Dysregulation of Extracellular Matrix in Diabetic Complications: Clinical Impacts and New Molecular Targets

Abstract

Diabetic complications include cardiomyopathy, hepatic diseases, retinopathy, nephropathy, neuropathy, and foot ulcers which impose a substantial burden on global health. Recent data from various literature indicate that the dysregulation of extracellular matrix (ECM) is considered as one of the primary culprits found in the pathological complications. Chronic hyperglycemia and insulin resistance promote ECM remodeling through oxidative stress, inflammatory cytokines, and advanced glycation end products (AGEs), leading to fibrosis, vascular dysfunction, and impaired tissue repair. In diabetic retinopathy, excessive ECM deposition thickens the retinal basement, compromising retinal microvasculature integrity. Similarly, in diabetic nephropathy, ECM accumulation in the glomerular basement membrane disrupts kidney filtration, accelerating disease progression. The dysregulated ECM also plays a role in diabetic cardiomyopathy, liver diseases, neuropathy, and diabetic foot ulcer due to impaired wound healing. Molecular mechanisms, including the TGF-beta/SMAD signaling pathway, matrix metalloproteinase (MMP) inhibition, and epigenetic modifications, contribute to ECM imbalances, exacerbating organ damage. Therapeutic strategies targeting ECM modulation, including TGF-beta inhibitors, AGE-RAGE pathway blockers, CXCLs and MMP activators, hold promise in mitigating these complications. Understanding ECM dynamics in diabetes thus offers novel insights into disease pathophysiology and potential intervention strategies aimed at preserving organ function and improving patient outcomes. In this article, we discuss clinical and new molecular basis for the ECM dysregulation in diabetic complications.