Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

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.


  1. World Health Organization . World Health Organization Diabetes Fact sheet no. 312. (2011)

  2. Diabetes Prevention Program (DPP) Research Group The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care 25, 2165–2171 (2002)

    Article  Google Scholar 

  3. Perseghin, G. et al. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes 48, 1600–1606 (1999)

    Article  CAS  Google Scholar 

  4. Samuel, V. T., Petersen, K. F. & Shulman, G. I. Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375, 2267–2277 (2010)

    Article  CAS  Google Scholar 

  5. Unger, R. H. Lipotoxic diseases. Annu. Rev. Med. 53, 319–336 (2002)

    Article  CAS  Google Scholar 

  6. Stumvoll, M., Goldstein, B. J. & van Haeften, T. W. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365, 1333–1346 (2005)

    Article  CAS  Google Scholar 

  7. Hagberg, C. E. et al. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464, 917–921 (2010)

    Article  ADS  CAS  Google Scholar 

  8. Zimmet, P., Alberti, K. G. & Shaw, J. Global and societal implications of the diabetes epidemic. Nature 414, 782–787 (2001)

    Article  ADS  CAS  Google Scholar 

  9. Schmitz-Peiffer, C. et al. Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes 46, 169–178 (1997)

    Article  CAS  Google Scholar 

  10. Schmitz-Peiffer, C. Targeting ceramide synthesis to reverse insulin resistance. Diabetes 59, 2351–2353 (2010)

    Article  CAS  Google Scholar 

  11. Boström, P. et al. SNARE proteins mediate fusion between cytosolic lipid droplets and are implicated in insulin sensitivity. Nature Cell Biol. 9, 1286–1293 (2007)

    Article  Google Scholar 

  12. Bostrom, P. et al. The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes. Diabetes 59, 1870–1878 (2010)

    Article  Google Scholar 

  13. Muoio, D. M. Metabolism and vascular fatty acid transport. N. Engl. J. Med. 363, 291–293 (2010)

    Article  CAS  Google Scholar 

  14. Lahteenvuo, J. E. et al. Vascular endothelial growth factor-B induces myocardium-specific angiogenesis and arteriogenesis via vascular endothelial growth factor receptor-1- and neuropilin receptor-1-dependent mechanisms. Circulation 119, 845–856 (2009)

    Article  Google Scholar 

  15. Olofsson, B. et al. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc. Natl Acad. Sci. USA 93, 2576–2581 (1996)

    Article  ADS  CAS  Google Scholar 

  16. Albrecht, I. et al. Suppressive effects of vascular endothelial growth factor-B on tumor growth in a mouse model of pancreatic neuroendocrine tumorigenesis. PLoS ONE 5, e14109 (2010)

    Article  ADS  Google Scholar 

  17. Olofsson, B. et al. Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc. Natl Acad. Sci. USA 95, 11709–11714 (1998)

    Article  ADS  CAS  Google Scholar 

  18. Makinen, T. et al. Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1. J. Biol. Chem. 274, 21217–21222 (1999)

    Article  CAS  Google Scholar 

  19. Aase, K. et al. Vascular endothelial growth factor-B-deficient mice display an atrial conduction defect. Circulation 104, 358–364 (2001)

    Article  CAS  Google Scholar 

  20. Karpanen, T. et al. Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy. Circ. Res. 103, 1018–1026 (2008)

    Article  CAS  Google Scholar 

  21. Genuth, S. M., Przybylski, R. J. & Rosenberg, D. M. Insulin resistance in genetically obese, hyperglycemic mice. Endocrinology 88, 1230–1238 (1971)

    Article  CAS  Google Scholar 

  22. Sparks, L. M. et al. A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 54, 1926–1933 (2005)

    Article  CAS  Google Scholar 

  23. Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genet. 34, 267–273 (2003)

    Article  ADS  CAS  Google Scholar 

  24. Randle, P. J. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab. Rev. 14, 263–283 (1998)

    Article  CAS  Google Scholar 

  25. Eckel, R. H., Grundy, S. M. & Zimmet, P. Z. The metabolic syndrome. Lancet 365, 1415–1428 (2005)

    Article  CAS  Google Scholar 

  26. Scotney, P. D. et al. Human vascular endothelial growth factor B: characterization of recombinant isoforms and generation of neutralizing monoclonal antibodies. Clin. Exp. Pharmacol. Physiol. 29, 1024–1029 (2002)

    Article  CAS  Google Scholar 

  27. Fujimoto, W. Y. The importance of insulin resistance in the pathogenesis of type 2 diabetes mellitus. Am. J. Med. 108 (suppl. 6a). 9–14 (2000)

    Article  Google Scholar 

  28. Chaggar, P. S., Shaw, S. M. & Williams, S. G. Review article: thiazolidinediones and heart failure. Diab. Vasc. Dis. Res. 6, 146–152 (2009)

    Article  Google Scholar 

  29. Kim, F. et al. Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance. Arterioscler. Thromb. Vasc. Biol. 28, 1982–1988 (2008)

    Article  CAS  Google Scholar 

  30. Kubota, T. et al. Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle. Cell Metab. 13, 294–307 (2011)

    Article  CAS  Google Scholar 

  31. Andrikopoulos, S., Blair, A. R., Deluca, N., Fam, B. C. & Proietto, J. Evaluating the glucose tolerance test in mice. Am. J. Physiol. Endocrinol. Metab. 295, E1323–E1332 (2008)

    Article  CAS  Google Scholar 

  32. Mangiafico, S. P. et al. A primary defect in glucose production alone cannot induce glucose intolerance without defects in insulin secretion. J. Endocrinol. 210, 335–347 (2011)

    Article  CAS  Google Scholar 

  33. Wong, N. et al. Deficiency in interferon-γ results in reduced body weight and better glucose tolerance in mice. Endocrinology 152, 3690–3699 (2011)

    Article  CAS  Google Scholar 

  34. Nyqvist, D., Kohler, M., Wahlstedt, H. & Berggren, P. O. Donor islet endothelial cells participate in formation of functional vessels within pancreatic islet grafts. Diabetes 54, 2287–2293 (2005)

    Article  CAS  Google Scholar 

  35. Kawasaki, F., Matsuda, M., Kanda, Y., Inoue, H. & Kaku, K. Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice. Am. J. Physiol. Endocrinol. Metab. 288, E510–E518 (2005)

    Article  CAS  Google Scholar 

  36. Lamont, B. J. et al. Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney. Diabetologia 46, 1338–1347 (2003)

    Article  CAS  Google Scholar 

  37. Visinoni, S. et al. Increased glucose production in mice overexpressing human fructose-1,6-bisphosphatase in the liver. Am. J. Physiol. Endocrinol. Metab. 295, E1132–E1141 (2008)

    Article  CAS  Google Scholar 

  38. Kraegen, E. W. et al. Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats. Diabetes 40, 1397–1403 (1991)

    Article  CAS  Google Scholar 

  39. Nolan, C. J. & Proietto, J. The feto-placental glucose steal phenomenon is a major cause of maternal metabolic adaptation during late pregnancy in the rat. Diabetologia 37, 976–984 (1994)

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Ethics declarations

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.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-12. (PDF 1402 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing