Lekkala, Sashank2021-03-122022-08-272020-08Lekkala_cornell_0058O_11079http://dissertations.umi.com/cornell:11079https://hdl.handle.net/1813/103191111 pagesIndividuals with type 2 diabetes mellitus (T2DM) have a greater risk of bone fracture compared to those with normal glucose tolerance (NGT) despite normal to high bone mineral density even after accounting for confounders like falls, BMI, and comorbidities. In contrast, individuals with impaired glucose tolerance (IGT) have a lower or similar risk of fracture. Our objective was to understand how progressive glycemic derangement affects the composition and mechanical properties of iliac bone from postmenopausal women with NGT (n = 35, age = 65±7y, HbA1c = 5.8%±0.3%), IGT; n = 26, age = 64±5y, HbA1c = 6.0±0.4%), and overt T2DM on insulin (n = 23, age = 64±6y, HbA1c = 9.1%±2.2%). The samples from NGT and T2DM were imaged with confocal/second harmonic generation microscopy to spatially resolve fluorescent advanced glycation endproducts (fAGEs) and collagen alignment. A subset of samples (n = 14 NGT, n = 14 T2DM) with the lowest serum bone resorption marker, CTx was analyzed with nanoindentation and Raman microscopy. Cortical bone from the T2DM group was stiffer (+9%, p = 0.021) and harder (+8%, p = 0.039) compared to that from the NGT group, but the trabecular bone had similar material properties across groups. Fluorescent AGE content was greater in bone from the T2DM vs. the NGT group (cortical +77%, p < 0.001; trabecular +57%, p < 0.001) and modestly correlated with HbA1c (R2 = 0.33, p < 0.001), but Raman spectroscopic properties did not differ across groups. When tissue material properties were assessed by sub-region (Cortical: osteonal, interstitial; Trabecular: fluorochrome label, center, edge), the relatively older tissue had higher stiffness, hardness, fAGE content, mineral content and crystallinity, and collagen maturity compared to the younger tissue. These results demonstrate that bone tissue fAGEs, which have previously been shown to embrittle bone, increase with worsening glycemic control. This relationship suggests a potential mechanism by which bone fragility may increase despite greater tissue stiffness and hardness in individuals with T2DM.enadvanced glycation endproducts (AGEs)bonecompositional propertiesmaterial propertiespostmenopausal womentype 2 diabetesdissertation or thesishttps://doi.org/10.7298/rtqe-bv36