Uncovering the Mechanisms that Lead to Bone Fragility as the Disease Progresses in a Type-2 Zucker Diabetic Fatty (ZDF) Rat

Type-2 Diabetes (T2D) is associated with a 3-fold increase in bone fracture risk, even though bone mineral density is not reduced. This implies that T2D impairs bone quality, whereby the intrinsic material properties of the bone matrix are altered. However, current diagnostic techniques are unable to predict fracture probability in T2D as they are based on measures of bone quantity. It is believed that abnormal crosslinks between proteins in the organic bone matrix, that form due to the high-level of glucose in the blood (known as Advanced Glycated End-Products (AGEs)), are responsible for bone fragility in T2D. Yet, there has still been no clear causal relationship established between AGEs and bone fragility in T2Ds. This project is a multiscale experimental framework which aims to uncover the mechanisms leading to an increased risk of fracture using an animal model of T2D and assessing them at different stages of the disease such as short-term (12-weeks), established (26-weeks) and long-term (46-weeks) T2D. Throughout this project a variety of structural, composition and mechanical analysis was carried out to explore the factors that contribute to bone fragility.