In Vivo Models of Diabetes: Unravelling Molecular Pathways in Metabolic and Skeletal Complications

<b>Background/Objectives</b>: Diabetic osteoporosis (DOP) is a metabolic bone disorder marked by reduced bone mass, impaired microarchitecture and elevated fracture risk arising from type 1 and type 2 diabetes. Understanding its pathophysiology is essential for developing effective interventions. <b>Method</b>: A broad literature search of Scopus and PubMed (2015-2025) using diabetic osteoporosis-related keywords identified relevant English in vivo studies, which were screened, extracted, and narratively summarised for this review. <b>Results</b>: In vivo models, including high-fat-diet (HFD), streptozotocin (STZ) and combined HFD + STZ protocols, are widely used to investigate DOP mechanisms. HFD models mimic obesity-induced insulin resistance, chronic hyperglycaemia and low-grade inflammation, leading to suppressed osteoblast activity, enhanced osteoclastogenesis and accumulation of advanced glycation end products (AGEs). Ultimately, they compromise bone microarchitecture and mechanical strength. STZ models replicate type 1 diabetes by inducing β-cell destruction, insulin deficiency, oxidative stress, osteoblast apoptosis and inflammatory pathways promoting bone resorption. The combined HFD + STZ model integrates insulin resistance and partial β-cell dysfunction, closely reflecting type 2 diabetes pathology, including trabecular bone loss, collagen glycation and disrupted osteoblast-osteoclast signalling. Mechanistically, DOP involves impaired insulin/IGF-I signalling, AGE-RAGE interactions, oxidative stress and inflammation, resulting in diminished bone formation and quality. These models provide robust platforms for exploring molecular mechanisms and evaluating potential therapies, including Wnt pathway modulators, antioxidants and ferroptosis inhibitors. <b>Conclusions</b>: Collectively, preclinical in vivo models are indispensable for understanding DOP pathophysiology and developing strategies to mitigate diabetic bone fragility.