PROJECT SUMMARY Over the last decades, the drastic rise in sugar consumption, lack of activity and socio-economic factors has led to a rapid increase in obese and type 2 diabetic populations. Diabetic adults have double the risk of fracture compared with non-diabetic adults with a similar bone mass. If it is becoming clear that high blood glucose affects bone quality and is involved in fragility fracture, the pathogenesis and mechanisms of increased fracture risk in T2D are not well understood. Our recent findings in a diabetic rat model indicate that brittle behavior in type 2 diabetic bone was primarilty due to a substantial reduction in collagen capacity of deformation rather than change in bone structure. This is thought to be associated with the increase of specific non-enzymatic cross-links known as Advanced Glycation End products (AGEs), preventing the collagen molecules to slide onto each other. However, the independent influence of AGEs cross-links on the whole-bone resistance to fracture is unknown. The overall objective of this project is to characterize the collagen nanoscale behavior to establish the role of AGE collagen crosslinks on the whole-bone mechanical behavior and bone fragility in T2D. We propose to identify these mechanisms by combining multiscale numerical modeling with dedicated experimentation. Realistic molecular-scale numerical models of mineralized collagen fibrils and finite element models will be used to establish the effect of AGEs concentration on whole-bone resistance. Synchrotron and AFM experiments will then be used to test bone’s behavior at each length scale with different AGEs concentration (achieved via ribosylation) to validate our numerical models and quantify collagen deformation as a function of whole-bone deformation. This new multiscale model will establish a new quantitative understanding of the mechanisms by which changes at the collagen level of cortical bone increase bone fracture risk in the diabetic population, ultimately identifying a novel pathway to prevent and treat fracture in diabetic patients.