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• W2002174005 abstract "Ectopic lipid deposition in muscle and liver is associated with the pathogenesis of type II diabetes. Hagberg et al., 2012Hagberg C.E. Mehlem A. Falkevall A. Muhl L. Fam B.C. Ortsäter H. Scotney P. Nyqvist D. Samén E. Lu L. et al.Nature. 2012; 490: 426-430Crossref PubMed Scopus (209) Google Scholar report that targeting the vascular endothelial growth factor (VEGF)-B restores insulin sensitivity and glucose tolerance by inhibiting endothelial-to-tissue lipid transport, opening promising avenues for diabetes therapy. Ectopic lipid deposition in muscle and liver is associated with the pathogenesis of type II diabetes. Hagberg et al., 2012Hagberg C.E. Mehlem A. Falkevall A. Muhl L. Fam B.C. Ortsäter H. Scotney P. Nyqvist D. Samén E. Lu L. et al.Nature. 2012; 490: 426-430Crossref PubMed Scopus (209) Google Scholar report that targeting the vascular endothelial growth factor (VEGF)-B restores insulin sensitivity and glucose tolerance by inhibiting endothelial-to-tissue lipid transport, opening promising avenues for diabetes therapy. Type II diabetes represents a formidable unmet medical health problem with more than 300 million people estimated to be affected worldwide. Individuals with diabetes have an elevated risk of vascular disease (atherosclerosis, stroke) and other complications. Diabetes-related deaths are expected to rise at an alarming speed over the coming years. Insulin resistance has been linked to accumulation of toxic lipid intermediates (ceramides, diacylglycerol) in skeletal muscle and liver. Hence, strategies preventing lipid deposition may offer therapeutic benefit but are not widely available (Samuel and Shulman, 2012Samuel V.T. Shulman G.I. Cell. 2012; 148: 852-871Abstract Full Text Full Text PDF PubMed Scopus (1475) Google Scholar). Hagberg et al., 2012Hagberg C.E. Mehlem A. Falkevall A. Muhl L. Fam B.C. Ortsäter H. Scotney P. Nyqvist D. Samén E. Lu L. et al.Nature. 2012; 490: 426-430Crossref PubMed Scopus (209) Google Scholar demonstrate that targeting the vascular endothelial growth factor B (VEGF-B) restores insulin sensitivity and prevents type II diabetes by reducing lipid accumulation in muscle. How can an angiogenic growth factor like VEGF-B be linked to diabetes? VEGF-B was one of the later members of the VEGF family to be identified, and its activity remains poorly understood (Fischer et al., 2008Fischer C. Mazzone M. Jonckx B. Carmeliet P. Nat. Rev. Cancer. 2008; 8: 942-956Crossref PubMed Scopus (474) Google Scholar). It is expressed in the heart, skeletal muscle, and brown fat and binds to VEGF receptor-1 (VEGFR1; flt-1) and its coreceptor neuropilin-1 (NRP1). Genetic studies indicate that VEGF-B’s angiogenic capacity is contextual and largely restricted to the heart, while pharmacological blockade inhibits ocular angiogenesis. In cancer, VEGF-B is, however, anti-angiogenic. Overall, its activity is less potent than other traditional angiogenic signals, but it induces strong arterialization of the coronary vasculature in rats (Bry et al., 2010Bry M. Kivelä R. Holopainen T. Anisimov A. Tammela T. Soronen J. Silvola J. Saraste A. Jeltsch M. Korpisalo P. et al.Circulation. 2010; 122: 1725-1733Crossref PubMed Scopus (116) Google Scholar). Importantly, VEGF-B overexpression in mouse but not in rat hearts leads to hypertrophy and signs of mitochondrial lipotoxicity, suggesting a possible role in cardiac metabolism (Bry et al., 2010Bry M. Kivelä R. Holopainen T. Anisimov A. Tammela T. Soronen J. Silvola J. Saraste A. Jeltsch M. Korpisalo P. et al.Circulation. 2010; 122: 1725-1733Crossref PubMed Scopus (116) Google Scholar; Karpanen et al., 2008Karpanen T. Bry M. Ollila H.M. Seppänen-Laakso T. Liimatta E. Leskinen H. Kivelä R. Helkamaa T. Merentie M. Jeltsch M. et al.Circ. Res. 2008; 103: 1018-1026Crossref PubMed Scopus (109) Google Scholar). However, VEGF-B does not affect mitochondrial function per se (Hagberg et al., 2010Hagberg C.E. Falkevall A. Wang X. Larsson E. Huusko J. Nilsson I. van Meeteren L.A. Samen E. Lu L. Vanwildemeersch M. et al.Nature. 2010; 464: 917-921Crossref PubMed Scopus (352) Google Scholar; Karpanen et al., 2008Karpanen T. Bry M. Ollila H.M. Seppänen-Laakso T. Liimatta E. Leskinen H. Kivelä R. Helkamaa T. Merentie M. Jeltsch M. et al.Circ. Res. 2008; 103: 1018-1026Crossref PubMed Scopus (109) Google Scholar). Rather, it promotes lipid transport across the endothelial barrier by upregulating the fatty acid transport proteins (FATP)-3/4 (Hagberg et al., 2010Hagberg C.E. Falkevall A. Wang X. Larsson E. Huusko J. Nilsson I. van Meeteren L.A. Samen E. Lu L. Vanwildemeersch M. et al.Nature. 2010; 464: 917-921Crossref PubMed Scopus (352) Google Scholar). Indeed, lipid uptake and deposition in muscle were reduced, and lipids were shunted to white adipose tissue in VEGF-B-deficient mice. Consequently, the fat mass and body weight increased, and glucose uptake to the heart was enhanced. These initial observations prompted Hagberg et al., 2012Hagberg C.E. Mehlem A. Falkevall A. Muhl L. Fam B.C. Ortsäter H. Scotney P. Nyqvist D. Samén E. Lu L. et al.Nature. 2012; 490: 426-430Crossref PubMed Scopus (209) Google Scholar to investigate the potential of anti-VEGF-B therapy for insulin resistance. In their follow-up study, Hagberg et al., 2012Hagberg C.E. Mehlem A. Falkevall A. Muhl L. Fam B.C. Ortsäter H. Scotney P. Nyqvist D. Samén E. Lu L. et al.Nature. 2012; 490: 426-430Crossref PubMed Scopus (209) Google Scholar demonstrate that genetic deficiency of VEGF-B in mouse models of insulin resistance and type II diabetes, including db/db diabetic mice (which carry mutations in the leptin receptor gene) and mice fed a high-fat diet, reduces lipid storage in muscle, heart, and pancreas—but not liver. VEGF-B inhibition reduced plasma triglyceride and nonesterified fatty acid levels and normalized the HDL-c to LDL-c ratio, indicating a reduced risk for cardioavascular pathology. However, the body weight of VEGF-B-deficient mice on a high-fat diet was increased. Nevertheless, VEGF-B deficiency lowered blood glucose levels without increasing insulin secretion and restored insulin sensitivity and glucose uptake in the muscle and heart. Pharmacological inhibition of VEGF-B via the administration of an anti-VEGF-B antibody to db/db mice or rats fed a high-fat diet largely phenocopied the genetic findings and enhanced insulin sensitivity. In a preventive setting (prediabetic db/db mice), VEGF-B blockade prevented the development of hyperglycemia, reduced lipid uptake in muscle, improved glucose tolerance, and protected against dyslipidemia. In a therapeutic setting (diabetic db/db mice), VEGF-B inhibition halted the progression of hyperglycemia and muscle lipid uptake. In addition, VEGF-B blockade improved pancreatic islet morphology, restored insulin and glucagon expression in the islets, and reduced islet cell death in both models. In another high-fat diet rat model, coincident initiation of the high-fat diet and anti-VEGF-B treatment normalized glucose tolerance and glucose-stimulated insulin secretion, reduced glucose infusion and disposal rates in a hyperinsulinemic/euglycemic clamp study, and promoted glucose uptake in muscle—evidence of improved insulin sensitivity. These results support the idea that VEGF-B regulates lipid uptake by muscles. Given that VEGF-B regulates lipid transport across the endothelium, the findings suggest that the endothelium acts as a prominent barrier controlling muscle lipid uptake. Furthermore, blocking VEGF-B provides a mechanism to ameliorate or even prevent type II diabetes (Figure 1). As with any breakthrough, this study raises a number of questions. For instance, is the effect of VEGF-B on trans-endothelial lipid transport the only mechanism? VEGF-B has a poor angiogenic activity in healthy conditions, but an effect of this growth factor on the vasculature in conditions of insulin resistance remains possible. Another question is whether VEGF-B can control insulin signaling in endothelial cells, a process known to increase insulin delivery to muscle (Kubota et al., 2011Kubota T. Kubota N. Kumagai H. Yamaguchi S. Kozono H. Takahashi T. Inoue M. Itoh S. Takamoto I. Sasako T. et al.Cell Metab. 2011; 13: 294-307Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). Since insulin also promotes lipid uptake in muscle, VEGF-B’s activity might also depend on effects on insulin. It would also be interesting to test whether endothelial deletion of NRP1 or VEGFR1, known to reduce the levels of the FATP4 transport protein in vitro (Hagberg et al., 2010Hagberg C.E. Falkevall A. Wang X. Larsson E. Huusko J. Nilsson I. van Meeteren L.A. Samen E. Lu L. Vanwildemeersch M. et al.Nature. 2010; 464: 917-921Crossref PubMed Scopus (352) Google Scholar), phenocopies the protective effects of VEGF-B blockade in vivo. Given that different VEGF-B-deficient mouse strains exhibit distinct phenotypes in baseline conditions (Aase et al., 2001Aase K. von Euler G. Li X. Pontén A. Thorén P. Cao R. Cao Y. Olofsson B. Gebre-Medhin S. Pekny M. et al.Circulation. 2001; 104: 358-364Crossref PubMed Scopus (131) Google Scholar; Bellomo et al., 2000Bellomo D. Headrick J.P. Silins G.U. Paterson C.A. Thomas P.S. Gartside M. Mould A. Cahill M.M. Tonks I.D. Grimmond S.M. et al.Circ. Res. 2000; 86: E29-E35Crossref PubMed Google Scholar), a confirmation of the antidiabetic phenotype in another VEGF-B-deficient strain would strengthen the current findings. It would also be interesting to explore if VEGF-B has additional prodiabetic effects through other changes in endothelial cells, perhaps modifying endothelial cell metabolism or endothelial-to-adipocyte differentiation, or altering vascular inflammation, a process known to modify insulin sensitivity. For anti-VEGF-B treatment to be clinically relevant, the data of the Hagberg et al., 2012Hagberg C.E. Mehlem A. Falkevall A. Muhl L. Fam B.C. Ortsäter H. Scotney P. Nyqvist D. Samén E. Lu L. et al.Nature. 2012; 490: 426-430Crossref PubMed Scopus (209) Google Scholar paper should be relevant for humans. While the authors paid great effort to test various rodent models, genetic association studies have not yet overwhelmingly identified VEGF-B as a possible risk factor for diabetes in humans. Another clinically relevant question is whether therapeutic blockade of VEGF-B therapy is safe. Deficiency of VEGF-B is well tolerated. Nonetheless, VEGF-B has been implicated in neurogenesis and neuroprotection (Poesen et al., 2008Poesen K. Lambrechts D. Van Damme P. Dhondt J. Bender F. Frank N. Bogaert E. Claes B. Heylen L. Verheyen A. et al.J. Neurosci. 2008; 28: 10451-10459Crossref PubMed Scopus (109) Google Scholar) and ischemic cardiac revascularization, raising the question whether VEGF-B blockade might worsen diabetic neuropathy or ischemic heart disease. The role of VEGF-B in inhibiting tumor angiogenesis will also deserve consideration. Overall, this work places the endothelium and its regulation by the VEGF-B ligand at the center stage of tissue lipid homeostasis, with promising therapeutic potential in the context of diabetes, obesity, and dyslipidemia." @default.
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• W2002174005 title "Treating Diabetes by Blocking a Vascular Growth Factor" @default.
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