Over 8% of the global adult population is affected by diabetes mellitus, which frequently leads to microvascular manifestations. Current therapeutic approaches for diabetic retinopathy and nephropathy often prove inadequate, and improper management can result in irreversible outcomes such as vision loss and renal failure. A recent study published in the Journal of Cardiovascular Diabetology identifies a new class of inhibitor drugs that could potentially prevent microvascular complications linked to diabetes.
Heparanase is an enzyme responsible for the degradation of heparan sulfate, a key component of the endothelial glycocalyx. In diabetes mellitus, increased heparanase activity exacerbates glycocalyx damage, contributing to vascular dysfunction and complications such as diabetic retinopathy and nephropathy.
Dr. Gamez and colleagues used two mouse models to study the effects of heparan sulfate loss on microvascular barrier function. Changes in endothelial glycocalyx were measured using fluorescence microscopy and transmission electron microscopy. Barrier function was assessed through sodium fluorescein angiography in the eye and a glomerular albumin permeability assay in the kidney. In a type 2 diabetic mouse model, the researchers tested a novel heparanase inhibitor, OVZ/HS-1638, to prevent heparan sulfate damage. By preserving the integrity of the endothelial glycocalyx, they demonstrated that the development of diabetic eye and kidney diseases could be effectively halted.
Researchers noticed that in models of heparan sulfate depletion, endothelial glycocalyx depth decreased, leading to increased retinal solute flux and glomerular albumin permeability. Type 2 diabetes mice treated with OVZ/HS-1638 exhibited improved glycocalyx measurements and protection from microvascular permeability changes associated with diabetic retinopathy and diabetic kidney disease. This suggests a single medication could prevent diverse diabetic complications. Targeting heparanase to preserve glycocalyx integrity offers a promising molecular-level intervention, potentially preventing diabetic complications.
Inhibitors targeting heparanase activity offer a potential strategy for safeguarding the glycocalyx integrity and ameliorating diabetic complications. This research signifies a significant advancement in the realm of innovative treatments for diabetic complications. The exploration of heparanase inhibitors presents a promising avenue for preventing microvascular issues, However, it is imperative to conduct further pre-clinical studies and clinical trials to thoroughly evaluate the safety and efficacy of heparanase inhibitors in human subjects. The success of these trials could herald a transformative era in the management of diabetic complications.
Reference
Gamez M, Elhegni HE, Fawaz S, Ho KH, Campbell NW, Copland DA, et al. Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes. Cardiovascular Diabetology. 2024 Feb 1;23(1):50.