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Therefore, increased risk of fragility fractures in T2D is often confounded by the effects of obesity. This study was conducted to elucidate the mechanistic basis by which T2D alone leads to skeletal fragility. We hypothesized that obesity independent T2D would deteriorate bone's material quality by accumulating defects in the mineral matrix and undesired modifications in its organic matrix associated with increased oxidative stress and hyperglycemia. To test this hypothesis, we used 15\u2010week\u2010old male non\u2010obese mice with engineered muscle creatine kinase promoter\/human dominant negative insulin growth factor 1 (IGF\u2010I) receptor (MKR) and FVB\/N wild\u2010type (WT) controls (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u200912\/group). MKR mice exhibit reduced insulin production and loss of glycemic control leading to diabetic hyperglycemia, verified by fasting blood glucose measurements (&gt;250\u2009mg\/dL), without an increase in body weight. MKR mice showed a significant decrease in femoral radial geometry (cortical area, moment of inertia, cortical thickness, endosteal diameter, and periosteal diameter). Bone mineral density (BMD), as assessed by micro\u2013computed tomography (\u03bcCT), remained unchanged; however, the quality of bone mineral was altered. In contrast to controls, MKR mice had significantly increased hydroxyapatite crystal thickness, measured by small\u2010angle X\u2010ray scattering, and elongated\n                    <jats:italic>c<\/jats:italic>\n                    \u2010axis length of the crystals evaluated by confocal Raman spectroscopy. There was an increase in changes in the organic matrix of MKR mice, associated with enhanced glycoxidation (carboxymethyl\u2010lysine [CML] and pentosidine) and overall glycation (fluorescent advanced glycation end products), both of which were associated with various measures of bone fragility. Moreover, increased CML formation positively correlated with elongated mineral crystal length, supporting the role of this negatively charged side chain to attract calcium ions, promote growth of hydroxyapatite, and build a physical link between mineral and collagen. Collectively, our results show, for the first time, changes in bone matrix in a non\u2010obese T2D model in which skeletal fragility is attributable to alterations in the mineral quality and undesired organic matrix modifications. \u00a9 2021 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10583","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T06:05:24Z","timestamp":1637647524000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Non\u2010Obese\n                    <scp>MKR<\/scp>\n                    Mouse Model of Type 2 Diabetes Reveals Skeletal Alterations in Mineralization and Material Properties"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4530-4978","authenticated-orcid":false,"given":"Matthew J.L.","family":"Tice","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacyann","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5158-1787","authenticated-orcid":false,"given":"Gra\u017cyna E.","family":"Sroga","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily J.","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine Icahn School of Medicine at Mount Sinai New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Vashishth","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-15-0860"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.135236"},{"issue":"3","key":"e_1_2_8_4_1","first-page":"197","article-title":"On the pathophysiology of late onset non\u2010insulin dependent diabetes mellitus. 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