Novel and Reversible Mechanisms of Smoking-Induced Insulin Resistance in Humans

被引:104
作者
Bergman, Bryan C. [1 ]
Perreault, Leigh [1 ]
Hunerdosse, Devon [1 ]
Kerege, Anna [1 ]
Playdon, Mary [1 ]
Samek, Ali M. [1 ]
Eckel, Robert H. [1 ]
机构
[1] Univ Colorado, Dept Endocrinol Diabet & Metab, Denver, CO 80202 USA
基金
美国国家卫生研究院;
关键词
CARDIOVASCULAR RISK-FACTORS; TYPE-2; DIABETES-MELLITUS; SKELETAL-MUSCLE CELLS; MIDDLE-AGED MEN; CIGARETTE-SMOKING; GLUCOSE-UPTAKE; RECEPTOR SUBSTRATE-1; SECONDHAND SMOKE; US POPULATION; NICOTINE;
D O I
10.2337/db12-0418
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Smoking is the most common cause of preventable morbidity and mortality in the United States, in part because it is an independent risk factor for the development of insulin resistance and type 2 diabetes. However, mechanisms responsible for smoking-induced insulin resistance are unclear. In this study, we found smokers were less insulin sensitive compared with controls, which increased after either 1 or 2 weeks of smoking cessation. Improvements in insulin sensitiviy after smoking cessation occurred with normalization of IRS-1(ser636) phosphorylation. In muscle cell culture, nicotine exposure significantly increased IRS-1(ser636) phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. The two pathways known to stimulate IRS-1(ser636) phosphorylation (p44/42 mitogen-activated protein kinase [MAPK] and mammalian target of rapamycin [mTOR]) were both stimulated by nicotine in culture. Inhibition of mTOR, but not p44/42 MAPK, during nicotine exposure prevented IRS-1(ser636) phosphorylation and normalized insulin sensitivity. These data indicate nicotine induces insulin resistance in skeletal muscle by activating mTOR. Therapeutic agents designed to oppose skeletal muscle mTOR activation may prevent insulin resistance in humans who are unable to stop smoking or are chronically exposed to second-hand smoke. Diabetes 61:3156-3166, 2012
引用
收藏
页码:3156 / 3166
页数:11
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