Scientists have used an antibody targeting VEGF-B to prevent and even reverse the development and progression of type 2 diabetes in genetic and dietary rodent models. The Karolinska Institutet-headed team say their results, which include four separate rodent studies reported in their published Nature paper, point to a completely new therapeutic and preventive approach to type 2 diabetes, a disease that already affects an estimated 310 million worldwide and is rapidly on the increase. The antibody tested, 2H10, is in development by Australian biopharma CSL, which part funded the Karolinska team’s work.
Type 2 diabetes is linked with obesity-related insulin resistance, and fat deposition in extra-adipose tissues such as muscles, blood vessels, and the heart. A potential link between fat deposition and VEGF-B was made by Ulf Eriksson, Ph.D.’s team at the Karolinska Institutet, who previously found that the protein acts on the vascular endothelium to regulate transendothelial transport of circulating fatty acids into cardiac and skeletal muscle.
Building on this work, the Karolinska team, working with collaborators at CSL and the Ludwig Institute of Cancer Research, have now shown that either deleting the VEGF-B gene or using an antibody to inhibit VEGF-B signaling prevents ectopic lipid deposition, increases muscle glucose uptake, and restores insulin sensitivity and glucose tolerance in rodent models of type 2 diabetes. Pharmacological inhibition of VEGF-B signaling by antibody administration to db/db mice also led to preserved pancreatic islet architecture and improved β-cell function and ameliorated dyslipidaemia, which are key elements of type 2 diabetes and metabolic syndrome. And in rats fed a high-fat diet, antibody blockade of VEGF-B normalized insulin sensitivity and increased glucose uptake by skeletal muscle and the heart.
“To our knowledge, this is the first study where the barrier function of the vascular endothelium has been harnessed to prevent development of insulin resistance and type 2 diabetes,” the investigators state. “We propose that inhibition of VEGF-B signaling represents a novel and promising treatment option that targets the underlying pathology of type 2 diabetes, thereby improving several adverse metabolic consequences of the disease.” The investigators report their results in Nature, in a paper titled “Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes.”
CSL says the published findings have spurred it to start evaluating further development of the anti-VEGF-B antibody, including human trials in type 2 diabetes and those at risk of the disease. “We are very hopeful that the antibody-based drug that we have developed and tested together with Professor Eriksson will ultimately lead to a new treatment option for people with diabetes, states Andrew Nash, Ph.D., svp for research at CSL. “It’s a great feeling to present these results,” Professor Eriksson adds. “We discovered VEGF-B back in 1995, and since then the VEGF-B project has been a lengthy sojourn in the wilderness, but now we’re making one important discovery after the other. In this present study we’ve shown that VGF-B inhibition can be used to prevent and treat type 2 diabetes, and that this can be done with a drug candidate.”