The increasing prevalence of the metabolic syndrome and type 2 diabetes (T2D) is of major concern 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 T2D. Few treatments exist that directly target ectopic lipid accumulation, and those that do have significant safety concerns. Vascular Endothelial Growth Factor B (VEGF-B) controls endothelial uptake and transport of fatty acids into heart and skeletal muscle1. We have shown that decreased VEGF-B signalling in rodent models of T2D restores insulin sensitivity and improves glucose tolerance2. Genetic deletion of Vegfb in obese db/db mice prevented ectopic lipid deposition, increased glucose uptake and maintained normoglycaemia. Pharmacological inhibition of VEGF-B signalling by an antibody administered to obese db/db mice enhanced glucose tolerance, preserved pancreatic islet architecture and β-cell function, and ameliorated dyslipidaemia, key elements of T2D and the metabolic syndrome. The therapeutic potential of VEGF-B neutralisation in T2D was further investigated in rats fed a high fat diet, where it normalised insulin sensitivity and increased glucose uptake to skeletal muscle and heart. The results demonstrate that the vascular endothelium can function as an efficient barrier towards excess lipid uptake under conditions of severe obesity and T2D, and that this barrier can be maintained by inhibition of VEGF-B signalling. We propose VEGF-B antagonism as a novel pharmacological approach for T2D, targeting the lipid transport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal.