The prevalence of type 2 diabetes is rapidly increasing, with severe socioeconomic impacts1,2. Excess lipid deposition in peripheral tissues impairs insulin sensitivity and glucose uptake, and has been proposed to contribute to the pathology of type 2 diabetes3,4,5. However, few treatment options exist that directly target ectopic lipid accumulation6. Recently it was found that vascular endothelial growth factor B (VEGF-B) controls endothelial uptake and transport of fatty acids in heart and skeletal muscle7. 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.
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We thank S. Wittgren and A. Gustafsson for technical assistance, and G. Christofori for the RIP VEGF-B mice. C.E.H. was supported by the Frans Wilhelm och Waldemar von Frenckells Fond and Wilhelm och Else Stockmanns Stiftelse. D.N. was supported by the Swedish Society for Medical Research. This study was supported by the Ludwig Institute for Cancer Research, the Novo Nordisk Foundation, the Swedish Cancer Foundation, the Swedish Research Council, Torsten och Ragnar Söderbergs Stiftelser, Dr Peter Wallenbergs Foundation for Economics and Technology, the Swedish Heart and Lung Foundation, the Diabetes Foundation and Karolinska Institutet.
U.E. is a consultant to CSL Limited and is an inventor on a patent describing the role of VEGF-B in type 2 diabetes; P.S. and A.N. are employees of CSL Limited, own shares in CSL Limited and are inventors on a patent describing the antibody 2H10.
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Hagberg, C., Mehlem, A., Falkevall, A. et al. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature 490, 426–430 (2012). https://doi.org/10.1038/nature11464
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