{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:47:41Z","timestamp":1792180061304,"version":"4.4.0"},"reference-count":48,"publisher":"Elsevier BV","issue":"4","license":[{"start":{"date-parts":[[2016,4,1]],"date-time":"2016-04-01T00:00:00Z","timestamp":1459468800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2016,4,1]],"date-time":"2016-04-01T00:00:00Z","timestamp":1459468800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2017,4,1]],"date-time":"2017-04-01T00:00:00Z","timestamp":1491004800000},"content-version":"vor","delay-in-days":365,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","oarsijournal.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Osteoarthritis and Cartilage"],"published-print":{"date-parts":[[2016,4]]},"DOI":"10.1016\/j.joca.2015.10.017","type":"journal-article","created":{"date-parts":[[2015,11,5]],"date-time":"2015-11-05T22:15:14Z","timestamp":1446761714000},"page":"731-739","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":109,"title":["Insulin decreases autophagy and leads to cartilage degradation"],"prefix":"10.1016","volume":"24","author":[{"given":"M.","family":"Ribeiro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"L\u00f3pez de Figueroa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.J.","family":"Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.F.","family":"Mendes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Caram\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.joca.2015.10.017_bib1","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1023\/A:1020185404126","article-title":"Aging, articular cartilage chondrocyte senescence and osteoarthritis","volume":"3","author":"Martin","year":"2002","journal-title":"Biogerontology"},{"key":"10.1016\/j.joca.2015.10.017_bib2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.diabres.2013.11.002","article-title":"Global estimates of diabetes prevalence for 2013 and projections for 2035","volume":"103","author":"Guariguata","year":"2014","journal-title":"Diabetes Res Clin Pract"},{"key":"10.1016\/j.joca.2015.10.017_bib3","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1080\/030097401300162969","article-title":"Non-insulin dependent diabetes mellitus (NIDDM) and patterns of osteoarthritis. The Ulm osteoarthritis study","volume":"30","author":"Sturmer","year":"2001","journal-title":"Scand J Rheumatol"},{"key":"10.1016\/j.joca.2015.10.017_bib4","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1136\/ard.2010.146399","article-title":"Diabetes-induced osteoarthritis: from a new paradigm to a new phenotype","volume":"70","author":"Berenbaum","year":"2011","journal-title":"Ann Rheum Dis"},{"key":"10.1016\/j.joca.2015.10.017_bib5","doi-asserted-by":"crossref","first-page":"403","DOI":"10.2337\/dc12-0924","article-title":"Diabetes is an independent predictor for severe osteoarthritis: results from a longitudinal cohort study","volume":"36","author":"Schett","year":"2013","journal-title":"Diabetes Care"},{"key":"10.1016\/j.joca.2015.10.017_bib6","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1002\/art.34453","article-title":"Osteoarthritis: a disease of the joint as an organ","volume":"64","author":"Loeser","year":"2012","journal-title":"Arthritis Rheum"},{"key":"10.1016\/j.joca.2015.10.017_bib7","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.gene.2013.05.069","article-title":"A\u00a0current review of molecular mechanisms regarding osteoarthritis and pain","volume":"527","author":"Lee","year":"2013","journal-title":"Gene"},{"key":"10.1016\/j.joca.2015.10.017_bib8","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.jbspin.2013.09.007","article-title":"Is osteoarthritis a metabolic disease?","volume":"80","author":"Sellam","year":"2013","journal-title":"Joint Bone Spine"},{"key":"10.1016\/j.joca.2015.10.017_bib9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev.med.56.082103.104751","article-title":"Metabolic syndrome: a clinical and molecular perspective","volume":"56","author":"Moller","year":"2005","journal-title":"Annu Rev Med"},{"issue":"Suppl 1","key":"10.1016\/j.joca.2015.10.017_bib10","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.2337\/dc13-S067","article-title":"Diagnosis and classification of diabetes mellitus","volume":"36","author":"American Diabetes A","year":"2013","journal-title":"Diabetes Care"},{"key":"10.1016\/j.joca.2015.10.017_bib11","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s11684-013-0243-9","article-title":"Impact of diabetes and its treatments on skeletal diseases","volume":"7","author":"Yan","year":"2013","journal-title":"Front Med"},{"key":"10.1016\/j.joca.2015.10.017_bib12","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1002\/art.20170","article-title":"Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis","volume":"50","author":"DeGroot","year":"2004","journal-title":"Arthritis Rheum"},{"key":"10.1016\/j.joca.2015.10.017_bib13","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s00590-011-0915-6","article-title":"Trends 2001 to 2008 in incidence and immediate postoperative outcomes for major joint replacement among Spanish adults suffering diabetes","volume":"23","author":"Martinez-Huedo","year":"2013","journal-title":"Eur J Orthop Surg Traumatol"},{"key":"10.1016\/j.joca.2015.10.017_bib14","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1007\/s11999-013-3026-3","article-title":"Veterans with diabetes receive arthroplasty more frequently and at a younger age","volume":"471","author":"King","year":"2013","journal-title":"Clin Orthop Relat Res"},{"key":"10.1016\/j.joca.2015.10.017_bib15","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cell.2007.12.018","article-title":"Autophagy in the pathogenesis of disease","volume":"132","author":"Levine","year":"2008","journal-title":"Cell"},{"key":"10.1016\/j.joca.2015.10.017_bib16","doi-asserted-by":"crossref","first-page":"5720","DOI":"10.1093\/emboj\/19.21.5720","article-title":"LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing","volume":"19","author":"Kabeya","year":"2000","journal-title":"EMBO J"},{"key":"10.1016\/j.joca.2015.10.017_bib17","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.4161\/cc.10.12.15858","article-title":"mTOR signaling in protein homeostasis: less is more?","volume":"10","author":"Conn","year":"2011","journal-title":"Cell Cycle"},{"key":"10.1016\/j.joca.2015.10.017_bib18","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.biocel.2010.09.018","article-title":"Functions and regulation of the 70kDa ribosomal S6 kinases","volume":"43","author":"Fenton","year":"2011","journal-title":"Int J Biochem Cell Biol"},{"key":"10.1016\/j.joca.2015.10.017_bib19","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/cr.2013.161","article-title":"Autophagy and human diseases","volume":"24","author":"Jiang","year":"2014","journal-title":"Cell Res"},{"key":"10.1016\/j.joca.2015.10.017_bib20","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/path.3025","article-title":"Autophagy and disease: always two sides to a problem","volume":"226","author":"Sridhar","year":"2012","journal-title":"J\u00a0Pathol"},{"key":"10.1016\/j.joca.2015.10.017_bib21","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1002\/art.27305","article-title":"Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis","volume":"62","author":"Carames","year":"2010","journal-title":"Arthritis Rheum"},{"key":"10.1016\/j.joca.2015.10.017_bib22","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1136\/annrheumdis-2013-204599","article-title":"Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis","volume":"74","author":"Zhang","year":"2015","journal-title":"Ann Rheum Dis"},{"key":"10.1016\/j.joca.2015.10.017_bib23","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1136\/annrheumdis-2011-200557","article-title":"Autophagy activation by rapamycin reduces severity of experimental osteoarthritis","volume":"71","author":"Carames","year":"2012","journal-title":"Ann Rheum Dis"},{"key":"10.1016\/j.joca.2015.10.017_bib24","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1002\/art.34323","article-title":"Autophagy modulates osteoarthritis-related gene expression in human chondrocytes","volume":"64","author":"Sasaki","year":"2012","journal-title":"Arthritis Rheum"},{"key":"10.1016\/j.joca.2015.10.017_bib25","first-page":"329","article-title":"Molecular regulation of autophagy and its implications for metabolic diseases","volume":"17","author":"Ryter","year":"2014","journal-title":"Curr Opin Clin Nutr Metab Care"},{"key":"10.1016\/j.joca.2015.10.017_bib26","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1007\/s00125-009-1347-2","article-title":"Autophagy in human type 2 diabetes pancreatic beta cells","volume":"52","author":"Masini","year":"2009","journal-title":"Diabetologia"},{"key":"10.1016\/j.joca.2015.10.017_bib27","doi-asserted-by":"crossref","first-page":"235","DOI":"10.2119\/molmed.2010.00023","article-title":"Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes","volume":"16","author":"Ost","year":"2010","journal-title":"Mol Med"},{"key":"10.1016\/j.joca.2015.10.017_bib28","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.molmed.2007.04.002","article-title":"mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer","volume":"13","author":"Dann","year":"2007","journal-title":"Trends Mol Med"},{"key":"10.1016\/j.joca.2015.10.017_bib29","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1172\/JCI117595","article-title":"Interleukin-1 beta-modulated gene expression in immortalized human chondrocytes","volume":"94","author":"Goldring","year":"1994","journal-title":"J\u00a0Clin Invest"},{"key":"10.1016\/j.joca.2015.10.017_bib30","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1002\/art.39025","article-title":"Autophagy activation protects from mitochondrial dysfunction in human chondrocytes","volume":"67","author":"L\u00f3pez de Figueroa","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"10.1016\/j.joca.2015.10.017_bib31","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1073\/pnas.0806062106","article-title":"Aging-related loss of the chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis","volume":"106","author":"Taniguchi","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1016\/j.joca.2015.10.017_bib32","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.cell.2010.01.028","article-title":"Methods in mammalian autophagy research","volume":"140","author":"Mizushima","year":"2010","journal-title":"Cell"},{"issue":"10","key":"10.1016\/j.joca.2015.10.017_bib33","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1007\/s00296-006-0114-7","article-title":"Role of mitogen-activated protein kinases and NFkappaB on IL-1beta-induced effects on collagen type II, MMP-1 and 13 mRNA expression in normal articular human chondrocytes","volume":"26","author":"Fan","year":"2006","journal-title":"Rheumatol Int"},{"key":"10.1016\/j.joca.2015.10.017_bib34","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1172\/JCI64099","article-title":"Rapalogs and mTOR inhibitors as anti-aging therapeutics","volume":"123","author":"Lamming","year":"2013","journal-title":"J\u00a0Clin Invest"},{"key":"10.1016\/j.joca.2015.10.017_bib35","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1002\/jcb.23196","article-title":"Role of glucose as a modulator of anabolic and catabolic gene expression in normal and osteoarthritic human chondrocytes","volume":"112","author":"Rosa","year":"2011","journal-title":"J\u00a0Cell Biochem"},{"key":"10.1016\/j.joca.2015.10.017_bib36","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1002\/jcp.21258","article-title":"Osteoarthritis","volume":"213","author":"Goldring","year":"2007","journal-title":"J\u00a0Cell Physiol"},{"key":"10.1016\/j.joca.2015.10.017_bib37","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nrrheum.2011.109","article-title":"Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA","volume":"7","author":"Lotz","year":"2011","journal-title":"Nat Rev Rheumatol"},{"key":"10.1016\/j.joca.2015.10.017_bib38","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/jor.22289","article-title":"Apoptosis, senescence, and autophagy in rat nucleus pulposus cells: implications for diabetic intervertebral disc degeneration","volume":"31","author":"Jiang","year":"2013","journal-title":"J\u00a0Orthop Res"},{"key":"10.1016\/j.joca.2015.10.017_bib39","doi-asserted-by":"crossref","first-page":"R15","DOI":"10.1530\/JOE-14-0437","article-title":"Autophagy in diabetic nephropathy","volume":"224","author":"Ding","year":"2015","journal-title":"J\u00a0Endocrinol"},{"key":"10.1016\/j.joca.2015.10.017_bib40","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.bbadis.2014.05.020","article-title":"Autophagy and mitophagy in diabetic cardiomyopathy","volume":"1852","author":"Kobayashi","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"10.1016\/j.joca.2015.10.017_bib41","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1161\/01.CIR.101.13.1539","article-title":"Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells","volume":"101","author":"Zeng","year":"2000","journal-title":"Circulation"},{"key":"10.1016\/j.joca.2015.10.017_bib42","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1210\/me.2002-0074","article-title":"Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells","volume":"16","author":"Montagnani","year":"2002","journal-title":"Mol Endocrinol"},{"key":"10.1016\/j.joca.2015.10.017_bib43","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1007\/s10495-010-0517-5","article-title":"Insulin increases H2O2-induced pancreatic beta cell death","volume":"15","author":"Sampson","year":"2010","journal-title":"Apoptosis"},{"key":"10.1016\/j.joca.2015.10.017_bib44","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.joca.2011.02.004","article-title":"Expression and function of the insulin receptor in normal and osteoarthritic human chondrocytes: modulation of anabolic gene expression, glucose transport and GLUT-1 content by insulin","volume":"19","author":"Rosa","year":"2011","journal-title":"Osteoarthritis Cartilage"},{"key":"10.1016\/j.joca.2015.10.017_bib45","doi-asserted-by":"crossref","first-page":"55","DOI":"10.2147\/DMSO.S48260","article-title":"Akt\/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes","volume":"7","author":"Mackenzie","year":"2014","journal-title":"Diabetes Metab Syndr Obes"},{"key":"10.1016\/j.joca.2015.10.017_bib46","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1002\/art.33444","article-title":"Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection","volume":"64","author":"Carames","year":"2012","journal-title":"Arthritis Rheum"},{"key":"10.1016\/j.joca.2015.10.017_bib47","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2174\/138920108783497659","article-title":"Joint diseases and matrix metalloproteinases: a role for MMP-13","volume":"9","author":"Takaishi","year":"2008","journal-title":"Curr Pharm Biotechnol"},{"key":"10.1016\/j.joca.2015.10.017_bib48","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1053\/joca.2002.0813","article-title":"A\u00a0slow release formulation of insulin as a treatment for osteoarthritis","volume":"10","author":"Cai","year":"2002","journal-title":"Osteoarthritis Cartilage"}],"container-title":["Osteoarthritis and Cartilage"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1063458415013709?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1063458415013709?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T03:41:18Z","timestamp":1761018078000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1063458415013709"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4]]},"references-count":48,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2016,4]]}},"alternative-id":["S1063458415013709"],"URL":"https:\/\/doi.org\/10.1016\/j.joca.2015.10.017","relation":{},"ISSN":["1063-4584"],"issn-type":[{"value":"1063-4584","type":"print"}],"subject":[],"published":{"date-parts":[[2016,4]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Insulin decreases autophagy and leads to cartilage degradation","name":"articletitle","label":"Article Title"},{"value":"Osteoarthritis and Cartilage","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.joca.2015.10.017","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Copyright \u00a9 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.","name":"copyright","label":"Copyright"}]}}