{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T03:06:31Z","timestamp":1776481591061,"version":"3.51.2"},"reference-count":43,"publisher":"Portland Press Ltd.","issue":"15","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","award":["2020-01372"],"award-info":[{"award-number":["2020-01372"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","award":["2023-02508"],"award-info":[{"award-number":["2023-02508"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"name":"EFSD\/Novo Nordisk Foundation Future Leaders Award","award":["NNF22SA0081227"],"award-info":[{"award-number":["NNF22SA0081227"]}]},{"name":"Foundation for Geriatric Diseases","award":["2023-01860"],"award-info":[{"award-number":["2023-01860"]}]},{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"crossref","award":["20200326"],"award-info":[{"award-number":["20200326"]}],"id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"crossref","award":["20220264"],"award-info":[{"award-number":["20220264"]}],"id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"crossref","award":["20190266"],"award-info":[{"award-number":["20190266"]}],"id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"crossref","award":["20220210"],"award-info":[{"award-number":["20220210"]}],"id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"crossref","award":["20230386"],"award-info":[{"award-number":["20230386"]}],"id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"crossref","award":["20240072"],"award-info":[{"award-number":["20240072"]}],"id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,8,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The mechanisms underlying endothelial dysfunction in Type 1 and Type 2 diabetes (T1DM and T2DM) are unresolved. The red blood cells (RBCs) with increased arginase activity induce endothelial dysfunction in T2DM, but the implications of RBCs and the role of arginase inhibition in T1DM are unexplored. We aimed to investigate the differences in endothelial function in patients with T1DM and T2DM, with focus on RBCs and arginase. Thirteen patients with T1DM and twenty-six patients with T2DM, matched for HbA1c and sex were included. In vivo endothelium-dependent and -independent vasodilation (EDV and EIDV) were assessed by venous occlusion plethysmography before and after administration of an arginase inhibitor. RBCs were co-incubated with rat aortic segments for 18h followed by evaluation of endothelium-dependent (EDR) and -independent relaxation (EIDR) in isolated organ chambers. In vivo EDV, but not EIDV, was significantly impaired in patients with T2DM compared with patients with T1DM. Arginase inhibition resulted in improved EDV only in T2DM. RBCs from patients with T2DM induced impaired EDR but not EIDR in isolated aortic segments, whereas RBCs from patients with T1DM did not affect EDR nor EIDR. The present study demonstrates markedly impaired EDV in patients with T2DM in comparison with T1DM. In addition, it highlights the divergent roles of RBCs and arginase in mediating endothelial dysfunction in T1DM and T2DM. While endothelial dysfunction is mediated via RBCs and arginase in T2DM, these phenomena are not prominent in T1DM thereby indicating distinct differences in underlying mechanisms.<\/jats:p>","DOI":"10.1042\/cs20240447","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T15:19:01Z","timestamp":1721661541000},"page":"975-985","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Differences in endothelial function between patients with Type 1 and Type 2 diabetes: effects of red blood cells and arginase"],"prefix":"10.1042","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3608-160X","authenticated-orcid":false,"given":"John","family":"Tengbom","sequence":"first","affiliation":[{"name":"1Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eftychia","family":"Kontidou","sequence":"additional","affiliation":[{"name":"1Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aida","family":"Collado","sequence":"additional","affiliation":[{"name":"1Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiangning","family":"Yang","sequence":"additional","affiliation":[{"name":"1Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Alvarsson","sequence":"additional","affiliation":[{"name":"2Division of Endocrinology and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonas","family":"Brinck","sequence":"additional","affiliation":[{"name":"3Division of Endocrinology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"R\u00f6ssner","sequence":"additional","affiliation":[{"name":"3Division of Endocrinology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhichao","family":"Zhou","sequence":"additional","affiliation":[{"name":"1Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Pernow","sequence":"additional","affiliation":[{"name":"1Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Mahdi","sequence":"additional","affiliation":[{"name":"1Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2024,8,5]]},"reference":[{"key":"2024080512065472000_B1","doi-asserted-by":"publisher","first-page":"S81","DOI":"10.2337\/dc14-S081","article-title":"Diagnosis and classification of diabetes mellitus","volume":"37","author":"Grant","year":"2014","journal-title":"Diabetes Care."},{"key":"2024080512065472000_B2","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.ijcard.2018.03.099","article-title":"Type 1 and type 2 diabetes mellitus and incidence of seven cardiovascular diseases","volume":"262","author":"Larsson","year":"2018","journal-title":"Int. J. Cardiol."},{"key":"2024080512065472000_B3","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1001\/archopht.1984.01040030398010","article-title":"The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years","volume":"102","author":"Klein","year":"1984","journal-title":"Arch. Ophthalmol."},{"key":"2024080512065472000_B4","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1001\/archopht.1984.01040030405011","article-title":"The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years","volume":"102","author":"Klein","year":"1984","journal-title":"Arch. Ophthalmol."},{"key":"2024080512065472000_B5","doi-asserted-by":"publisher","first-page":"241","DOI":"10.2337\/db16-0806","article-title":"Differentiation of diabetes by pathophysiology, natural history, and prognosis","volume":"66","author":"Skyler","year":"2016","journal-title":"Diabetes"},{"key":"2024080512065472000_B6","doi-asserted-by":"publisher","first-page":"2436","DOI":"10.1093\/eurheartj\/eht149","article-title":"Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I","volume":"34","author":"Paneni","year":"2013","journal-title":"Eur. Heart J."},{"key":"2024080512065472000_B7","doi-asserted-by":"publisher","first-page":"2444","DOI":"10.1093\/eurheartj\/eht142","article-title":"Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II","volume":"34","author":"Beckman","year":"2013","journal-title":"Eur. Heart J."},{"key":"2024080512065472000_B8","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1001\/jama.2016.9400","article-title":"Comparison offnalysis","volume":"316","author":"Palmer","year":"2016","journal-title":"JAMA"},{"key":"2024080512065472000_B9","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1056\/NEJMoa0806470","article-title":"10-year follow-up of intensive glucose control in type 2 diabetes","volume":"359","author":"Holman","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"2024080512065472000_B10","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1056\/NEJM199309303291401","article-title":"The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus","volume":"329","author":"Nathan","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"2024080512065472000_B11","doi-asserted-by":"publisher","first-page":"5695","DOI":"10.2174\/1381612811319320005","article-title":"Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases","volume":"19","author":"Fiorentino","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"2024080512065472000_B12","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1161\/CIRCRESAHA.107.155028","article-title":"Diabetes-induced coronary vascular dysfunction involves increased arginase activity","volume":"102","author":"Romero","year":"2008","journal-title":"Circ. Res."},{"key":"2024080512065472000_B13","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1177\/1479164116643916","article-title":"Amino acid metabolism reflecting arginase activity is increased in patients with type 2 diabetes and associated with endothelial dysfunction","volume":"13","author":"K\u00f6vamees","year":"2016","journal-title":"Diab. Vasc. Dis. Res."},{"key":"2024080512065472000_B14","doi-asserted-by":"publisher","first-page":"155","DOI":"10.2174\/1570161114666151202205617","article-title":"The emerging role of arginase in endothelial dysfunction in diabetes","volume":"14","author":"Pernow","year":"2016","journal-title":"Curr. Vasc. Pharmacol."},{"key":"2024080512065472000_B15","doi-asserted-by":"publisher","first-page":"2943","DOI":"10.1161\/CIRCULATIONAHA.112.140335","article-title":"Arginase inhibition improves endothelial function in patients with coronary artery disease and type 2 diabetes mellitus","volume":"126","author":"Shemyakin","year":"2012","journal-title":"Circulation"},{"key":"2024080512065472000_B16","doi-asserted-by":"publisher","first-page":"3952","DOI":"10.1210\/jc.2016-2007","article-title":"Arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes mellitus","volume":"101","author":"K\u00f6vamees","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2024080512065472000_B17","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1111\/joim.12785","article-title":"Arginase inhibition improves endothelial function in patients with type 2 diabetes mellitus despite intensive glucose-lowering therapy","volume":"284","author":"Mahdi","year":"2018","journal-title":"J. Intern. Med."},{"key":"2024080512065472000_B18","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.jacbts.2018.03.006","article-title":"Red blood cells in type 2 diabetes impair cardiac post-ischemic recovery through an arginase-dependent modulation of nitric oxide synthase and reactive oxygen species","volume":"3","author":"Yang","year":"2018","journal-title":"JACC Basic Transl. Sci."},{"key":"2024080512065472000_B19","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/j.jacc.2018.05.052","article-title":"Erythrocytes from patients with type 2 diabetes induce endothelial dysfunction via arginase I","volume":"72","author":"Zhou","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"2024080512065472000_B20","volume-title":"Diagnosis and management of type 2 diabetes (HEARTS-D), WHO\/UCN\/NCD\/20.1, Editor","author":"Organization., W.H.","year":"2020"},{"key":"2024080512065472000_B21","doi-asserted-by":"publisher","first-page":"15049","DOI":"10.1073\/pnas.1307058110","article-title":"Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity","volume":"110","author":"Yang","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2024080512065472000_B22","doi-asserted-by":"publisher","first-page":"2510","DOI":"10.1161\/01.CIR.88.6.2510","article-title":"Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus","volume":"88","author":"Johnstone","year":"1993","journal-title":"Circulation"},{"key":"2024080512065472000_B23","doi-asserted-by":"publisher","first-page":"1750","DOI":"10.1161\/01.CIR.0000124725.46165.2C","article-title":"Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes","volume":"109","author":"J\u00e4rvisalo","year":"2004","journal-title":"Circulation"},{"key":"2024080512065472000_B24","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1111\/pedi.12874","article-title":"Subclinical arterial damage in children and adolescents with type 1 diabetes: a systematic review and meta-analysis","volume":"20","author":"Giannopoulou","year":"2019","journal-title":"Pediatr. Diabetes"},{"key":"2024080512065472000_B25","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/s00467-021-05050-7","article-title":"Early microvascular complications in type 1 and type 2 diabetes: recent developments and updates","volume":"37","author":"Tommerdahl","year":"2022","journal-title":"Pediatr. Nephrol."},{"key":"2024080512065472000_B26","doi-asserted-by":"publisher","first-page":"2000","DOI":"10.1161\/01.CIR.0000092948.04444.C7","article-title":"Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels","volume":"108","author":"Berkowitz","year":"2003","journal-title":"Circulation"},{"key":"2024080512065472000_B27","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1089\/rej.2018.2135","article-title":"Arginase inhibition improves endothelial function in an age-dependent manner in healthy elderly humans","volume":"22","author":"Mahdi","year":"2018","journal-title":"Rejuvenation Res."},{"key":"2024080512065472000_B28","doi-asserted-by":"publisher","first-page":"2465","DOI":"10.1007\/s00125-014-3369-7","article-title":"Impact of age, age at diagnosis and duration of diabetes on the risk of macrovascular and microvascular complications and death in type 2 diabetes","volume":"57","author":"Zoungas","year":"2014","journal-title":"Diabetologia"},{"key":"2024080512065472000_B29","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1001\/archinternmed.2009.193","article-title":"Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration: the diabetes control and complications trial\/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005)","volume":"169","author":"Nathan","year":"2009","journal-title":"Arch. Intern. Med."},{"key":"2024080512065472000_B30","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1074\/jbc.M103728200","article-title":"Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells","volume":"277","author":"Montagnani","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2024080512065472000_B31","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1016\/S0735-1097(01)01129-9","article-title":"Improved endothelial function with metformin in type 2 diabetes mellitus","volume":"37","author":"Mather","year":"2001","journal-title":"J. Am. Coll. Cardiol."},{"key":"2024080512065472000_B32","first-page":"1","article-title":"Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors, or both? Expectations from the ONTARGET Trial Programme","volume":"3","author":"Ruilope","year":"2007","journal-title":"Vasc. Health Risk Manag."},{"key":"2024080512065472000_B33","doi-asserted-by":"publisher","first-page":"1198","DOI":"10.1089\/ars.2013.5430","article-title":"Statins as regulators of redox state in the vascular endothelium: beyond lipid lowering","volume":"20","author":"Margaritis","year":"2014","journal-title":"Antioxid Redox Signal"},{"key":"2024080512065472000_B34","doi-asserted-by":"publisher","first-page":"2093","DOI":"10.1113\/jphysiol.2010.203935","article-title":"Oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolaemic humans","volume":"589","author":"Holowatz","year":"2011","journal-title":"J. Physiol."},{"key":"2024080512065472000_B35","doi-asserted-by":"publisher","first-page":"134","DOI":"10.2337\/dc07-1198","article-title":"Insulin reduces plasma arginase activity in type 2 diabetic patients","volume":"31","author":"Kashyap","year":"2008","journal-title":"Diabetes Care."},{"key":"2024080512065472000_B36","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1093\/cvr\/cvx164","article-title":"Obesity-induced vascular dysfunction and arterial stiffening requires endothelial cell arginase 1","volume":"113","author":"Bhatta","year":"2017","journal-title":"Cardiovasc. Res."},{"key":"2024080512065472000_B37","doi-asserted-by":"publisher","first-page":"H1785","DOI":"10.1152\/ajpheart.00318.2002","article-title":"Role of ceramide in TNF-alpha-induced impairment of endothelium-dependent vasorelaxation in coronary arteries","volume":"283","author":"Zhang","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2024080512065472000_B38","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.ejphar.2018.11.027","article-title":"Hyperglycemia-impaired aortic vasorelaxation mediated through arginase elevation: Role of stress kinase pathways","volume":"844","author":"Chandra","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"2024080512065472000_B39","first-page":"247","article-title":"Enhancement of red blood cell aggregation by plasma triglycerides","volume":"24","author":"Cicha","year":"2001","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"2024080512065472000_B40","doi-asserted-by":"publisher","first-page":"265","DOI":"10.3109\/10715768709069792","article-title":"The relationship between lipid composition of red blood cells and their susceptibility to lipid peroxidation","volume":"3","author":"Clemens","year":"1987","journal-title":"Free Radic. Res. Commun."},{"issue":"11","key":"2024080512065472000_B41","doi-asserted-by":"publisher","first-page":"e159179","DOI":"10.1172\/JCI159179","article-title":"MicroRNAs as therapeutic targets in cardiovascular disease","volume":"132","author":"Laggerbauer","year":"2022","journal-title":"J. Clin. Invest."},{"key":"2024080512065472000_B42","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1161\/ATVBAHA.123.319027","article-title":"Erythrocyte-derived microRNAs: emerging players in cardiovascular and metabolic disease","volume":"43","author":"Kontidou","year":"2023","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2024080512065472000_B43","doi-asserted-by":"publisher","first-page":"285","DOI":"10.2337\/db21-0093","article-title":"Downregulation of erythrocyte miR-210 induces endothelial dysfunction in type 2 diabetes","volume":"71","author":"Zhou","year":"2022","journal-title":"Diabetes"}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/138\/15\/975\/959698\/cs-2024-0447.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/138\/15\/975\/959698\/cs-2024-0447.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T12:17:46Z","timestamp":1722860266000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/138\/15\/975\/234723\/Differences-in-endothelial-function-between"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8]]},"references-count":43,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2024,8,7]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20240447","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,8]]},"published":{"date-parts":[[2024,8]]}}}