The prevalence of
type 2 diabetes is rapidly increasing, with severe socioeconomic impacts. Excess
lipid deposition in peripheral tissues impairs
insulin sensitivity and
glucose uptake, and has been proposed to contribute to the pathology of
type 2 diabetes. However, few treatment options exist that directly target ectopic
lipid accumulation. Recently it was found that
vascular endothelial growth factor B (
VEGF-B) controls endothelial uptake and transport of
fatty acids in heart and skeletal muscle. Here we show that decreased
VEGF-B signalling in rodent models of
type 2 diabetes restores
insulin sensitivity and improves
glucose tolerance. Genetic deletion of Vegfb in diabetic db/db mice prevented ectopic
lipid deposition, increased muscle
glucose uptake and maintained normoglycaemia. Pharmacological inhibition of
VEGF-B signalling by antibody administration to db/db mice enhanced
glucose tolerance, preserved pancreatic islet architecture, improved β-cell function and ameliorated dyslipidaemia, key elements of
type 2 diabetes and the
metabolic syndrome. The potential use of
VEGF-B neutralization in
type 2 diabetes was further elucidated in rats fed a high-fat diet, in which it normalized
insulin sensitivity and increased
glucose uptake in skeletal muscle and heart. Our results demonstrate that the vascular endothelium can function as an efficient barrier to excess muscle
lipid uptake even under conditions of
severe obesity and
type 2 diabetes, and that this barrier can be maintained by inhibition of
VEGF-B signalling. We propose
VEGF-B antagonism as a novel pharmacological approach for
type 2 diabetes, targeting the
lipid-transport properties of the endothelium to improve muscle
insulin sensitivity and
glucose disposal.