{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:55:33Z","timestamp":1792788933784,"version":"4.5.0"},"reference-count":50,"publisher":"American Diabetes Association","issue":"7","license":[{"start":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T00:00:00Z","timestamp":1712880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"Astellas Pharma Inc.","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"AMED-CREST grant","award":["JP21gm0910013"],"award-info":[{"award-number":["JP21gm0910013"]}]},{"name":"JSPS KAKENHI grants","award":["23H05481, 22H05572, and 20H00493"],"award-info":[{"award-number":["23H05481, 22H05572, and 20H00493"]}]},{"name":"Taisho Pharmaceutical Co., Ltd.","award":["none"],"award-info":[{"award-number":["none"]}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","award":["none"],"award-info":[{"award-number":["none"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,7,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>The early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we used streptozotocin-induced diabetic mice to investigate the early pathogenic alterations in DR and the protective effect of sodium\u2013glucose 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 showed 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, SGLT2 inhibitors may directly prevent early pathogenic mechanisms, thereby potentially playing a role in preventing DR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                  <\/jats:sec>","DOI":"10.2337\/db22-0970","type":"journal-article","created":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T17:05:10Z","timestamp":1712941510000},"page":"1153-1166","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":35,"title":["The Early Pathogenesis of Diabetic Retinopathy and Its Attenuation by Sodium\u2013Glucose Transporter 2 Inhibitors"],"prefix":"10.2337","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4962-7632","authenticated-orcid":false,"given":"Mayumi","family":"Yamato","sequence":"first","affiliation":[{"name":"1Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nao","family":"Kato","sequence":"additional","affiliation":[{"name":"1Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken-ichi","family":"Yamada","sequence":"additional","affiliation":[{"name":"1Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7344-6199","authenticated-orcid":false,"given":"Toyoshi","family":"Inoguchi","sequence":"additional","affiliation":[{"name":"2Fukuoka City Health Promotion Support Center, Fukuoka City Medical Association, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2024,4,12]]},"reference":[{"key":"2024062715253247500_B1","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/S0140-6736(09)62124-3","article-title":"Diabetic retinopathy","volume":"376","author":"Cheung","year":"2010","journal-title":"Lancet"},{"key":"2024062715253247500_B2","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1080\/09286580701396720","article-title":"Overview of epidemiologic studies of diabetic retinopathy","volume":"14","author":"Klein","year":"2007","journal-title":"Ophthalmic Epidemiol"},{"key":"2024062715253247500_B3","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1136\/bjo.50.3.134","article-title":"Pericytes in diabetic retinopathy","volume":"50","author":"de Oliveira","year":"1966","journal-title":"Br J Ophthalmol"},{"key":"2024062715253247500_B4","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1001\/archopht.1968.00980050334007","article-title":"Studies on diabetic retinopathy. 3. Influence of diabetes on intramural pericytes","volume":"80","author":"Speiser","year":"1968","journal-title":"Arch Ophthalmol"},{"key":"2024062715253247500_B5","doi-asserted-by":"crossref","first-page":"e90905","DOI":"10.1172\/jci.insight.90905","article-title":"Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown","volume":"2","author":"Ogura","year":"2017","journal-title":"JCI Insight"},{"key":"2024062715253247500_B6","doi-asserted-by":"crossref","first-page":"161","DOI":"10.2147\/DMSO.S233538","article-title":"Extraglycemic effects of SGLT2 inhibitors: a review of the evidence","volume":"13","author":"Bonora","year":"2020","journal-title":"Diabetes Metab Syndr Obes"},{"key":"2024062715253247500_B7","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1016\/j.jacc.2018.01.085","article-title":"SGLT-2 inhibitors and cardiovascular risk: an analysis of CVD-REAL","volume":"71","author":"Cavender","year":"2018","journal-title":"J Am Coll Cardiol"},{"key":"2024062715253247500_B8","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/S2213-8587(18)30141-4","article-title":"Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials","volume":"6","author":"Perkovic","year":"2018","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2024062715253247500_B9","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N Engl J Med"},{"key":"2024062715253247500_B10","doi-asserted-by":"crossref","first-page":"e000130","DOI":"10.1136\/bmjophth-2017-000130","article-title":"The efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of chronic diabetic macular oedema in vitrectomised eyes: a retrospective study","volume":"3","author":"Mieno","year":"2018","journal-title":"BMJ Open Ophthalmol"},{"key":"2024062715253247500_B11","doi-asserted-by":"crossref","first-page":"e0224549","DOI":"10.1371\/journal.pone.0224549","article-title":"Effects of sodium-glucose cotransporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors on diabetic retinopathy and its progression: a real-world Korean study","volume":"14","author":"Chung","year":"2019","journal-title":"PLoS One"},{"key":"2024062715253247500_B12","doi-asserted-by":"crossref","first-page":"e53","DOI":"10.2337\/dc18-1355","article-title":"Retinopathy outcomes with empagliflozin versus placebo in the EMPA-REG OUTCOME trial","volume":"42","author":"Inzucchi","year":"2019","journal-title":"Diabetes Care"},{"key":"2024062715253247500_B13","first-page":"692","article-title":"Sodium-glucose co-transporter 2 inhibitors reduce macular edema in patients with diabetes mellitus","volume":"12","author":"Tatsumi","year":"2022","journal-title":"Life (Basel)"},{"key":"2024062715253247500_B14","doi-asserted-by":"crossref","first-page":"e2348431","DOI":"10.1001\/jamanetworkopen.2023.48431","article-title":"Sodium-glucose cotransporter 2 inhibitors and risk of retinopathy in patients with type 2 diabetes","volume":"6","author":"Yen","year":"2023","journal-title":"JAMA Netw Open"},{"key":"2024062715253247500_B15","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1159\/000500026","article-title":"Pathophysiology of diabetic retinopathy: contribution and limitations of laboratory research","volume":"62","author":"Kern","year":"2019","journal-title":"Ophthalmic Res"},{"key":"2024062715253247500_B16","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.exer.2006.11.007","article-title":"New quantitative analysis, using high-resolution images, of oxygen-induced retinal neovascularization in mice","volume":"84","author":"Chikaraishi","year":"2007","journal-title":"Exp Eye Res"},{"key":"2024062715253247500_B17","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.3390\/ijms18122720","article-title":"Ophthalmic formulation containing nilvadipine nanoparticles prevents retinal dysfunction in rats injected with streptozotocin","volume":"18","author":"Deguchi","year":"2017","journal-title":"Int J Mol Sci"},{"key":"2024062715253247500_B18","doi-asserted-by":"crossref","first-page":"15296","DOI":"10.1038\/ncomms15296","article-title":"Plastic roles of pericytes in the blood-retinal barrier","volume":"8","author":"Park","year":"2017","journal-title":"Nat Commun"},{"key":"2024062715253247500_B19","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1152\/physrev.00011.2010","article-title":"Physiology of microglia","volume":"91","author":"Kettenmann","year":"2011","journal-title":"Physiol Rev"},{"key":"2024062715253247500_B20","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1038\/nature05704","article-title":"UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis","volume":"446","author":"Koizumi","year":"2007","journal-title":"Nature"},{"key":"2024062715253247500_B21","doi-asserted-by":"crossref","first-page":"583687","DOI":"10.3389\/fimmu.2020.583687","article-title":"The role of inflammation in diabetic retinopathy","volume":"11","author":"Forrester","year":"2020","journal-title":"Front Immunol"},{"key":"2024062715253247500_B22","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1172\/JCI118815","article-title":"Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids","volume":"98","author":"McLaren","year":"1996","journal-title":"J Clin Invest"},{"key":"2024062715253247500_B23","doi-asserted-by":"crossref","first-page":"e96902","DOI":"10.1172\/jci.insight.96902","article-title":"Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models","volume":"3","author":"Sasaki","year":"2018","journal-title":"JCI Insight"},{"key":"2024062715253247500_B24","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1007\/s00125-017-4509-7","article-title":"Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+\/H+ exchanger, lowering of cytosolic Na+ and vasodilation","volume":"61","author":"Uthman","year":"2018","journal-title":"Diabetologia"},{"key":"2024062715253247500_B25","doi-asserted-by":"crossref","first-page":"3107","DOI":"10.3390\/cells11193107","article-title":"Anti-inflammatory properties of the SGLT2 inhibitor empagliflozin in activated primary microglia","volume":"11","author":"Heimke","year":"2022","journal-title":"Cells"},{"key":"2024062715253247500_B26","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1007\/s00125-018-4770-4","article-title":"Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models","volume":"62","author":"Ting","year":"2019","journal-title":"Diabetologia"},{"key":"2024062715253247500_B27","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s00125-020-05299-x","article-title":"Erythropoietin protects the inner blood-retinal barrier by inhibiting microglia phagocytosis via Src\/Akt\/cofilin signalling in experimental diabetic retinopathy","volume":"64","author":"Xie","year":"2021","journal-title":"Diabetologia"},{"key":"2024062715253247500_B28","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1002\/(SICI)1098-1136(199612)18:4<269::AID-GLIA2>3.0.CO;2-T","article-title":"Effects of GM-CSF and ordinary supplements on the ramification of microglia in culture: a morphometrical study","volume":"18","author":"Fujita","year":"1996","journal-title":"Glia"},{"key":"2024062715253247500_B29","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3390\/ijms19010110","article-title":"The role of microglia in diabetic retinopathy: inflammation, microvasculature defects and neurodegeneration","volume":"19","author":"Altmann","year":"2018","journal-title":"Int J Mol Sci"},{"key":"2024062715253247500_B30","doi-asserted-by":"crossref","first-page":"4150","DOI":"10.1182\/blood-2003-10-3685","article-title":"The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies","volume":"103","author":"Fiedler","year":"2004","journal-title":"Blood"},{"key":"2024062715253247500_B31","doi-asserted-by":"crossref","first-page":"100954","DOI":"10.1016\/j.preteyeres.2021.100954","article-title":"VEGFR1 signaling in retinal angiogenesis and microinflammation","volume":"84","author":"Uemura","year":"2021","journal-title":"Prog Retin Eye Res"},{"key":"2024062715253247500_B32","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S1534-5807(02)00217-4","article-title":"Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1","volume":"3","author":"Gale","year":"2002","journal-title":"Dev Cell"},{"key":"2024062715253247500_B33","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1126\/science.277.5322.55","article-title":"Angiopoietin-2, a natural antagonist for Tie2 that disrupts in\u00a0vivo angiogenesis","volume":"277","author":"Maisonpierre","year":"1997","journal-title":"Science"},{"key":"2024062715253247500_B34","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1111\/j.1523-1755.2000.00363.x","article-title":"Hypoxia up-regulates angiopoietin-2, a Tie-2 ligand, in mouse mesangial cells","volume":"58","author":"Yuan","year":"2000","journal-title":"Kidney Int"},{"key":"2024062715253247500_B35","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/359843a0","article-title":"Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis","volume":"359","author":"Shweiki","year":"1992","journal-title":"Nature"},{"key":"2024062715253247500_B36","first-page":"849","article-title":"Altered expression patterns of VEGF receptors in human diabetic retina and in experimental VEGF-induced retinopathy in monkey","volume":"43","author":"Witmer","year":"2002","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2024062715253247500_B37","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1159\/000453207","article-title":"Blocking mammalian target of rapamycin (mTOR) attenuates HIF-1\u03b1 pathways engaged-vascular endothelial growth factor (VEGF) in diabetic retinopathy","volume":"40","author":"Wei","year":"2016","journal-title":"Cell Physiol Biochem"},{"key":"2024062715253247500_B38","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1126\/science.284.5422.1994","article-title":"Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF","volume":"284","author":"Holash","year":"1999","journal-title":"Science"},{"key":"2024062715253247500_B39","doi-asserted-by":"crossref","first-page":"e0219164","DOI":"10.1371\/journal.pone.0219164","article-title":"Reduced vessel density in the superficial and deep plexuses in diabetic retinopathy is associated with structural changes in corresponding retinal layers","volume":"14","author":"Lavia","year":"2019","journal-title":"PLoS One"},{"key":"2024062715253247500_B40","doi-asserted-by":"crossref","first-page":"113222","DOI":"10.1016\/j.biopha.2022.113222","article-title":"SGLT2 inhibitor-empagliflozin treatment ameliorates diabetic retinopathy manifestations and exerts protective effects associated with augmenting branched chain amino acids catabolism and transportation in db\/db mice","volume":"152","author":"Gong","year":"2022","journal-title":"Biomed Pharmacother"},{"key":"2024062715253247500_B41","doi-asserted-by":"crossref","first-page":"BSR20212209","DOI":"10.1042\/BSR20212209","article-title":"Determining the role of SGLT2 inhibition with Empagliflozin in the development of diabetic retinopathy","volume":"42","author":"Matthews","year":"2022","journal-title":"Biosci Rep"},{"key":"2024062715253247500_B42","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.3390\/ijms23031362","article-title":"The effect of sodium-dependent glucose cotransporter 2 inhibitor tofogliflozin on neurovascular coupling in the retina in type 2 diabetic mice","volume":"23","author":"Hanaguri","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2024062715253247500_B43","doi-asserted-by":"crossref","first-page":"4703","DOI":"10.1038\/s41598-019-41253-7","article-title":"Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells","volume":"9","author":"Maki","year":"2019","journal-title":"Sci Rep"},{"key":"2024062715253247500_B44","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/s42003-022-03605-4","article-title":"Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects","volume":"5","author":"Takashima","year":"2022","journal-title":"Commun Biol"},{"key":"2024062715253247500_B45","doi-asserted-by":"crossref","first-page":"100049","DOI":"10.1016\/j.metop.2020.100049","article-title":"Low dose of sodium-glucose transporter 2 inhibitor ipragliflozin attenuated renal dysfunction and interstitial fibrosis in adenine-induced chronic kidney disease in mice without diabetes","volume":"7","author":"Yamato","year":"2020","journal-title":"Metabol Open"},{"key":"2024062715253247500_B46","doi-asserted-by":"crossref","first-page":"e0151585","DOI":"10.1371\/journal.pone.0151585","article-title":"Sodium glucose cotransporter 2 (SGLT2) plays as a physiological glucose sensor and regulates cellular contractility in rat mesangial cells","volume":"11","author":"Wakisaka","year":"2016","journal-title":"PLoS One"},{"key":"2024062715253247500_B47","doi-asserted-by":"crossref","first-page":"e98720","DOI":"10.1172\/jci.insight.98720","article-title":"SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy","volume":"3","author":"Cassis","year":"2018","journal-title":"JCI Insight"},{"key":"2024062715253247500_B48","doi-asserted-by":"crossref","first-page":"5335","DOI":"10.1074\/jbc.M117.779520","article-title":"SGLT2 protein expression is increased in human diabetic nephropathy: SGLT2 protein inhibition decreases renal lipid accumulation, inflammation and the development of nephropathy in diabetic mice","volume":"292","author":"Wang","year":"2017","journal-title":"J Biol Chem"},{"key":"2024062715253247500_B49","doi-asserted-by":"crossref","first-page":"E4111","DOI":"10.1073\/pnas.1511698112","article-title":"Functional expression of sodium-glucose transporters in cancer","volume":"112","author":"Scafoglio","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024062715253247500_B50","doi-asserted-by":"crossref","first-page":"15210","DOI":"10.1523\/JNEUROSCI.3950-10.2010","article-title":"Activation of microglia depends on Na+\/H+ exchange-mediated H+ homeostasis","volume":"30","author":"Liu","year":"2010","journal-title":"J Neurosci"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/73\/7\/1153\/774981\/db220970.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/73\/7\/1153\/774981\/db220970.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T11:30:06Z","timestamp":1719487806000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/73\/7\/1153\/154474\/The-Early-Pathogenesis-of-Diabetic-Retinopathy-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,12]]},"references-count":50,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,4,12]]},"published-print":{"date-parts":[[2024,7,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db22-0970","relation":{},"ISSN":["0012-1797"],"issn-type":[{"value":"0012-1797","type":"print"}],"subject":[],"published":{"date-parts":[[2024,4,12]]}}}