Interplay between the skeleton and glucose homeostasis in the context of type 2 diabetes mellitus

Metabolic disorders such as osteoporosis, obesity and diabetes represent a global health concern, affecting millions of people worldwide. These conditions are linked in many ways. Type 2 diabetes mellitus (T2DM) impacts negatively on glucose homeostasis and multiple organs, including the skeleton, typically leading to poor bone quality, increased fracture risk, and impaired bone regeneration. Conversely, bone itself also affects energy metabolism, through multiple mechanisms. Our preceding work suggested that osteoblasts, the bone-building cells, may contribute directly to whole-body glucose homeostasis, in ways linked to their cellular metabolism and regulated by hypoxia signaling pathways. Here, we build further on these findings while focusing our continued studies on the setting of obesity-associated hyperglycemia modeling T2DM. By using mouse genetics, metabolic phenotyping, lineage tracing and imaging methods, and single cell transcriptomics, we will gain in-depth insights in the cellular-molecular mechanisms underlying the pathophysiological interplay between bone and glucose homeostasis in T2DM and diabetic fracture repair. Moreover, we aim to uncover whether and how HIF-modulating therapeutic approaches could improve energy metabolism and bone health and repair in coupled ways. This project will deliver mechanistic understanding and therapeutic outlooks relevant to T2DM, an increasingly prevalent metabolic disorder that compromises bone health and repair profoundly.