The mechanisms of the nicotine-induction of insulin resistance

描述(由申请人提供)：吸烟者表现出较高的心血管死亡率。考虑到吸烟和尼古丁都会导致减肥，而且减肥应该是预防心血管疾病的，这一点令人惊讶。一项研究表明，与不吸烟的人相比，吸烟者对胰岛素更具抵抗力，并患有血脂异常，这是对吸烟和心血管疾病之间关系理解的一大进步。后来，人们证明尼古丁是香烟烟雾中可能导致胰岛素抵抗的成分。尽管吸烟和胰岛素抵抗之间的形成数据以及这种联系对公共健康的影响，但很少有研究探讨尼古丁诱导的啮齿动物胰岛素抵抗的机制。由于尼古丁和吸烟会导致高皮质醇血症，糖皮质激素过量会导致胰岛素抵抗，因此有人认为，糖皮质激素是吸烟和胰岛素抵抗之间缺失的一环。然而，使问题复杂化的是，最近对啮齿类动物和人类的研究表明，在肥胖和代谢综合征的发展过程中，组织而不是血浆糖皮质激素过剩起到了作用。这是通过11b-羟基类固醇脱氢酶1型(11b-HSD1)使肝脏和脂肪中活性的糖皮质激素在细胞内重新激活而发生的。通过扩大细胞内糖皮质激素的可获得性，11b-HSD1被认为是导致胰岛素抵抗和肥胖的一个强有力的病理生理因素。此外，糖皮质激素的作用是由糖皮质激素受体(GR)介导的，因此，GR的上调也可以放大糖皮质激素的作用。我们希望通过研究以下假设来探索尼古丁和组织糖皮质激素之间的令人兴奋的关系，这些糖皮质激素介导胰岛素抵抗：1)尼古丁在正常小鼠和饮食诱导肥胖(DIO)小鼠中诱导/加剧胰岛素抵抗及其后遗症。2)尼古丁诱导的胰岛素抵抗是通过11b-HSD1表达增加和GR表达增加导致组织糖皮质激素作用增强而介导的。我们预计这些研究将揭示尼古丁诱导胰岛素抵抗及其后遗症的潜在机制，为预防吸烟造成的一些毁灭性的心血管后果提供理论基础。

DESCRIPTION (provided by applicant): Smokers exhibit a high degree of cardiovascular mortality. This is surprising considering both smoking and nicotine cause weight loss and the weight loss should be protective against cardiovascular disease. A major advance in the understanding of the relationship between smoking and cardiovascular disease came from a study showing that smokers are more insulin resistant and have dyslipidemia compared to non-smokers. Later, it was demonstrated that nicotine is the likely component in cigarette smoke leading to insulin resistance. In spite of the formative data between smoking and insulin resistance and the public health implications of this connection, there is a paucity of studies exploring the mechanisms of the nicotine-induced insulin resistance in rodents. As nicotine and cigarette smoking induce hypercortisolemia and glucocorticoid excess is known to induce insulin resistance, it has been suggested that glucocorticoids are the missing link between cigarette smoking and insulin resistance. However to complicate the matter, recent studies in rodents and humans suggest a role for tissue rather than plasma glucocorticoid excess in the development of obesity and the metabolic syndrome. This occurs via intracellular steroid reactivation of active glucocorticoids in liver and adipose fat by the enzyme, 11b-hydroxysteroid dehydrogenase, type 1 (11b-HSD1). By amplifying intracellular glucocorticoid availability, 11b-HSD1 has been implicated to be a potent pathophysiological factor leading to insulin resistance and obesity. Additionally, glucocorticoid action is mediated by the glucocorticoid receptor (GR), and thus, up-regulation of GRs can also amplify glucocorticoid action. We wish to explore this exciting relationship between nicotine and tissue glucocorticoids mediating insulin resistance by studying the following hypotheses in this pilot (R21) grant: 1) Nicotine induces/exacerbates insulin resistance and its sequelae in normal mice and mice with diet- induced obesity (DIO). 2) The nicotine-induction of insulin resistance is mediated by increased 11b-HSD1 expression and GR expression leading to increased tissue glucocorticoid action. We expect that these studies will uncover the mechanisms underlying nicotine-induction of insulin resistance and its sequelae that would provide a rationale basis for preventing some of the devastating cardiovascular consequences of smoking.