| Vascular insulin-like growth factor-I resistance and diet-induced obesity. | |
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MedLine Citation:
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PMID: 19608653 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Helen Imrie; Afroze Abbas; Hema Viswambharan; Adil Rajwani; Richard M Cubbon; Matthew Gage; Matthew Kahn; Vivienne A Ezzat; Edward R Duncan; Peter J Grant; Ramzi Ajjan; Stephen B Wheatcroft; Mark T Kearney |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't Date: 2009-07-16 |
Journal Detail:
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Title: Endocrinology Volume: 150 ISSN: 1945-7170 ISO Abbreviation: Endocrinology Publication Date: 2009 Oct |
Date Detail:
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Created Date: 2009-09-22 Completed Date: 2009-10-22 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0375040 Medline TA: Endocrinology Country: United States |
Other Details:
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Languages: eng Pagination: 4575-82 Citation Subset: AIM; IM |
Affiliation:
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Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds LS2 9JT, United Kingdom. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aorta / physiology Dietary Fats / adverse effects* Endothelium, Vascular / metabolism Enzyme Activation Humans Insulin Resistance Insulin-Like Growth Factor I / metabolism* Male Mice Mice, Inbred C57BL Nitric Oxide / metabolism* Nitric Oxide Synthase Type III / metabolism Obesity / etiology, metabolism*, physiopathology Phosphorylation Receptor, Insulin / metabolism Serine / metabolism Vasodilation* |
| Chemical | |
Reg. No./Substance:
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0/Dietary Fats; 10102-43-9/Nitric Oxide; 56-45-1/Serine; 67763-96-6/Insulin-Like Growth Factor I; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 2.7.10.1/Receptor, Insulin |
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