title: Vascular insulin-like growth factor-I resistance and diet-induced obesity.
abstract: Obesity and type 2 diabetes mellitus are characterized by insulin resistance, reduced bioavailability of the antiatherosclerotic signaling molecule nitric oxide (NO), and accelerated atherosclerosis. IGF-I, the principal growth-stimulating peptide, which shares many of the effects of insulin, may, like insulin, also be involved in metabolic and vascular homeostasis. We examined the effects of IGF-I on NO bioavailability and the effect of obesity/type 2 diabetes mellitus on IGF-I actions at a whole-body level and in the vasculature. In aortic rings IGF-I blunted phenylephrine-mediated vasoconstriction and relaxed rings preconstricted with phenylephrine, an effect blocked by N(G)-monomethyl L-arginine. IGF-I increased NO synthase activity to an extent similar to that seen with insulin and in-vivo IGF-I led to serine phosphorylation of endothelial NO synthase (eNOS). Mice rendered obese using a high-fat diet were less sensitive to the glucose-lowering effects of insulin and IGF-I. IGF-I increased aortic phospho-eNOS levels in lean mice, an effect that was blunted in obese mice. eNOS activity in aortae of lean mice increased 1.6-fold in response to IGF-I compared with obese mice. IGF-I-mediated vasorelaxation was blunted in obese mice. These data demonstrate that IGF-I increases eNOS phosphorylation in-vivo, increases eNOS activity, and leads to NO-dependent relaxation of conduit vessels. Obesity is associated with resistance to IGF-I at a whole-body level and in the endothelium. Vascular IGF-I resistance may represent a novel therapeutic target to prevent or slow the accelerated vasculopathy seen in humans with obesity or type 2 diabetes mellitus.
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds LS2 9JT, United Kingdom.
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: Adil
authors.initials: A
authors.lastname: Rajwani
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cubbon
authors.forename: Matthew
authors.initials: M
authors.lastname: Gage
authors.forename: Matthew
authors.initials: M
authors.lastname: Kahn
authors.forename: Vivienne A
authors.initials: VA
authors.lastname: Ezzat
authors.forename: Edward R
authors.initials: ER
authors.lastname: Duncan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Grant
authors.forename: Ramzi
authors.initials: R
authors.lastname: Ajjan
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wheatcroft
authors.forename: Mark T
authors.initials: MT
authors.lastname: Kearney
mesh_terms: D000818:Animals; D001011:Aorta / Q000502:physiology; D004041:Dietary Fats / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D066298:In Vitro Techniques; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D014664:Vasodilation
chemical_list: D004041:Dietary Fats; D009569:Nitric Oxide; D012694:Serine; D007334:Insulin-Like Growth Factor I; D052250:Nitric Oxide Synthase Type III; D011972:Receptor, Insulin