Wnt/β-Catenin Signaling in Diabetic Complications: Mechanisms and Therapeutic Potential

Diabetic complications, driven by chronic hyperglycemia and complex pathogenic mechanisms, are a major global health challenge, yet the basis of tissue-specific injury and repair remains unclear. Wnt/β-catenin signaling has emerged as an important regulator in these complications, but its role is highly context dependent, promoting pathological remodeling in some tissues while impairing repair in others. This review is distinguished by its integration of current evidence on the dual and often opposing roles of Wnt/β-catenin signaling across six major diabetic complications: diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic cutaneous ulcers (DCU), diabetic cardiomyopathy (DCM), diabetic neuropathy, and diabetic osteoporosis (DOP). We first outline the major pathological features and clinical significance of each complication, highlighting the recurring observation that hyperglycemia often causes aberrant activation of this pathway in DN, DR, and DCM, where it promotes epithelial-to-mesenchymal transition, extracellular matrix accumulation, fibrosis, inflammation, and pathological angiogenesis. In contrast, we then examine conditions in which Wnt/β-catenin signaling is suppressed, particularly in DCU, DOP, and certain forms or stages of DPN, leading to impaired wound healing, reduced bone formation, and defective nerve regeneration. We subsequently analyze the cell type- and stage-specific mechanisms underlying these divergent effects, including cross-talk with oxidative stress, the renin-angiotensin system, and transforming growth factor-β signaling. Following a detailed discussion of emerging therapeutic strategies, such as LRP6-targeting biologics, small-molecule modulators, and agents derived from traditional Chinese medicine, we summarize preclinical evidence showing that carefully tuned, context-specific modulation of Wnt/β-catenin can improve both pathological and functional outcomes. This review is intended to clarify the potential mechanisms linking Wnt/β-catenin signaling to diabetic complications and to guide the rational development of new therapies that take into account its tissue-specific and stage-specific effects.