Insulin therapy improves bone microstructure and material properties without restoring whole-bone strength in male...

Type 1 diabetes is associated with increased fracture risk, yet the respective contributions of insulin deficiency and replacement to skeletal fragility remain poorly understood. Using insulin-deficient male Akita mice, we characterized skeletal alterations and assessed the effects of early insulin therapy. Untreated male Akita mice displayed severe hyperglycemia, impaired growth, low bone formation, and marked trabecular and cortical deficits, resulting in reduced whole-bone structural mechanical properties. Insulin therapy initiated at early diabetes onset normalized glycemia, restored bone formation, and fully recovered cortical material properties. However, cortical porosity remained elevated, cortical geometry was not fully restored, and whole-bone structural mechanical properties did not improve. Gene expression profiling showed downregulation of osteoblast, osteocyte, mechanosensing, and Wnt-related genes in male Akita mice. Notably, Sp7 (Osterix) and Ostn (Osteocrin), key regulators of osteocyte dendrite formation, were downregulated in male Akita mice, suggesting disrupted osteocyte network development. Insulin upregulated osteogenic and Wnt signaling targets but incompletely restored mechanosensing pathways. Importantly, expression of the Wnt inhibitors Sost (Sclerostin) and Dkk1 (Dickkopf-1) remained elevated despite insulin treatment, potentially maintaining an inhibitory environment that limits the anabolic response to mechanical loading. These findings show that early insulin therapy improves bone health in type 1 diabetes, including turnover, trabecular structure, and cortical tissue material properties, but fails to fully rescue cortical integrity and whole-bone structural mechanical properties. This incomplete recovery likely reflects persistent defects in osteocyte function and mechanosensing in insulin-deficient bone and highlights potential therapeutic targets beyond glycemic control to reduce fracture risk in type 1 diabetes.