Mouse Models of Diabetic Complications: Dissecting Molecular Mechanisms of Disease Progression.

Abstract

Diabetes mellitus leads to chronic, multi-organ complications, most notably diabetic nephropathy, peripheral neuropathy, and retinopathy. While hyperglycemia serves as the initiating insult, disease progression involves a complex interplay of molecular mechanisms, including oxidative stress, mitochondrial dysfunction, inflammation, and impaired antioxidant defenses. This focused review examines how these shared pathways contribute to organ-specific damage and how they are reflected in experimental mouse models. Key regulatory networks-including nuclear factor kappa B (NF-κB), transforming growth factor-β (TGF-β), protein kinase C (PKC), the advanced glycation end product (AGE)-receptor for AGE (RAGE) axis, and nuclear factor erythroid 2-related factor 2 (Nrf2)-link metabolic stress to fibrosis, vascular dysfunction, and neural injury. Mitochondrial dysfunction is also a commonly shared pathological feature across affected tissues. To investigate these mechanisms, this review outlines the characteristics of widely used mouse models-streptozotocin (STZ)-induced,mice (harboring themutation),, and Black and Tan Brachyury (BTBR)-in relation to specific diabetic complications. STZ-induced andmice effectively model hyperglycemia-induced injury, whileand BTBRmice recapitulate insulin resistance, dyslipidemia, and systemic inflammation. We describe how each model reflects distinct pathogenic features-such as TGF-β-mediated podocyte loss in nephropathy, aldose reductase activation and mast cell dysfunction in neuropathy, and PKC-dependent pericyte apoptosis in retinopathy. Therapeutic strategies targeting these conserved molecular pathways-including Nrf2 activation, NF-κB inhibition, or mitochondrial restoration-have demonstrated efficacy across multiple models. By aligning pathophysiological mechanisms with appropriate experimental systems, this review provides a practical framework for selecting preclinical tools and developing multi-targeted interventions to prevent or slow the progression of diabetic complications.