The Insulin-Like Growth Factor-1 Receptor Is a Negative Regulator of Nitric Oxide Bioavailability and Insulin Sensitivity in the Endothelium

被引：81

作者：

Abbas, Afroze ^{[1
]}

Imrie, Helen ^{[1
]}

Viswambharan, Hema ^{[1
]}

Sukumar, Piruthivi ^{[1
]}

Rajwani, Adil ^{[1
]}

Cubbon, Richard M. ^{[1
]}

Gage, Matthew ^{[1
]}

Smith, Jessica ^{[1
]}

Galloway, Stacey ^{[1
]}

Yuldeshava, Nadira ^{[1
]}

Kahn, Matthew ^{[1
]}

Xuan, Shouhong ^{[2
]}

Grant, Peter J. ^{[1
]}

Channon, Keith M. ^{[3
]}

Beech, David J. ^{[1
]}

Wheatcroft, Stephen B. ^{[1
]}

Kearney, Mark T. ^{[1
]}

机构：

[1] Univ Leeds, Leeds Multidisciplinary Cardiovasc Res Ctr, Div Cardiovasc & Diabet Res, Leeds, W Yorkshire, England

[2] Columbia Univ, Dept Genet & Dev, New York, NY USA

[3] Univ Oxford, British Heart Fdn Ctr Res Excellence, Oxford, England

来源：

DIABETES | 2011年 / 60卷 / 08期

基金：

英国医学研究理事会;

关键词：

SOUTH ASIAN MEN; HYBRID RECEPTORS; OXIDATIVE STRESS; CARDIOVASCULAR-DISEASE; INCREASED ABUNDANCE; SKELETAL-MUSCLE; IGF-I; RESISTANCE; CELLS; VIVO;

D O I：

10.2337/db11-0197

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

OBJECTIVE-In mice, haploinsufficiency of the IGF-1 receptor (IGF-1R(+/-)), at a whole-body level, increases resistance to inflammation and oxidative stress, but the underlying mechanisms are unclear. We hypothesized that by forming insulin-resistant heterodimers composed of one IGF-1R alpha beta and one insulin receptor (IR), IR alpha beta complex in endothelial cells (ECs), IGF-1R reduces free IR, which reduces EC insulin sensitivity and generation of the antioxidant/anti-inflammatory signaling radical nitric oxide (NO). RESEARCH DESIGN AND METHODS-Using a number of complementary gene-modified mice with reduced IGF-1R at a whole-body level and specifically in EC, and complementary studies in EC in vitro, we examined the effect of changing IGF-1R/IR stoichiometry on EC insulin sensitivity and NO bioavailability. RESULTS-IGF-1R(+/-) mice had enhanced insulin-mediated glucose lowering. Aortas from these mice were hypocontractile to phenylephrine (PE) and had increased basal NO generation and augmented insulin-mediated NO release from EC. To dissect EC from whole-body effects we generated mice with EC-specific knockdown of IGF-1R. Aortas from these mice were also hypocontractile to PE and had increased basal NO generation. Whole-body and EC deletion of IGF-1R reduced hybrid receptor formation. By reducing IGF-1R in IR-haploinsufficient mice we reduced hybrid formation, restored insulin-mediated vasorelaxation in aorta, and insulin stimulated NO release in EC. Complementary studies in human umbilical vein EC in which IGF-1R was reduced using siRNA confirmed that reducing IGF-1R has favorable effects on NO bioavailability and EC insulin sensitivity. CONCLUSIONS-These data demonstrate that IGF-1R is a critical negative regulator of insulin sensitivity and NO bioavailability in the endothelium. Diabetes 60:2169-2178, 2011

引用

页码：2169 / 2178

页数：10

共 51 条

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