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Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes

Nature volume 490, pages 426–430 (2012)Cite this article

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Abstract

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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Figure 1: Vegfb deficiency protects db/db mice against the onset of type 2 diabetes.
Figure 2: Vegfb deficiency ameliorates the metabolic syndrome.
Figure 3: Pharmacological VEGF-B neutralization enhances glucose tolerance in diabetic mouse and rat models.
Figure 4: Preventative and therapeutic VEGF-B neutralization preserves insulin production and pancreatic islet morphology in db/db mice.

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Acknowledgements

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.

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Author notes

  1. Carolina E. Hagberg and Annika Mehlem: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Tissue Biology Group, Karolinska Institutet, SE-171 77 Stockholm, Sweden,

    Carolina E. Hagberg, Annika Mehlem, Annelie Falkevall, Lars Muhl, Daniel Nyqvist & Ulf Eriksson

  2. Ludwig Institute for Cancer Research Ltd, Stockholm Branch, Karolinska Institutet, Box 240, Stockholm, SE-171 77, Sweden

    Carolina E. Hagberg, Annelie Falkevall & Lars Muhl

  3. Department of Medicine (AH), University of Melbourne, Heidelberg, 3091, Victoria, Australia

    Barbara C. Fam, Joseph Proietto & Sofianos Andrikopoulos

  4. Department of Clinical Science and Education, Diabetes Research Unit, Södersjukhuset, Karolinska Institutet, Stockholm, SE-118 83, Sweden

    Henrik Ortsäter & Åke Sjöholm

  5. CSL Limited, Parkville, 3052, Victoria, Australia

    Pierre Scotney & Andrew Nash

  6. Neuroradiology Department and Karolinska Experimental Research and Imaging Center, Karolinska University Hospital, Solna, Stockholm, SE-17176, Sweden

    Erik Samén, Li Lu & Sharon Stone-Elander

  7. Clinical Neurosciences, Karolinska Institutet, Stockholm, SE-171 76, Sweden

    Erik Samén & Sharon Stone-Elander

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Contributions

C.E.H. designed and performed in vivo mouse experiments, collected the material, performed transcriptional analysis and wrote the paper; A.M. performed in vivo mouse experiments, transcriptional analyses, ORO analyses, plasma analyses, triglyceride content measurements, all histological analyses of the pancreas and helped write the paper; A.F. performed ORO analyses, assisted with in vivo mouse studies and helped write the paper; L.M. assisted with in vivo studies; B.C.F. performed the rat study; P.S. helped design and interpret the rat study, helped write the paper and developed and supplied the 2H10, rat/mouse chimaeric 2H10 and 6H6 antibodies; D.N. performed the islet isolation and triglyceride content measurements; E.S., L.L. and S.S.-E. performed and analysed the PET scan data; J.P. and S.A. designed, supervised and analysed the rat study; H.O. and Å.S. provided expertise in diabetes, advised on islet analysis, interpreted results and commented on the manuscript; A.N. helped design and interpret the rat study, and helped write the paper; U.E. designed and supervised the study, analysed and interpreted the data and helped write the paper. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Ulf Eriksson.

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Competing interests

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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