{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:15:18Z","timestamp":1790806518307,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,29]],"date-time":"2021-08-29T00:00:00Z","timestamp":1630195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K08564; 21K1685; 19K17960; 21K16116; 19K17738; 21K16160)."],"award-info":[{"award-number":["20K08564; 21K1685; 19K17960; 21K16116; 19K17738; 21K16160)."]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic \u03b2-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional \u03b2-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit \u03b2-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of \u03b2-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic \u03b2-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet \u03b2-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.<\/jats:p>","DOI":"10.3390\/cells10092237","type":"journal-article","created":{"date-parts":[[2021,8,29]],"date-time":"2021-08-29T21:45:16Z","timestamp":1630273516000},"page":"2237","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus"],"prefix":"10.3390","volume":"10","author":[{"given":"Yuko","family":"Okano","sequence":"first","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"},{"name":"Department of Diabetes and Endocrinology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuro","family":"Takeshita","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"},{"name":"Department of Diabetes and Endocrinology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Yasuma","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"},{"name":"Department of Diabetes and Endocrinology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Toda","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Nishihama","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Fridman D\u2019Alessandro","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chisa","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2164-5775","authenticated-orcid":false,"given":"Corina N.","family":"D\u2019Alessandro-Gabazza","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsu","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Yano","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5748-1499","authenticated-orcid":false,"given":"Esteban C.","family":"Gabazza","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1016\/S0140-6736(16)31679-8","article-title":"Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990\u20132015: A systematic analysis for the Global Burden of Disease Study 2015","volume":"388","author":"Collaborators","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"107843","DOI":"10.1016\/j.diabres.2019.107843","article-title":"Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas","volume":"157","author":"Saeedi","year":"2019","journal-title":"Diabetes Res. 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