Abstract
Type 2 diabetes affects multiple organ systems, including the skeletal system. Diabetes reduces bone's mechanical properties and impacts bone cells, such as osteocytes, which are crucial to preserving bone health. Osteocytes maintain bone health through the lacunar canalicular network (LCN), a highly interconnected system vital for remodeling, mechanotransduction, and nutrient transport. Yet the specific impact diabetes has on this network has remained unclear. Here, we used confocal laser scanning microscopy combined with advanced connectomics modeling to achieve high-resolution, three-dimensional reconstructions of the LCN in Zucker Diabetic Sprague Dawley rats, a polygenic model that closely mimics human type 2 diabetes. Diabetes profoundly disrupted LCN connectivity in the femoral mid-cortex, with canalicular and node density reduced by 21% and 30%, respectively. Additionally, we observed a 30-40% increase in lacunar density and highly connected nodes. These architectural shifts impair bone permeability, diminishing mechanosensitivity and compromising nutrient and oxygen transport. Our findings uncover a previously unrecognized mechanism of skeletal fragility in diabetes and highlight the LCN as a promising therapeutic target.