Vascular Insulin-Like Growth Factor-I Resistance and Diet-Induced Obesity

• Published in: Endocrinology (Philadelphia) 2009-10, Vol.150 (10), p.4575-4582
• Main Authors: Imrie, Helen, Abbas, Afroze, Viswambharan, Hema, Rajwani, Adil, Cubbon, Richard M, Gage, Matthew, Kahn, Matthew, Ezzat, Vivienne A, Duncan, Edward R, Grant, Peter J, Ajjan, Ramzi, Wheatcroft, Stephen B, Kearney, Mark T
• Format: Article
• Language: English
• Subjects: Animals; Aorta; Aorta - physiology; Arginine; Arteriosclerosis; Atherosclerosis; Bioavailability; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diet; Dietary Fats - adverse effects; Endothelium; Endothelium, Vascular - metabolism; Enzyme Activation; Growth factors; High fat diet; Homeostasis; Humans; In Vitro Techniques; Insulin; Insulin Resistance; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; Male; Mice; Mice, Inbred C57BL; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Obesity; Obesity - etiology; Obesity - metabolism; Obesity - physiopathology; Phenylephrine; Phosphorylation; Receptor, Insulin - metabolism; Resistance factors; Serine - metabolism; Therapeutic targets; Vascular diseases; Vasoconstriction; Vasodilation
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2008-1641

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 NG-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. Dietary-induced obesity leads to whole body and vascular IGF-1 resistance.