feeding. This line of research has established the DRN as an important regulator of energy balance and opens up exciting new lines of inquiry into the neural control mechanism governing food intake and body weight. This article is part of a series of perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program. ARTICLE HIGHLIGHTS The dorsal raphe nucleus (DRN) is a key regulator of food intake and body weight. The DRN has historically been associated with feeding, as it houses the single largest population of serotonergic neurons in the mammalian brain. Few studies have demonstrated a direct role for DRN serotonergic neurons in regulating feeding; none of these studies have demonstrated effects near those elicited by serotonin, itself. There are many nonserotonergic cell types in the DRN that play an integral role in feeding. These DRN cell types play important roles in both hunger and satiation.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"3 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cushing Syndrome, Hypercortisolism, and Glucose Homeostasis: A Review","authors":"Ralph A. DeFronzo, Richard J. Auchus","doi":"10.2337/db25-0120","DOIUrl":"https://doi.org/10.2337/db25-0120","url":null,"abstract":"Until recently, the prevalence of endogenous Cushing syndrome has been considered to be low. However, improved diagnostic strategies and increased awareness have broadened our understanding of hypercortisolism and its role in the pathophysiology of type 2 diabetes, obesity, hypertension, and cardiovascular disease. Recent studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with difficult-to-control type 2 diabetes, despite treatment with multiple glucose-lowering agents, have hypercortisolism as a causative factor in their poorly managed diabetes. In this review, we examine the pathophysiologic mechanisms via which excess cortisol contributes to the impairment in glucose homeostasis and recommend that hypercortisolism be added to the Ominous Octet to form the Noxious Nine as the pathophysiologic foundation for the development of type 2 diabetes. ARTICLE HIGHLIGHTS Hypercortisolism as a causative factor in the development of type 2 diabetes has received scant attention. Studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with poorly managed type 2 diabetes, despite treatment with multiple glucose-lowering agents, have endogenous hypersecretion of cortisol as a causative factor for their hyperglycemia. In vivo and in vitro studies in animals and humans have demonstrated that excess exposure to glucocorticoids can promote insulin resistance in muscle, liver, and adipocytes and impair insulin secretion. We propose a reverberating cycle in which hypercortisolism disrupts the normal circadian rhythm causing insulin resistance and hyperinsulinemia, which in turn further disrupts the hypothalamic-pituitary-adrenal axis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"2 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treating Sarcopenic Obesity in the Era of Incretin Therapies: Perspectives and Challenges","authors":"Alissa S. Chen, John A. Batsis","doi":"10.2337/dbi25-0004","DOIUrl":"https://doi.org/10.2337/dbi25-0004","url":null,"abstract":"Sarcopenic obesity, a subtype of obesity, is marked by reduced skeletal muscle mass and function, or sarcopenia, and poses a significant health challenge to older adults as it affects an estimated 28.3% of people aged >60 years. This subtype is unique to older adults as aging exacerbates sarcopenia and obesity due to changes in energy metabolism, hormones and inflammatory markers, and lifestyle factors. Traditional treatments for sarcopenic obesity have been focused on exercise and dietary modifications to reduce fat while maintaining muscle mass. Newer glucagon-like peptide 1 receptor agonists (GLP-1RA) and dual gastric inhibitory polypeptide/GLP-1 receptor agonists (GIP/GLP-1RAs), including liraglutide, semaglutide, and tirzepatide, have shown great promise to reduce weight, treat obesity-related complications, improve physical function, and improve quality of life, in younger clinical trial populations. However, the use of GLP-1RAs and GIP/GLP-1RAs has not been exhaustively evaluated in older adults with sarcopenic obesity. These medications come with the risk of loss of muscle mass and an increased rate of adverse events. Thus, clinicians should use them cautiously by weighing the potential benefits against their risks. Herein, we discuss a possible approach to using GLP-1RAs and GIP/GLP-1RAs in patients with sarcopenic obesity, including considerations for patient identification, monitoring, maintenance, and discontinuation. In this article we also discuss the emerging treatments that will be available, which may include activin type II receptor antibodies and selective androgen receptor agonists. We conclude by highlighting the advancement of geroscience as a promising field for individualizing treatments in the future. Article Highlights Sarcopenic obesity, reduced muscle mass and strength coupled with obesity, poses significant health risks to older adults. Aging exacerbates sarcopenia and obesity due to metabolic, hormonal, inflammatory, and lifestyle changes. Traditional interventions emphasize exercise and diet to reduce fat mass while preserving muscle mass. Incretin therapies show promise in weight reduction and physical improvement in younger populations but are minimally studied in older adults. These medications can be used to treat several obesity-related complications, which older adults with sarcopenic obesity are prone to developing. These medications need to be used cautiously among older adults, considering potential muscle mass loss and adverse events.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"12 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}