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
Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds LS2 9JT, United Kingdom.
Endocrinology. 2009 Oct;150(10):4575-82. doi: 10.1210/en.2008-1641. Epub 2009 Jul 16.
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.
肥胖症和2型糖尿病的特征是胰岛素抵抗、抗动脉粥样硬化信号分子一氧化氮（NO）的生物利用度降低以及动脉粥样硬化加速。胰岛素样生长因子-I（IGF-I）是主要的生长刺激肽，与胰岛素有许多共同作用，可能也像胰岛素一样参与代谢和血管稳态。我们在全身水平和血管系统中研究了IGF-I对NO生物利用度的影响以及肥胖症/2型糖尿病对IGF-I作用的影响。在主动脉环中，IGF-I减弱了去氧肾上腺素介导的血管收缩，并使预先用去氧肾上腺素收缩的环舒张，这种作用被N（G）-单甲基-L-精氨酸阻断。IGF-I使一氧化氮合酶活性增加的程度与胰岛素相似，并且体内IGF-I导致内皮型一氧化氮合酶（eNOS）的丝氨酸磷酸化。用高脂饮食诱导肥胖的小鼠对胰岛素和IGF-I的降糖作用不太敏感。IGF-I增加了瘦小鼠主动脉中磷酸化eNOS的水平，而在肥胖小鼠中这种作用减弱。与肥胖小鼠相比，瘦小鼠主动脉中的eNOS活性对IGF-I的反应增加了1.6倍。肥胖小鼠中IGF-I介导的血管舒张减弱。这些数据表明，IGF-I在体内增加eNOS磷酸化，增加eNOS活性，并导致传导血管的NO依赖性舒张。肥胖在全身水平和内皮中与对IGF-I的抵抗有关。血管IGF-I抵抗可能代表一个新的治疗靶点，以预防或减缓肥胖或2型糖尿病患者中出现的加速血管病变。
