Diabetes：吸烟诱导胰岛素耐受性机制

根据一项于2012年9月10日刊登在Diabetes期刊上的研究，吸烟诱导的胰岛素耐受性可能是由于哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)激活而导致的。戒烟能够改善这种胰岛素耐受性。

为了研究吸烟诱导胰岛素耐受性的机制，来自美国科罗拉多大学丹佛分校的Bryan C. Bergman博士和同事们研究了12名健康的久坐不动的不吸烟者和10名吸烟者的胰岛素敏感性。

研究人员发现吸烟者对胰岛素更加不敏感，但是当他们停止吸烟一到两周之后，他们对胰岛素的敏感性发生改善。这一改善与胰岛素受体底物1(insulin receptor substrate-1, IRS-1)第636位丝氨酸残基的正常磷酸化相关联。利用尼古丁处理肌细胞能够降低胰岛素敏感性，同时与IRS-1第636位丝氨酸残基的磷酸化水平提高相关联。已知有两种可能的途径促进IRS-1磷酸化。其中一种途径是mTOR，尼古丁能够激活这种途径。当暴露在尼古丁之中时，mTOR也阻止IRS-1磷酸化，当抑制mTOR时，能够让胰岛素敏感性恢复正常。

Bergman和同事们作出结论，“这些数据表明尼古丁通过激活mTOR而诱导骨骼肌产生胰岛素耐受性。经设计阻止骨骼肌中mTOR激活的治疗性试剂可能是一种新的策略来治疗有较高风险患上糖尿病和心血管疾病的人们，这是因为他们不能停止吸烟或者处于被动吸烟当中。”

doi: 10.2337/db12-0418
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Novel and Reversible Mechanisms of Smoking-Induced Insulin Resistance in Humans

Bryan C. Bergman, Leigh Perreault, Devon Hunerdosse, Anna Kerege, Mary Playdon, Ali M. Samek and Robert H. Eckel

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 sensitivity after smoking cessation occurred with normalization of IRS-1ser636 phosphorylation. In muscle cell culture, nicotine exposure significantly increased IRS-1ser636 phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. The two pathways known to stimulate IRS-1ser636 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-1ser636 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 secondhand smoke.