title: Insulin stimulates the clonogenic potential of angiogenic endothelial progenitor cells by IGF-1 receptor-dependent signaling.
abstract: Endothelial progenitor cells (EPCs) have been shown to be involved in vascular regeneration and angiogenesis in experimental diabetes. Because insulin therapy mobilizes circulating progenitor cells, we studied the effects of insulin on outgrowth of EPCs from peripheral blood mononuclear cells of healthy volunteers and patients with type 2 diabetes. Insulin increased the formation of EPC colony-forming units in a dose-dependent manner, half-maximal at 1.5 nM and peaking at 15 nM. Inhibiting the insulin receptor with neutralizing antibodies or antisense oligonucleotides had no effect on EPC outgrowth.(1) In contrast, targeting the human insulin-like growth factor 1 (IGF-1) receptor with neutralizing antibodies significantly suppressed insulin-induced outgrowth of EPCs from both healthy controls and patients with type 2 diabetes. This IGF-1 receptor-mediated insulin effect on EPC growth was at least in part dependent on MAP kinases(2) and was abrogated when extracellular signal-regulated kinase 1/2 (Erk1/2) and protein kinase 38 (p38) activity was inhibited. To study the functional relevance of the observed insulin effects, we studied EPC-induced tube formation of bovine endothelial cells in vitro. Insulin-stimulated EPCs incorporated into the endothelial tubes and markedly enhanced tube formation. In conclusion, this is the first study showing an insulin-mediated activation of the IGF-1 receptor leading to an increased clonogenic and angiogenic potential of EPCs in vitro.
authors.affiliation: Department of Medicine I and Clinical Chemistry, University Clinics Heidelberg, Germany. per.humpert@med.uni-heidelberg.de
authors.forename: Per M
authors.initials: PM
authors.lastname: Humpert
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Djuric
authors.forename: Ulf
authors.initials: U
authors.lastname: Zeuge
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Oikonomou
authors.forename: Yuri
authors.initials: Y
authors.lastname: Seregin
authors.forename: Klaus
authors.initials: K
authors.lastname: Laine
authors.forename: Volker
authors.initials: V
authors.lastname: Eckstein
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D007328:Insulin; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin