title: Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes.
abstract: 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.
authors.affiliation: Tissue Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Carolina E
authors.initials: CE
authors.lastname: Hagberg
authors.forename: Annika
authors.initials: A
authors.lastname: Mehlem
authors.forename: Annelie
authors.initials: A
authors.lastname: Falkevall
authors.forename: Lars
authors.initials: L
authors.lastname: Muhl
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Fam
authors.forename: Henrik
authors.initials: H
authors.lastname: Ortsäter
authors.forename: Pierre
authors.initials: P
authors.lastname: Scotney
authors.forename: Daniel
authors.initials: D
authors.lastname: Nyqvist
authors.forename: Erik
authors.initials: E
authors.lastname: Samén
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.forename: Sharon
authors.initials: S
authors.lastname: Stone-Elander
authors.forename: Joseph
authors.initials: J
authors.lastname: Proietto
authors.forename: Sofianos
authors.initials: S
authors.lastname: Andrikopoulos
authors.forename: Ake
authors.initials: A
authors.lastname: Sjöholm
authors.forename: Andrew
authors.initials: A
authors.lastname: Nash
authors.forename: Ulf
authors.initials: U
authors.lastname: Eriksson
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000188:drug therapy / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000033:anatomy & histology / Q000166:cytology / Q000473:pathology; D050356:Lipid Metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009132:Muscles / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D042561:Vascular Endothelial Growth Factor B / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D042561:Vascular Endothelial Growth Factor B; D005947:Glucose