In the article cited above, Fig. 7G mistakenly featured the same images as Fig. 7E due to an error during manuscript preparation. The corresponding graphs and associated data interpretation were not affected, and the conclusions remain unchanged. The correct image for Fig. 7G appears below. The authors apologize for the error. The online version of the article (https://doi.org/10.2337/db22-0745) has been updated with the correct image.
在上文引用的文章中，由于稿件准备过程中的错误，图 7G 与图 7E 误用了相同的图像。相应的图表和相关数据解释未受影响，结论保持不变。图 7G 的正确图像如下。作者对此错误深表歉意。文章的网络版 (https://doi.org/10.2337/db22-0745) 已经更新了正确的图片。
{"title":"Erratum. Liraglutide and Exercise Synergistically Attenuate Vascular Inflammation and Enhance Metabolic Insulin Action in Early Diet-Induced Obesity. Diabetes 2023;72:918–931","authors":"Jia Liu, Kevin W. Aylor, Zhenqi Liu","doi":"10.2337/db24-er07a","DOIUrl":"https://doi.org/10.2337/db24-er07a","url":null,"abstract":"In the article cited above, Fig. 7G mistakenly featured the same images as Fig. 7E due to an error during manuscript preparation. The corresponding graphs and associated data interpretation were not affected, and the conclusions remain unchanged. The correct image for Fig. 7G appears below. The authors apologize for the error. The online version of the article (https://doi.org/10.2337/db22-0745) has been updated with the correct image.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140640348","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}
Body fat distribution is a predictor of metabolic health in obesity. In this Classics in Diabetes article, we revisit a 1985 Diabetes article by Swedish investigators Ohlson et al. This work was one of the first prospective population-based studies that established a relationship between abdominal adiposity and the risk for developing diabetes. Here, we discuss evolving concepts regarding the link between regional adiposity and diabetes and other chronic disorders. Moreover, we highlight fundamental questions that remain unresolved.
{"title":"The Expanding Problem of Regional Adiposity: Revisiting a 1985 Diabetes Classic by Ohlson et al.","authors":"Olga T. Gupta, Rana K. Gupta","doi":"10.2337/dbi24-0021","DOIUrl":"https://doi.org/10.2337/dbi24-0021","url":null,"abstract":"Body fat distribution is a predictor of metabolic health in obesity. In this Classics in Diabetes article, we revisit a 1985 Diabetes article by Swedish investigators Ohlson et al. This work was one of the first prospective population-based studies that established a relationship between abdominal adiposity and the risk for developing diabetes. Here, we discuss evolving concepts regarding the link between regional adiposity and diabetes and other chronic disorders. Moreover, we highlight fundamental questions that remain unresolved.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140621496","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}
An agreed-upon consensus model of glucose-stimulated insulin secretion from healthy β-cells is essential for understanding diabetes pathophysiology. Since the discovery of the KATP channel in 1984, an oxidative phosphorylation (OxPhos)–driven rise in ATP has been assumed to close KATP channels to initiate insulin secretion. This model lacks any evidence, genetic or otherwise, that mitochondria possess the bioenergetics to raise the ATP/ADP ratio to the triggering threshold, and conflicts with genetic evidence demonstrating that OxPhos is dispensable for insulin secretion. It also conflates the stoichiometric yield of OxPhos with thermodynamics, and overestimates OxPhos by failing to account for established features of β-cell metabolism, such as leak, anaplerosis, cataplerosis, and NADPH production that subtract from the efficiency of mitochondrial ATP production. We have proposed an alternative model, based on the spatial and bioenergetic specializations of β-cell metabolism, in which glycolysis initiates insulin secretion. The evidence for this model includes that 1) glycolysis has high control strength over insulin secretion; 2) glycolysis is active at the correct time to explain KATP channel closure; 3) plasma membrane–associated glycolytic enzymes control KATP channels; 4) pyruvate kinase has favorable bioenergetics, relative to OxPhos, for raising ATP/ADP; and 5) OxPhos stalls before membrane depolarization and increases after. Although several key experiments remain to evaluate this model, the 1984 model is based purely on circumstantial evidence and must be rescued by causal, mechanistic experiments if it is to endure.
{"title":"Glucose Regulation of β-Cell KATP Channels: It Is Time for a New Model!","authors":"Matthew J. Merrins, Richard G. Kibbey","doi":"10.2337/dbi23-0032","DOIUrl":"https://doi.org/10.2337/dbi23-0032","url":null,"abstract":"An agreed-upon consensus model of glucose-stimulated insulin secretion from healthy β-cells is essential for understanding diabetes pathophysiology. Since the discovery of the KATP channel in 1984, an oxidative phosphorylation (OxPhos)–driven rise in ATP has been assumed to close KATP channels to initiate insulin secretion. This model lacks any evidence, genetic or otherwise, that mitochondria possess the bioenergetics to raise the ATP/ADP ratio to the triggering threshold, and conflicts with genetic evidence demonstrating that OxPhos is dispensable for insulin secretion. It also conflates the stoichiometric yield of OxPhos with thermodynamics, and overestimates OxPhos by failing to account for established features of β-cell metabolism, such as leak, anaplerosis, cataplerosis, and NADPH production that subtract from the efficiency of mitochondrial ATP production. We have proposed an alternative model, based on the spatial and bioenergetic specializations of β-cell metabolism, in which glycolysis initiates insulin secretion. The evidence for this model includes that 1) glycolysis has high control strength over insulin secretion; 2) glycolysis is active at the correct time to explain KATP channel closure; 3) plasma membrane–associated glycolytic enzymes control KATP channels; 4) pyruvate kinase has favorable bioenergetics, relative to OxPhos, for raising ATP/ADP; and 5) OxPhos stalls before membrane depolarization and increases after. Although several key experiments remain to evaluate this model, the 1984 model is based purely on circumstantial evidence and must be rescued by causal, mechanistic experiments if it is to endure.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140621495","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 canonical model of glucose-induced increase in insulin secretion involves the metabolism of glucose via glycolysis and the citrate cycle, resulting in increased ATP synthesis by the respiratory chain and the closure of ATP-sensitive K+ (KATP) channels. The resulting plasma membrane depolarization, followed by Ca2+ influx through L-type Ca2+ channels, then induces insulin granule fusion. Merrins and colleagues have recently proposed an alternative model whereby KATP channels are controlled by pyruvate kinase, using glycolytic and mitochondrial phosphoenolpyruvate (PEP) to generate microdomains of high ATP/ADP immediately adjacent to KATP channels. This model presents several challenges. First, how mitochondrially generated PEP, but not ATP produced abundantly by the mitochondrial F1F0-ATP synthase, can gain access to the proposed microdomains is unclear. Second, ATP/ADP fluctuations imaged immediately beneath the plasma membrane closely resemble those in the bulk cytosol. Third, ADP privation of the respiratory chain at high glucose, suggested to drive alternating, phased-locked generation by mitochondria of ATP or PEP, has yet to be directly demonstrated. Finally, the approaches used to explore these questions may be complicated by off-target effects. We suggest instead that Ca2+ changes, well known to affect both ATP generation and consumption, likely drive cytosolic ATP/ADP oscillations that in turn regulate KATP channels and membrane potential. Thus, it remains to be demonstrated that a new model is required to replace the existing, mitochondrial bioenergetics–based model.
葡萄糖诱导胰岛素分泌增加的典型模式包括葡萄糖通过糖酵解和柠檬酸循环进行新陈代谢，从而导致呼吸链合成 ATP 增加以及 ATP 敏感的 K+ (KATP) 通道关闭。由此产生的质膜去极化，随后 Ca2+ 通过 L 型 Ca2+ 通道流入，进而诱导胰岛素颗粒融合。梅林斯及其同事最近提出了另一种模式，即 KATP 通道受丙酮酸激酶控制，利用糖酵解和线粒体磷酸烯醇丙酮酸（PEP）产生紧邻 KATP 通道的高 ATP/ADP 微域。这种模式面临着几个挑战。首先，目前还不清楚线粒体产生的 PEP（而非线粒体 F1F0-ATP 合成酶产生的大量 ATP）如何进入拟议的微域。其次，质膜下的 ATP/ADP 波动与大量细胞质中的 ATP/ADP 波动非常相似。第三，在高糖条件下，呼吸链的 ADP 缺失被认为会驱动线粒体交替、分阶段锁定地产生 ATP 或 PEP，但这一点尚未得到直接证实。最后，用于探讨这些问题的方法可能会因脱靶效应而变得复杂。我们认为，众所周知会影响 ATP 生成和消耗的 Ca2+ 变化可能会驱动细胞膜 ATP/ADP 振荡，进而调节 KATP 通道和膜电位。因此，还需要证明需要一种新的模型来取代现有的基于线粒体生物能的模型。
{"title":"Glucose Regulation of β-Cell KATP Channels: Is a New Model Needed?","authors":"Guy A. Rutter, Ian R. Sweet","doi":"10.2337/dbi23-0031","DOIUrl":"https://doi.org/10.2337/dbi23-0031","url":null,"abstract":"The canonical model of glucose-induced increase in insulin secretion involves the metabolism of glucose via glycolysis and the citrate cycle, resulting in increased ATP synthesis by the respiratory chain and the closure of ATP-sensitive K+ (KATP) channels. The resulting plasma membrane depolarization, followed by Ca2+ influx through L-type Ca2+ channels, then induces insulin granule fusion. Merrins and colleagues have recently proposed an alternative model whereby KATP channels are controlled by pyruvate kinase, using glycolytic and mitochondrial phosphoenolpyruvate (PEP) to generate microdomains of high ATP/ADP immediately adjacent to KATP channels. This model presents several challenges. First, how mitochondrially generated PEP, but not ATP produced abundantly by the mitochondrial F1F0-ATP synthase, can gain access to the proposed microdomains is unclear. Second, ATP/ADP fluctuations imaged immediately beneath the plasma membrane closely resemble those in the bulk cytosol. Third, ADP privation of the respiratory chain at high glucose, suggested to drive alternating, phased-locked generation by mitochondria of ATP or PEP, has yet to be directly demonstrated. Finally, the approaches used to explore these questions may be complicated by off-target effects. We suggest instead that Ca2+ changes, well known to affect both ATP generation and consumption, likely drive cytosolic ATP/ADP oscillations that in turn regulate KATP channels and membrane potential. Thus, it remains to be demonstrated that a new model is required to replace the existing, mitochondrial bioenergetics–based model.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140621590","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}
Christian S. Carl, Marie M. Jensen, Kim A. Sjøberg, Dumitru Constantin-Teodosiu, Ian R. Hill, Rasmus Kjøbsted, Paul L. Greenhaff, Jørgen F.P. Wojtaszewski, Erik A. Richter, Andreas M. Fritzen, Bente Kiens
Insulin resistance is a risk factor for type 2 diabetes and exercise can improve insulin sensitivity. However, following exercise high circulating fatty acid (FA) levels might counteract this. We hypothesized that such inhibition would be reduced by forcibly increasing carbohydrate oxidation through pharmacological activation of the pyruvate dehydrogenase complex (PDC). Insulin-stimulated glucose uptake was examined with a cross-over design in healthy young men (n = 8) in a previously exercised and a rested leg during a hyperinsulinemiceuglycemic clamp five hours after one-legged exercise with: 1) infusion of saline, 2) infusion of intralipid imitating circulating FA levels during recovery from whole-body exercise, and 3) infusion of intralipid + oral PDC-activator, dichloroacetate (DCA). Intralipid infusion reduced insulin-stimulated glucose uptake by 19% in the previously exercised leg, which was not observed in the contralateral rested leg. Interestingly, this effect of intralipid in the exercised leg was abolished by DCA, which increased muscle PDC activity (130%) and flux (acetylcarnitine 130%) and decreased inhibitory phosphorylation of PDC on Ser293 (∼40%) and Ser300 (∼80%). Novel insight is provided into the regulatory interaction between glucose and lipid metabolism during exercise recovery. Coupling exercise and PDC flux activation upregulated the capacity for both glucose transport (exercise) and oxidation (DCA), which seems necessary to fully stimulate insulin-stimulated glucose uptake during recovery.
{"title":"Pharmacological activation of PDC flux reverses lipid-induced inhibition of insulin action in muscle during recovery from exercise","authors":"Christian S. Carl, Marie M. Jensen, Kim A. Sjøberg, Dumitru Constantin-Teodosiu, Ian R. Hill, Rasmus Kjøbsted, Paul L. Greenhaff, Jørgen F.P. Wojtaszewski, Erik A. Richter, Andreas M. Fritzen, Bente Kiens","doi":"10.2337/db23-0879","DOIUrl":"https://doi.org/10.2337/db23-0879","url":null,"abstract":"Insulin resistance is a risk factor for type 2 diabetes and exercise can improve insulin sensitivity. However, following exercise high circulating fatty acid (FA) levels might counteract this. We hypothesized that such inhibition would be reduced by forcibly increasing carbohydrate oxidation through pharmacological activation of the pyruvate dehydrogenase complex (PDC). Insulin-stimulated glucose uptake was examined with a cross-over design in healthy young men (n = 8) in a previously exercised and a rested leg during a hyperinsulinemiceuglycemic clamp five hours after one-legged exercise with: 1) infusion of saline, 2) infusion of intralipid imitating circulating FA levels during recovery from whole-body exercise, and 3) infusion of intralipid + oral PDC-activator, dichloroacetate (DCA). Intralipid infusion reduced insulin-stimulated glucose uptake by 19% in the previously exercised leg, which was not observed in the contralateral rested leg. Interestingly, this effect of intralipid in the exercised leg was abolished by DCA, which increased muscle PDC activity (130%) and flux (acetylcarnitine 130%) and decreased inhibitory phosphorylation of PDC on Ser293 (∼40%) and Ser300 (∼80%). Novel insight is provided into the regulatory interaction between glucose and lipid metabolism during exercise recovery. Coupling exercise and PDC flux activation upregulated the capacity for both glucose transport (exercise) and oxidation (DCA), which seems necessary to fully stimulate insulin-stimulated glucose uptake during recovery.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550681","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}
Christian Springer, Christian Binsch, Deborah Weide, Laura Toska, Anna Lena Cremer, Heiko Backes, Anna K. Scheel, Lena Espelage, Jörg Kotzka, Sebastian Sill, Anette Kurowski, Daebin Kim, Sandra Karpinski, Theresia M. Schnurr, Torben Hansen, Sonja Hartwig, Stefan Lehr, Sandra Cames, Jens Brüning, Matthias Lienhard, Ralf Herwig, Stefan Börno, Bernd Timmermann, Hadi Al-Hasani, Alexandra Chadt
The RabGTPase-activating protein (RabGAP) TBC1D4 (=AS160) represents a key component in the regulation of glucose transport into skeletal muscle and white adipose tissue (WAT) and is therefore crucial during the development of insulin resistance and type-2 diabetes. Increased daily activity has been shown to be associated with improved postprandial hyperglycemia in allele carriers of a loss-of-function variant in the human TBC1D4 gene. Using conventional Tbc1d4-deficient mice (D4KO) fed a high-fat diet (HFD), we show that already a moderate endurance exercise training leads to substantially improved glucose and insulin tolerance and enhanced expression levels of markers for mitochondrial activity and browning in WAT from D4KO animals. Importantly, in vivo and ex vivo analyses of glucose uptake revealed increased glucose clearance in interscapular brown adipose tissue (iBAT) and WAT from trained D4KO mice. Thus, chronic exercise is able to overcome the genetically induced insulin resistance caused by the Tbc1d4-depletion. Gene variants in TBC1D4 may be relevant in future precision medicine as determinants of exercise response.
{"title":"Depletion of TBC1D4 improves the metabolic exercise response by overcoming genetically induced peripheral insulin resistance","authors":"Christian Springer, Christian Binsch, Deborah Weide, Laura Toska, Anna Lena Cremer, Heiko Backes, Anna K. Scheel, Lena Espelage, Jörg Kotzka, Sebastian Sill, Anette Kurowski, Daebin Kim, Sandra Karpinski, Theresia M. Schnurr, Torben Hansen, Sonja Hartwig, Stefan Lehr, Sandra Cames, Jens Brüning, Matthias Lienhard, Ralf Herwig, Stefan Börno, Bernd Timmermann, Hadi Al-Hasani, Alexandra Chadt","doi":"10.2337/db23-0463","DOIUrl":"https://doi.org/10.2337/db23-0463","url":null,"abstract":"The RabGTPase-activating protein (RabGAP) TBC1D4 (=AS160) represents a key component in the regulation of glucose transport into skeletal muscle and white adipose tissue (WAT) and is therefore crucial during the development of insulin resistance and type-2 diabetes. Increased daily activity has been shown to be associated with improved postprandial hyperglycemia in allele carriers of a loss-of-function variant in the human TBC1D4 gene. Using conventional Tbc1d4-deficient mice (D4KO) fed a high-fat diet (HFD), we show that already a moderate endurance exercise training leads to substantially improved glucose and insulin tolerance and enhanced expression levels of markers for mitochondrial activity and browning in WAT from D4KO animals. Importantly, in vivo and ex vivo analyses of glucose uptake revealed increased glucose clearance in interscapular brown adipose tissue (iBAT) and WAT from trained D4KO mice. Thus, chronic exercise is able to overcome the genetically induced insulin resistance caused by the Tbc1d4-depletion. Gene variants in TBC1D4 may be relevant in future precision medicine as determinants of exercise response.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550701","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}
In 2014, the American Diabetes Association instituted a novel funding paradigm to support diabetes research through its Pathway to Stop Diabetes® Program. Pathway took a multifaceted approach to provide key funding to diabetes researchers in advancing a broad spectrum of research programs centered on all aspects of understanding, managing, and treating diabetes. Herein the personal perspective of a 2019 Pathway Accelerator awardee is offered, describing a research program seeking to advance a materials-centered approach to engineering glucose-responsive devices and new delivery tools for better therapeutic outcomes in treating diabetes. This is offered alongside a personal reflection on five years of support from the ADA Pathway Program.
2014 年，美国糖尿病协会（American Diabetes Association）通过其 Pathway to Stop Diabetes® 计划推出了一种新的资助模式来支持糖尿病研究。Pathway 采取多方面的方法，为糖尿病研究人员提供关键资金，以推进以了解、管理和治疗糖尿病的各个方面为中心的广泛研究计划。在此，我们将从 2019 年 Pathway Accelerator 获奖者的个人角度出发，介绍一项研究计划，该计划旨在推进以材料为中心的方法，设计葡萄糖响应设备和新的传输工具，从而在治疗糖尿病方面取得更好的疗效。本文还对 ADA Pathway 计划五年来提供的支持进行了个人反思。
{"title":"Engineering a Pathway to Glucose-Responsive Therapeutics","authors":"Matthew J. Webber","doi":"10.2337/dbi23-0029","DOIUrl":"https://doi.org/10.2337/dbi23-0029","url":null,"abstract":"In 2014, the American Diabetes Association instituted a novel funding paradigm to support diabetes research through its Pathway to Stop Diabetes® Program. Pathway took a multifaceted approach to provide key funding to diabetes researchers in advancing a broad spectrum of research programs centered on all aspects of understanding, managing, and treating diabetes. Herein the personal perspective of a 2019 Pathway Accelerator awardee is offered, describing a research program seeking to advance a materials-centered approach to engineering glucose-responsive devices and new delivery tools for better therapeutic outcomes in treating diabetes. This is offered alongside a personal reflection on five years of support from the ADA Pathway Program.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550672","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 early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we investigated the early pathogenic alterations in DR using streptozotocin-induced diabetic mice and the protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors against these alterations. Retinal vascular leakage was assessed by dextran fluorescence angiography. Retinal thickness and vascular leakage were increased 2 and 4 weeks after onset of diabetes, respectively. Immunostaining showed that morphological change of microglia (amoeboid form) was observed at 2 weeks. Subsequently, increased angiopoietin-2 expression, simultaneous loss of pericytes and endothelial cells, decreased vessel density, retinal hypoxia, and increased vascular endothelial growth factor (VEGF)-A/VEGF receptor system occurred at 4 weeks. SGLT2 inhibitors (luseogliflozin and ipragliflozin) had a significant protective effect on retinal vascular leakage and retinal thickness at a low dose that did not show glucose-lowering effects. Furthermore, both inhibitors at this dose attenuated microglia morphological changes and these early pathogenic alterations in DR. In vitro study, both inhibitors attenuated the lipopolysaccharide-induced activation of primary microglia, along with morphological changes toward an inactive form, suggesting the direct inhibitory effect of SGLT2 inhibitors on microglia. In summary, SGLT2i may directly prevent early pathogenic mechanisms, thereby potentially playing a role in preventing DR.
糖尿病视网膜病变（DR）的早期致病机制及其治疗方法仍不清楚。因此，我们利用链脲佐菌素诱导的糖尿病小鼠研究了DR的早期致病性改变，以及钠-葡萄糖共转运体2（SGLT2）抑制剂对这些改变的保护作用。通过葡聚糖荧光血管造影术评估视网膜血管渗漏。糖尿病发生后2周和4周，视网膜厚度和血管渗漏分别增加。免疫染色显示，2周时观察到小胶质细胞的形态变化（变形体）。随后，血管生成素-2表达增加，周细胞和内皮细胞同时丢失，血管密度降低，视网膜缺氧，血管内皮生长因子（VEGF）-A/VEGF受体系统增加。SGLT2抑制剂（luseogliflozin和ipragliflozin）在低剂量时对视网膜血管渗漏和视网膜厚度有显著的保护作用，但没有降糖效果。此外，该剂量下的两种抑制剂都能减轻小胶质细胞形态学变化和DR的这些早期致病性改变。在体外研究中，这两种抑制剂都减轻了脂多糖诱导的原发性小胶质细胞的活化，以及向非活性形态的形态学变化，这表明 SGLT2 抑制剂对小胶质细胞有直接抑制作用。总之，SGLT2i 可直接阻止早期致病机制，从而有可能在预防 DR 方面发挥作用。
{"title":"The Early Pathogenesis of Diabetic Retinopathy and Its Attenuation by Sodium-Glucose Transporter 2 Inhibitors","authors":"Mayumi Yamato, Nao Kato, Ken-ichi Yamada, Toyoshi Inoguchi","doi":"10.2337/db22-0970","DOIUrl":"https://doi.org/10.2337/db22-0970","url":null,"abstract":"The early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we investigated the early pathogenic alterations in DR using streptozotocin-induced diabetic mice and the protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors against these alterations. Retinal vascular leakage was assessed by dextran fluorescence angiography. Retinal thickness and vascular leakage were increased 2 and 4 weeks after onset of diabetes, respectively. Immunostaining showed that morphological change of microglia (amoeboid form) was observed at 2 weeks. Subsequently, increased angiopoietin-2 expression, simultaneous loss of pericytes and endothelial cells, decreased vessel density, retinal hypoxia, and increased vascular endothelial growth factor (VEGF)-A/VEGF receptor system occurred at 4 weeks. SGLT2 inhibitors (luseogliflozin and ipragliflozin) had a significant protective effect on retinal vascular leakage and retinal thickness at a low dose that did not show glucose-lowering effects. Furthermore, both inhibitors at this dose attenuated microglia morphological changes and these early pathogenic alterations in DR. In vitro study, both inhibitors attenuated the lipopolysaccharide-induced activation of primary microglia, along with morphological changes toward an inactive form, suggesting the direct inhibitory effect of SGLT2 inhibitors on microglia. In summary, SGLT2i may directly prevent early pathogenic mechanisms, thereby potentially playing a role in preventing DR.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550714","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}
Julia Thorngren, Anja Brboric, Svitlana Vasylovska, Daisy Hjelmqvist, Gunilla T Westermark, Jonna Saarimäki-Vire, Jouni Kvist, Diego Balboa, Timo Otonkoski, Per-Ola Carlsson, Joey Lau
Pluripotent stem cell-derived islets (SC-islets) now emerge as a new source for beta-cell replacement therapy. While the function of human islet transplants is hampered by excessive cell death post-transplantation, contributing factors include inflammatory reactions, insufficient revascularization and islet amyloid formation, there is a gap in knowledge on the engraftment process of the SC-islets. In this experimental study, we investigated the engraftment capability of SC-islets at three months post-transplantation, and observed that the cell apoptosis rates were lower, but the vascular density was similar in SC-islets to that of human islets. While the human islet transplant vascular structures were a mixture of remnant donor endothelium and ingrowing blood vessels, the SC-islets contained ingrowing blood vessels only. The oxygenation of the SC-islet grafts was twice as high as in the corresponding grafts of human islets, suggesting better vascular functionality. Similar to the blood vessel ingrowth, also the reinnervation of the SC-islets was four- to five-fold higher than the human islets. Both SC-islets and the human islets contained amyloid at one and three months post-transplantation. We conclude that the vascular and neural engraftment of SC-islets is superior to human islets, but that grafts of both origins develop amyloid with potential long-term consequences.
{"title":"Efficient vascular and neural engraftment of stem cell-derived islets","authors":"Julia Thorngren, Anja Brboric, Svitlana Vasylovska, Daisy Hjelmqvist, Gunilla T Westermark, Jonna Saarimäki-Vire, Jouni Kvist, Diego Balboa, Timo Otonkoski, Per-Ola Carlsson, Joey Lau","doi":"10.2337/db23-0123","DOIUrl":"https://doi.org/10.2337/db23-0123","url":null,"abstract":"Pluripotent stem cell-derived islets (SC-islets) now emerge as a new source for beta-cell replacement therapy. While the function of human islet transplants is hampered by excessive cell death post-transplantation, contributing factors include inflammatory reactions, insufficient revascularization and islet amyloid formation, there is a gap in knowledge on the engraftment process of the SC-islets. In this experimental study, we investigated the engraftment capability of SC-islets at three months post-transplantation, and observed that the cell apoptosis rates were lower, but the vascular density was similar in SC-islets to that of human islets. While the human islet transplant vascular structures were a mixture of remnant donor endothelium and ingrowing blood vessels, the SC-islets contained ingrowing blood vessels only. The oxygenation of the SC-islet grafts was twice as high as in the corresponding grafts of human islets, suggesting better vascular functionality. Similar to the blood vessel ingrowth, also the reinnervation of the SC-islets was four- to five-fold higher than the human islets. Both SC-islets and the human islets contained amyloid at one and three months post-transplantation. We conclude that the vascular and neural engraftment of SC-islets is superior to human islets, but that grafts of both origins develop amyloid with potential long-term consequences.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140547931","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}
Yang Li, Guo-Chong Chen, Jee-Young Moon, Rhonda Arthur, Daniela Sotres-Alvarez, Martha L. Daviglus, Amber Pirzada, Josiemer Mattei, Krista M. Perreira, Jerome I. Rotter, Kent D. Taylor, Yii-Der Ida Chen, Sylvia Wassertheil-Smoller, Tao Wang, Thomas E. Rohan, Joel D. Kaufman, Robert Kaplan, Qibin Qi
Prediabetes is a heterogenous metabolic state with various risk for development of type 2 diabetes (T2D). In this study, we used genetic data on 7,227 US Hispanic/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and 400,149 non-Hispanic whites without diabetes from the UK Biobank (UKBB) to calculate five partitioned polygenetic risk scores (pPRSs) representing various pathways related to T2D. Consensus clustering was performed in participants with prediabetes in HCHS/SOL (n=3,677) and UKBB (n=16,284) separately, based on these pPRSs. Six clusters of individuals with prediabetes with distinctive patterns of pPRSs and corresponding metabolic traits were identified in the HCHS/SOL, five of which were confirmed in the UKBB. Although baseline glycemic traits were similar across clusters, individuals in Cluster 5 and Cluster 6 showed elevated risk of T2D during follow-up compared to Cluster 1 (RR=1.29 [95% CI 1.08-1.53] and1.34 [1.13-1.60], respectively). Inverse associations between a healthy lifestyle score and risk of T2D were observed across different clusters, with a suggestively stronger association observed in Cluster 5 compared to Cluster 1. Among individuals with healthy lifestyle, those in Cluster 5 had a similar risk of T2D compared to those in Cluster 1 (RR=1.03 [0.91-1.18]). This study identified genetic subtypes of prediabetes which differed in risk of progression to T2D and in benefits from healthy lifestyle.
{"title":"Genetic subtypes of prediabetes, healthy lifestyle, and risk of type 2 diabetes","authors":"Yang Li, Guo-Chong Chen, Jee-Young Moon, Rhonda Arthur, Daniela Sotres-Alvarez, Martha L. Daviglus, Amber Pirzada, Josiemer Mattei, Krista M. Perreira, Jerome I. Rotter, Kent D. Taylor, Yii-Der Ida Chen, Sylvia Wassertheil-Smoller, Tao Wang, Thomas E. Rohan, Joel D. Kaufman, Robert Kaplan, Qibin Qi","doi":"10.2337/db23-0699","DOIUrl":"https://doi.org/10.2337/db23-0699","url":null,"abstract":"Prediabetes is a heterogenous metabolic state with various risk for development of type 2 diabetes (T2D). In this study, we used genetic data on 7,227 US Hispanic/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and 400,149 non-Hispanic whites without diabetes from the UK Biobank (UKBB) to calculate five partitioned polygenetic risk scores (pPRSs) representing various pathways related to T2D. Consensus clustering was performed in participants with prediabetes in HCHS/SOL (n=3,677) and UKBB (n=16,284) separately, based on these pPRSs. Six clusters of individuals with prediabetes with distinctive patterns of pPRSs and corresponding metabolic traits were identified in the HCHS/SOL, five of which were confirmed in the UKBB. Although baseline glycemic traits were similar across clusters, individuals in Cluster 5 and Cluster 6 showed elevated risk of T2D during follow-up compared to Cluster 1 (RR=1.29 [95% CI 1.08-1.53] and1.34 [1.13-1.60], respectively). Inverse associations between a healthy lifestyle score and risk of T2D were observed across different clusters, with a suggestively stronger association observed in Cluster 5 compared to Cluster 1. Among individuals with healthy lifestyle, those in Cluster 5 had a similar risk of T2D compared to those in Cluster 1 (RR=1.03 [0.91-1.18]). This study identified genetic subtypes of prediabetes which differed in risk of progression to T2D and in benefits from healthy lifestyle.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140547929","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：