Study: Novel type of inhibitor may prevent microvascular diabetic complications

Diabetes Insulin Glucose Blood Social

A new type of inhibitor drug could prevent microvascular diabetic complications, such as diabetic eye and kidney disease, research suggests.

University of Bristol researchers found that heparanase inhibitors, which stop damage to the protective lining of blood vessels called the glycocalyx, could be developed as a medication to treat patients.

The results of mouse model studies have been published in Cardiovascular Diabetology.

"Our findings are exciting as we have shown that one type of medication might be able to prevent different diabetic complications, which is a global health problem for adults living with diabetes," said Dr. Rebecca Foster, a senior author and associate professor of microvascular medicine at Bristol Medical School.

Diabetes can result in life-altering complications through its impact on the small blood vessels of the body, known as the microvasculature. Two of the most common microvascular complications are diabetic retinopathy (DR), a leading cause of vision impairment and vision loss, and diabetic kidney disease (DKD), which affects up to 40% of diabetic patients and is the leading cause of end-stage renal failure.

Both DR and DKD are characterized by microvascular barrier dysfunction and studies suggest both have common mechanisms—the incidence of one complication significantly increases the likelihood of developing the other.

The heparan sulphate cleaving enzyme, heparanase, has previously been shown to contribute to diabetic microvascular complications, but the common underlying mechanism which results in microvascular dysfunction in conditions such as DR and DKD has not been determined.

The endothelial glycocalyx (eGlx), which lines the luminal surface of all vascular endothelial cells, has emerged as a key determinant of endothelial and vascular health, including through its role in barrier function.

The researchers showed in two mouse models how the eGlx can be therapeutically targeted with the novel heparanase inhibitor OVZ/HS-1638 to prevent microvascular dysfunction in diabetes in multiple vessel beds—e.g., eye and kidney.

Heparanase has gained interest as a “druggable target” in some diseases that are associated with chronic inflammation, such as cancer and diabetes, say the authors. Their study showed that microvascular complications in diabetes can be treated systemically, by targeting heparan sulphate (HS) in the eGlx to restore vascular barrier properties.

“To our knowledge, this study is the first to demonstrate systemic prevention of microvascular complications associated with diabetes, demonstrated in the eye and kidney,” they wrote.

“Our focus, in future work, is to achieve a pre-clinical experimental and safety package for OVZ/HS-1638 for treatment of DKD and DR in clinics.”

“With over 8% of the global adult population currently living with diabetes, we hope patients could benefit from our findings in the future," said Dr. Monica Gamez, corresponding author and University of Bristol research associate.

The study was funded by the Medical Research Council (MRC).

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