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Despite confounding factors, such as obesity, studies show that, after adjusting for age, body mass index and genetics (e.g. twins), patients with T2D experience disproportionate severity of IVD degeneration and\/or back pain than individuals without T2D. We hypothesized that chronic T2D fosters a proinflammatory microenvironment within the IVD that promotes degeneration and disrupts homeostasis. To test this, we evaluated two common mouse models of T2D \u2013 leptin-receptor deficient (db\/db) mice and mice with a chronic high-fat diet and impaired \u03b2-cell function (STZ-HFD). IVDs of STZ-HFD mice exhibited more severe degeneration and elevated chemokine expression than controls. RNA sequencing further revealed extensive transcriptional dysregulation in STZ-HFD IVDs not observed in db\/db IVDs. STZ-HFD IVDs expressed enzymes that enhance advanced glycation end product precursors, impaired non-AGE DAMP pathways and suppressed RAGE turnover. These results suggest that, under controlled genetic and environmental conditions, the STZ-HFD model more accurately reflects the multifactorial inflammatory milieu characteristic of T2D-induced IVD degeneration.<\/jats:p>","DOI":"10.1242\/dmm.052384","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T07:33:41Z","timestamp":1759736021000},"source":"Crossref","is-referenced-by-count":5,"title":["Degenerating intervertebral discs in the streptozotocin-high-fat diet model of type 2 diabetes show extensive inflammation"],"prefix":"10.1242","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4935-9498","authenticated-orcid":false,"given":"Christian E.","family":"Gonzalez","sequence":"first","affiliation":[{"name":"Washington University in St. Louis 1 Department of Biomedical Engineering , , St. Louis, MO 63130 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachana S.","family":"Vaidya","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine 2 Department of Orthopaedic Surgery , , St. Louis, MO 63110 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sade W.","family":"Clayton","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine 2 Department of Orthopaedic Surgery , , St. Louis, MO 63110 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5570-3921","authenticated-orcid":false,"given":"Simon Y.","family":"Tang","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis 1 Department of Biomedical Engineering , , St. Louis, MO 63130 ,","place":["USA"]},{"name":"Washington University School of Medicine 2 Department of Orthopaedic Surgery , , St. Louis, MO 63110 ,","place":["USA"]},{"name":"Institute of Material Science and Engineering, Washington University in St. Louis 3 , St. Louis, MO 63130 ,","place":["USA"]},{"name":"Washington University in St. Louis 4 Department of Mechanical Engineering and Materials Science , , St. Louis, MO 63130 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"2025112601404876900_DMM052384C1","doi-asserted-by":"publisher","first-page":"976810","DOI":"10.1155\/2013\/976810","article-title":"Analysis of inflammatory mediators in type 2 diabetes patients","volume":"2013","author":"Al-Shukaili","year":"2013","journal-title":"Int. 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