Blocking Vascular Endothelial Growth Factor B Cures Diabetes in Rodent Models

The VEGF family members regulate the formation of blood vessels and are involved in endothelial cell physiology. VEGF-B is a ligand for VEGFR-1 (vascular endothelial growth factor receptor 1) and NRP-1 (neuropilin-1). Studies in mice showed that this gene was coexpressed with nuclear-encoded mitochondrial genes, and the encoded protein specifically controlled endothelial uptake of fatty acids.

Investigators at Karolinska Institutet (Stockholm, Sweden) based their study on the relationship between VEGF-B and the uptake and storage of fats in the body. Among the model systems they employed was a genetically engineered line of diabetic mice that lacked the gene for VEGF-B. Another model was based on wild type mice that were fed to obesity with the subsequent development of type II diabetes. A similar type II diabetes model was established in rats. Some diabetic animals were treated with the candidate drug 2H10. This monoclonal antibody, developed by the biopharmaceutical company CSL Limited (Melbourne Australia), specifically blocks the activity of VEGF-B.

Results published in the September 26, 2012, online edition of the journal Nature showed that genetic deletion of VEGF-B in a line of diabetic mice prevented lipid deposition in muscles, blood vessels, and heart. These animals displayed increased muscle glucose uptake and maintained normal glucose metabolism.

Mice and rats that had developed type II diabetes spontaneously or were genetically destined to become diabetic (but had intact VEGF-B genes) were then treated with the drug 2H10. The genetically determined mice displayed enhanced glucose tolerance, preserved pancreatic islet architecture, improved beta-cell function, and corrected lipid metabolism following 2H10 treatment. The animals that spontaneously developed diabetes after high fat diets showed normalized insulin sensitivity and increased glucose uptake in skeletal muscle and heart following treatment with 2H10.

"It is a great feeling to present these results," said senior author Dr. Ulf Eriksson professor of the medical biochemistry and biophysics at Karolinska Institutet. "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 are making one important discovery after the other. In this present study we have shown that VEGF-B inhibition can be used to prevent and treat type II diabetes, and that this can be done with a drug candidate."

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