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
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.
{"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}
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
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.
目前的研究检测了恩格列净对2型糖尿病（T2D）患者和非2型糖尿病患者肝葡萄糖生成（HGP）和全身去甲肾上腺素（NE）转化的影响。该研究随机选择36名T2D患者和36名非T2D患者，以双盲方式接受恩帕列净或匹配的安慰剂（2:1比例），为期12周。在基线和开始使用恩格列净或安慰剂治疗后第1天和第12周，分别用[3-3H]葡萄糖和[3H]NE输注来测量HGP和NE的转换。恩帕列净使T2D患者的HGP升高22%，无T2D患者的HGP升高19%，并且HGP升高持续到第12周。在给予恩格列净1天后，两组的全身NE周转率均显著下降，且NE周转率持续下降12周。NE周转率的降低与第12周HGP的升高呈显著负相关(r = 0.64, P <；0.001)，但与给药第1天HGP升高无关（r = 0.09, P = ns）。这些结果表明，恩格列净导致NE周转的长期减少，并且NE周转的减少与HGP的增加密切相关。钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）对交感神经活动的调节可以解释SGLT2i的一些全身作用，但不能解释SGLT2i诱导的长期HGP升高。钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）导致肝糖生成（HGP）增加。我们之前的研究表明，SGLT2i导致全身去甲肾上腺素（NE）周转率迅速（在4小时内）增加，这可以解释HGP的增加。由于SGLT2i引起的HGP增加是持久的，因此我们研究了SGLT2i对NE周转率的长期影响。在开始治疗后的第1天和第12周，尽管葡萄糖产量增加，但恩帕列净引起的全身NE周转量下降，NE周转量下降的幅度与恩帕列净引起的HGP升高呈负相关。
{"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 &lt; 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}
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
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.
{"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}
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
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.
{"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}
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.
{"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}
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.
{"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}
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.
{"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 &gt;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}
The prevalence of prediabetes is increasing globally, driven by rising obesity rates. Prediabetes increases the risk of neurodegenerative diseases, which are linked by neuroinflammation. Protein tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. However, the role and underlying mechanisms of PTP1B in prediabetes-induced cognitive impairment remain poorly understood. Here, we observed elevated levels of PTP1B in the serum of individuals with obesity and prediabetes. In mouse model of obesity and prediabetes induced by a high-fat, high-sugar diet (HFHSD), the PTP1B level was significantly increased in the hippocampus, correlating with cognitive decline, microglial activation, and inflammatory response. In a series of mouse models with selective PTP1B deletion, the loss of PTP1B in the hippocampus, hippocampal neurons, and leptin receptor–expressing cells reversed impairments of hippocampal leptin synaptic signaling, synaptic ultrastructure and associated proteins, and cognitive function in HFHSD-fed prediabetic mice. In a palmitic acid-induced, prediabetic, hippocampal neuronal model, genetic knockout or pharmacological inhibition of PTP1B effectively restored synaptic signaling and neurite outgrowth. These findings underscore the critical role of hippocampal neuronal PTP1B in mediating impairments of synaptic signaling leading to cognitive decline in prediabetes and suggest its significant therapeutic potential in addressing neurodegeneration. Article Highlights The present study reveals a previously unknown molecular mechanism linking prediabetes to neurodegeneration, addressing a critical gap in understanding metabolic-neurological interplay. We investigated whether PTP1B mediates prediabetes-induced cognitive impairment. PTP1B impaired synaptic signaling and synaptic ultrastructure in hippocampal neurons, contributing to cognitive decline in prediabetes. PTP1B is a novel therapeutic target for prediabetes-associated neurodegeneration.
{"title":"Reducing PTP1B in the Hippocampus Protects Against Cognitive Decline in Prediabetes","authors":"Menglu Zhou, Xiaoying Yang, Xing Ge, Jiajia Chen, Wanyun Wu, Mingxuan Zheng, Xiaocheng Zhu, Xiaoying Cui, Renxian Tang, Kuiyang Zheng, Xu-Feng Huang, Libin Yao, Yinghua Yu","doi":"10.2337/db24-1167","DOIUrl":"https://doi.org/10.2337/db24-1167","url":null,"abstract":"The prevalence of prediabetes is increasing globally, driven by rising obesity rates. Prediabetes increases the risk of neurodegenerative diseases, which are linked by neuroinflammation. Protein tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. However, the role and underlying mechanisms of PTP1B in prediabetes-induced cognitive impairment remain poorly understood. Here, we observed elevated levels of PTP1B in the serum of individuals with obesity and prediabetes. In mouse model of obesity and prediabetes induced by a high-fat, high-sugar diet (HFHSD), the PTP1B level was significantly increased in the hippocampus, correlating with cognitive decline, microglial activation, and inflammatory response. In a series of mouse models with selective PTP1B deletion, the loss of PTP1B in the hippocampus, hippocampal neurons, and leptin receptor–expressing cells reversed impairments of hippocampal leptin synaptic signaling, synaptic ultrastructure and associated proteins, and cognitive function in HFHSD-fed prediabetic mice. In a palmitic acid-induced, prediabetic, hippocampal neuronal model, genetic knockout or pharmacological inhibition of PTP1B effectively restored synaptic signaling and neurite outgrowth. These findings underscore the critical role of hippocampal neuronal PTP1B in mediating impairments of synaptic signaling leading to cognitive decline in prediabetes and suggest its significant therapeutic potential in addressing neurodegeneration. Article Highlights The present study reveals a previously unknown molecular mechanism linking prediabetes to neurodegeneration, addressing a critical gap in understanding metabolic-neurological interplay. We investigated whether PTP1B mediates prediabetes-induced cognitive impairment. PTP1B impaired synaptic signaling and synaptic ultrastructure in hippocampal neurons, contributing to cognitive decline in prediabetes. PTP1B is a novel therapeutic target for prediabetes-associated neurodegeneration.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"35 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602898","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}
Ryota Inoue, Takahiro Tsuno, Takashi Nishimura, Setsuko Fukushima, Sayaka Hirai, Masayuki Shimoda, Yuto Yoshinari, Chisato Sakai, Tatsuya Kin, Euodia X. I. Hui Lim, Adrian Kee Keong Teo, Shinichi Matsumoto, A. M. James Shapiro, Jun Shirakawa
Imeglimin, a drug for type 2 diabetes, reportedly promotes β-cell proliferation and increases β-cell survival; however, the detailed underlying molecular mechanism remains unclear. Here, we investigated metabolites in pancreatic islets after imeglimin treatment via liquid chromatography with tandem mass spectrometry. Treatment with imeglimin for 1 h significantly altered the levels of 17 metabolites at 5.6 mmol/L glucose and 11 metabolites at 11.1 mmol/L glucose. After 24 h of treatment, imeglimin changed the levels of 12 metabolites at 5.6 mmol/L glucose and 28 metabolites at 11.1 mmol/L glucose. The metabolites altered by imeglimin under high-glucose conditions were involved in NAD synthesis, amino acid metabolism, and nucleic acid metabolism. Adenylosuccinate (S-AMP), produced by adenylosuccinate synthase (ADSS) from inosine monophosphate (IMP) and aspartate, increased 2.98-fold after treatment with imeglimin. The levels of IMP and aspartate and both the mRNA and protein levels of ADSS were elevated following imeglimin treatment in islets. Alanosine, an inhibitor of ADSS, suppressed imeglimin-induced β-cell proliferation and survival in mouse islets, human islets, human pluripotent stem cell–derived β-cells, and porcine islets. Taken together, these findings suggest that chronic treatment with imeglimin promotes β-cell proliferation and survival partly through an increase in S-AMP production. Article Highlights Although imeglimin promotes β-cell proliferation and ameliorates β-cell apoptosis, the detailed metabolic changes induced by imeglimin in β-cells are unknown. Imeglimin increases adenylosuccinate (S-AMP), which is produced by adenylosuccinate synthase (ADSS) from inosine monophosphate and aspartate, and imeglimin also increases amino acid content, including aspartate, in mouse islets. Inhibition of S-AMP production by an ADSS inhibitor reduces the ability of imeglimin to increase β-cell proliferation and ameliorate β-cell apoptosis in mouse islets, human islets, porcine islets, and human pluripotent stem cell–derived β-cells. Imeglimin increases S-AMP to promote β-cell proliferation and ameliorate β-cell apoptosis.
{"title":"Adenylosuccinate Mediates Imeglimin-Induced Proliferative and Antiapoptotic Effects in β-Cells","authors":"Ryota Inoue, Takahiro Tsuno, Takashi Nishimura, Setsuko Fukushima, Sayaka Hirai, Masayuki Shimoda, Yuto Yoshinari, Chisato Sakai, Tatsuya Kin, Euodia X. I. Hui Lim, Adrian Kee Keong Teo, Shinichi Matsumoto, A. M. James Shapiro, Jun Shirakawa","doi":"10.2337/db24-1090","DOIUrl":"https://doi.org/10.2337/db24-1090","url":null,"abstract":"Imeglimin, a drug for type 2 diabetes, reportedly promotes β-cell proliferation and increases β-cell survival; however, the detailed underlying molecular mechanism remains unclear. Here, we investigated metabolites in pancreatic islets after imeglimin treatment via liquid chromatography with tandem mass spectrometry. Treatment with imeglimin for 1 h significantly altered the levels of 17 metabolites at 5.6 mmol/L glucose and 11 metabolites at 11.1 mmol/L glucose. After 24 h of treatment, imeglimin changed the levels of 12 metabolites at 5.6 mmol/L glucose and 28 metabolites at 11.1 mmol/L glucose. The metabolites altered by imeglimin under high-glucose conditions were involved in NAD synthesis, amino acid metabolism, and nucleic acid metabolism. Adenylosuccinate (S-AMP), produced by adenylosuccinate synthase (ADSS) from inosine monophosphate (IMP) and aspartate, increased 2.98-fold after treatment with imeglimin. The levels of IMP and aspartate and both the mRNA and protein levels of ADSS were elevated following imeglimin treatment in islets. Alanosine, an inhibitor of ADSS, suppressed imeglimin-induced β-cell proliferation and survival in mouse islets, human islets, human pluripotent stem cell–derived β-cells, and porcine islets. Taken together, these findings suggest that chronic treatment with imeglimin promotes β-cell proliferation and survival partly through an increase in S-AMP production. Article Highlights Although imeglimin promotes β-cell proliferation and ameliorates β-cell apoptosis, the detailed metabolic changes induced by imeglimin in β-cells are unknown. Imeglimin increases adenylosuccinate (S-AMP), which is produced by adenylosuccinate synthase (ADSS) from inosine monophosphate and aspartate, and imeglimin also increases amino acid content, including aspartate, in mouse islets. Inhibition of S-AMP production by an ADSS inhibitor reduces the ability of imeglimin to increase β-cell proliferation and ameliorate β-cell apoptosis in mouse islets, human islets, porcine islets, and human pluripotent stem cell–derived β-cells. Imeglimin increases S-AMP to promote β-cell proliferation and ameliorate β-cell apoptosis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"22 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603078","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}
Xuan Ren, Gaobo Zhang, Boqian Zhou, Wenting Gu, Xue Jiang, Hongen Liao, Meng-Xing Tang, Xin Liu
Microvasculature and hemodynamic changes in the cerebrovascular system are valuable indicators for the investigation of diabetic cerebrovascular disease. However, it is challenging for conventional imaging techniques to capture these minute features, meaning that the specific effects of diabetes on the brain vasculature and its potential disruption of brain function remain inadequately investigated. Ultrasound localization microscopy, with its unprecedented subdiffraction resolution and microvascular sensitivity, enables previously unobserved subtle variations to be revealed. Here, we aimed to leverage this advanced imaging technology to explore the alterations of brain in a diabetic rodent model in vivo. Parallel comparisons were made between diabetic rats and age-matched controls, and longitudinal assessments were performed before and after development of diabetes. In parallel comparisons, we found that rats with diabetes had significantly reduced vascular density in several key brain regions, including the striatum (13.70%), basal forebrain (8.48%), thalamus (12.20%), hypothalamus (20.85%), and hippocampus (8.73%). These findings were further supported by vascular staining and high-field MRI results. In addition, we demonstrated that a slowing of blood flow could be observed in the above brain regions. These results pave the way to understanding the effects of diabetes on the cerebral vasculature and may enable the future development of therapeutic and intervention strategies for diabetic cerebrovascular lesions. ARTICLE HIGHLIGHTS Cerebral microvascular disease can be triggered in people with diabetes who have chronic hyperglycemia. The aim of our study was to understand what effect diabetes has on the cerebral vasculature. In a rodent model, diabetes caused varying degrees of reduced cerebral vascular density and slowed cerebral blood flow in the brain striatum, basal forebrain, thalamus, hypothalamus, and hippocampus. There is a correlation between vessel density and blood flow velocity and the correlation changes in the diabetic state.
{"title":"Revealing Cerebral Microvascular Changes in Diabetic Rodents With Ultrasound Localization Microscopy","authors":"Xuan Ren, Gaobo Zhang, Boqian Zhou, Wenting Gu, Xue Jiang, Hongen Liao, Meng-Xing Tang, Xin Liu","doi":"10.2337/db25-0007","DOIUrl":"https://doi.org/10.2337/db25-0007","url":null,"abstract":"Microvasculature and hemodynamic changes in the cerebrovascular system are valuable indicators for the investigation of diabetic cerebrovascular disease. However, it is challenging for conventional imaging techniques to capture these minute features, meaning that the specific effects of diabetes on the brain vasculature and its potential disruption of brain function remain inadequately investigated. Ultrasound localization microscopy, with its unprecedented subdiffraction resolution and microvascular sensitivity, enables previously unobserved subtle variations to be revealed. Here, we aimed to leverage this advanced imaging technology to explore the alterations of brain in a diabetic rodent model in vivo. Parallel comparisons were made between diabetic rats and age-matched controls, and longitudinal assessments were performed before and after development of diabetes. In parallel comparisons, we found that rats with diabetes had significantly reduced vascular density in several key brain regions, including the striatum (13.70%), basal forebrain (8.48%), thalamus (12.20%), hypothalamus (20.85%), and hippocampus (8.73%). These findings were further supported by vascular staining and high-field MRI results. In addition, we demonstrated that a slowing of blood flow could be observed in the above brain regions. These results pave the way to understanding the effects of diabetes on the cerebral vasculature and may enable the future development of therapeutic and intervention strategies for diabetic cerebrovascular lesions. ARTICLE HIGHLIGHTS Cerebral microvascular disease can be triggered in people with diabetes who have chronic hyperglycemia. The aim of our study was to understand what effect diabetes has on the cerebral vasculature. In a rodent model, diabetes caused varying degrees of reduced cerebral vascular density and slowed cerebral blood flow in the brain striatum, basal forebrain, thalamus, hypothalamus, and hippocampus. There is a correlation between vessel density and blood flow velocity and the correlation changes in the diabetic state.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"153 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593908","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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