title: Increasing circulating IGFBP1 levels improves insulin sensitivity, promotes nitric oxide production, lowers blood pressure, and protects against atherosclerosis.
abstract: Low concentrations of insulin-like growth factor (IGF) binding protein-1 (IGFBP1) are associated with insulin resistance, diabetes, and cardiovascular disease. We investigated whether increasing IGFBP1 levels can prevent the development of these disorders. Metabolic and vascular phenotype were examined in response to human IGFBP1 overexpression in mice with diet-induced obesity, mice heterozygous for deletion of insulin receptors (IR(+/-)), and ApoE(-/-) mice. Direct effects of human (h)IGFBP1 on nitric oxide (NO) generation and cellular signaling were studied in isolated vessels and in human endothelial cells. IGFBP1 circulating levels were markedly suppressed in dietary-induced obese mice. Overexpression of hIGFBP1 in obese mice reduced blood pressure, improved insulin sensitivity, and increased insulin-stimulated NO generation. In nonobese IR(+/-) mice, overexpression of hIGFBP1 reduced blood pressure and improved insulin-stimulated NO generation. hIGFBP1 induced vasodilatation independently of IGF and increased endothelial NO synthase (eNOS) activity in arterial segments ex vivo, while in endothelial cells, hIGFBP1 increased eNOS Ser(1177) phosphorylation via phosphatidylinositol 3-kinase signaling. Finally, in ApoE(-/-) mice, overexpression of hIGFBP1 reduced atherosclerosis. These favorable effects of hIGFBP1 on insulin sensitivity, blood pressure, NO production, and atherosclerosis suggest that increasing IGFBP1 concentration may be a novel approach to prevent cardiovascular disease in the setting of insulin resistance and diabetes.
authors.affiliation: Division of Cardiovascular and Diabetes Research, MultidisciplinaryCardiovascular Research Centre, University of Leeds, Leeds, U.K.
authors.forename: Adil
authors.initials: A
authors.lastname: Rajwani
authors.forename: Vivienne
authors.initials: V
authors.lastname: Ezzat
authors.forename: Jessica
authors.initials: J
authors.lastname: Smith
authors.forename: Nadira Y
authors.initials: NY
authors.lastname: Yuldasheva
authors.forename: Edward R
authors.initials: ER
authors.lastname: Duncan
authors.forename: Matthew
authors.initials: M
authors.lastname: Gage
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cubbon
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Kahn
authors.forename: Helen
authors.initials: H
authors.lastname: Imrie
authors.forename: Afroze
authors.initials: A
authors.lastname: Abbas
authors.forename: Hema
authors.initials: H
authors.lastname: Viswambharan
authors.forename: Amir
authors.initials: A
authors.lastname: Aziz
authors.forename: Piruthivi
authors.initials: P
authors.lastname: Sukumar
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.forename: Jaswinder K
authors.initials: JK
authors.lastname: Sethi
authors.forename: Shouhong
authors.initials: S
authors.lastname: Xuan
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Grant
authors.forename: Karen E
authors.initials: KE
authors.lastname: Porter
authors.forename: Mark T
authors.initials: MT
authors.lastname: Kearney
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wheatcroft
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000517:prevention & control*; D001794:Blood Pressure / Q000502:physiology*; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000378:metabolism*; D042783:Endothelial Cells; D017353:Gene Deletion; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis*; D009765:Obesity / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D009569:Nitric Oxide; D011972:Receptor, Insulin