{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:50:24Z","timestamp":1792601424259,"version":"4.5.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T00:00:00Z","timestamp":1705622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Type 1 diabetes mellitus (T1DM) development involves a complex interplay of genetic, environmental, and immunological factors. By modulating the activity of proteases and receptors, the protein tissue inhibitor of metalloproteinase 3 (TIMP3) plays a role in limiting the expression and function of pro-inflammatory cytokines, which have been implicated in the advancement of T1DM. This study was aimed at examining the effect of TIMP3 overexpression in myeloid cells on the development of T1DM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Twelve weeks after multiple low doses of streptozotocin (MLDS) treatment, diabetic mice overexpressing TIMP3 specifically in myeloid cells under the CD68 promoter (MacT3 mice) showed improved insulin secretion, islet morphology and vascularization, antioxidant defense system, and regulatory factors of mitochondrial biosynthesis and function. To get mechanistic insights into the origin of this protection, the severity of insulitis and inflammatory parameters were evaluated in pancreatic tissues 11 days after MLSD treatment, showing significantly reduced insulitis and levels of the pro-inflammatory cytokine tumor necrosis factor-\u03b1, interleukin -1\u03b2, and interferon -\u03b3 in MacT3 mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The results indicate that TIMP3 is involved in maintaining islet architecture and functions, at least in part, through modulation of pro-inflammatory cytokine production associated with insulitis and may represent a novel therapeutic strategy for T1DM.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1297847","type":"journal-article","created":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T09:39:45Z","timestamp":1705657185000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["TIMP3 overexpression in myeloid lineage alleviates pancreatic damage and confers resistance to the development of type 1 diabetes in the MLDS -induced model"],"prefix":"10.3389","volume":"14","author":[{"given":"Viviana","family":"Casagrande","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Menini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Intern\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Pugliese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Federici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Menghini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-018-0044-y","article-title":"Technology in the management of type 1 diabetes mellitus - current status and future prospects","volume":"14","author":"Tauschmann","year":"2018","journal-title":"Nat Rev Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-S081","article-title":"Diagnosis and classification of diabetes mellitus","volume":"37","year":"2014","journal-title":"Diabetes Care"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.4161\/isl.3.4.15728","article-title":"Insulitis in human type 1 diabetes: The quest for an elusive lesion","volume":"3","author":"In't Veld","year":"2011","journal-title":"Islets"},{"key":"B4","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/978-3-319-54090-0_2","article-title":"Development and functional differentiation of tissue resident versus monocyte-derived macrophages in inflammatory reactions","volume":"62","author":"Italiani","year":"2017","journal-title":"Results Probl Cell Differ"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201445013","article-title":"Macrophage dynamics are regulated by local macrophage proliferation and monocyte recruitment in injured pancreas","volume":"45","author":"Van Gassen","year":"2015","journal-title":"Eur J Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2005.12.002","article-title":"Structure and function of matrix metalloproteinases and TIMPs","volume":"69","author":"Nagase","year":"2006","journal-title":"Cardiovasc Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.10.079","article-title":"Tissue inhibitor of metalloproteinase 3 deficiency causes hepatic steatosis and adipose tissue inflammation in mice","volume":"136","author":"Menghini","year":"2009","journal-title":"Gastroenterology"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2337\/db09-0280","article-title":"TIMP3 is reduced in atherosclerotic plaques from subjects with type 2 diabetes and increased by SirT1","volume":"58","author":"Cardellini","year":"2009","journal-title":"Diabetes"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2337\/db11-0613","article-title":"TIMP3 overexpression in macrophages protects from insulin resistance, adipose inflammation, and nonalcoholic fatty liver disease in mice","volume":"61","author":"Menghini","year":"2012","journal-title":"Diabetes"},{"key":"B10","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1161\/ATVBAHA.111.238402","article-title":"Overexpression of tissue inhibitor of metalloproteinase 3 in macrophages reduces atherosclerosis in low-density lipoprotein receptor knockout mice","volume":"32","author":"Casagrande","year":"2012","journal-title":"ATVB"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e305","DOI":"10.1002\/ctm2.305","article-title":"Restoration of renal TIMP3 levels via genetics and pharmacological approach prevents experimental diabetic nephropathy","volume":"11","author":"Casagrande","year":"2021","journal-title":"Clin Transl Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05186-5","article-title":"Beta cell dysfunction in diabetes: the islet microenvironment as an unusual suspect","volume":"63","author":"Alma\u00e7a","year":"2020","journal-title":"Diabetologia"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1516","DOI":"10.3390\/ijms220415","article-title":"Resolvin D1 decreases severity of streptozotocin-induced type 1 diabetes mellitus by enhancing BDNF levels, reducing oxidative stress, and suppressing inflammation","volume":"22","author":"Bathina","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA","article-title":"MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1","volume":"120","author":"Menghini","year":"2009","journal-title":"Circulation"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.023","article-title":"Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha","volume":"38","author":"Lim","year":"2010","journal-title":"Mol Cell"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9896(199602)178:2","article-title":"Beta-cell apoptosis is responsible for the development of IDDM in the multiple low-dose streptozotocin model","volume":"178","author":"O'Brien","year":"1996","journal-title":"J Pathol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118490","article-title":"Protective effects of acarbose against insulitis in multiple low-dose streptozotocin-induced diabetic mice","volume":"263","author":"Zhao","year":"2020","journal-title":"Life Sci"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/dom.13031","article-title":"Signals in the pancreatic islet microenvironment influence \u03b2-cell proliferation","author":"Aamodt","year":"2017","journal-title":"Diabetes Obes Metab"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00187","article-title":"Sirtuins and type 2 diabetes: role in inflammation, oxidative stress, and mitochondrial function","volume":"10","author":"Kitada","year":"2019","journal-title":"Front Endocrinol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20743","article-title":"Nuclear control of respiratory gene expression in mammalian cells","author":"Scarpulla","year":"2006","journal-title":"J Cell Biochem"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3390\/biom12091228","article-title":"Role of reactive oxygen species in glucose metabolism disorder in diabetic pancreatic \u03b2-cells","volume":"12","author":"Mukai","year":"2022","journal-title":"Biomolecules"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401401101","article-title":"Erralpha and Gabpa\/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle","volume":"101","author":"Mootha","year":"2004","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.12.063","article-title":"Hypoxia-inducible factor-1\u03b1 mediates the expression of mature \u03b2 cell-disallowed genes in hypoxia-induced \u03b2 cell dedifferentiation","volume":"523","author":"Liu","year":"2020","journal-title":"Biochem Biophys Res Commun"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-006-0156-0","article-title":"Insulin activates hypoxia-inducible factor-1 in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways: impairment in insulin resistance owing to defects in insulin signalling","volume":"49","author":"Doronzo","year":"2006","journal-title":"Diabetologia"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-020-00443-4","article-title":"Type 1 diabetes mellitus as a disease of the \u03b2-cell (do not blame the immune system?)","volume":"17","author":"Roep","year":"2021","journal-title":"Nat Rev Endocrinol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1297847\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T09:39:48Z","timestamp":1705657188000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1297847\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,19]]},"references-count":25,"alternative-id":["10.3389\/fendo.2023.1297847"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1297847","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,19]]},"article-number":"1297847"}}