The mechanisms of the nicotine-induction of insulin resistance

描述（由申请人提供）：吸烟者心血管疾病死亡率高。考虑到吸烟和尼古丁都会导致体重下降，而体重下降应该可以预防心血管疾病，这一点令人惊讶。一项研究表明，与不吸烟者相比，吸烟者有更多的胰岛素抵抗和血脂异常，这在了解吸烟与心血管疾病之间的关系方面取得了重大进展。后来，研究证明尼古丁可能是香烟烟雾中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性数据以及这种联系的公共卫生影响，但在啮齿动物中探索尼古丁诱导的胰岛素抵抗机制的研究很少。由于尼古丁和吸烟会导致高皮质醇血症，而已知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，使问题更复杂的是，最近对啮齿动物和人类的研究表明，在肥胖和代谢综合征的发展中，组织而不是血浆糖皮质激素过量发挥了作用。通过11b-羟基类固醇脱氢酶，1型（11b-HSD1），肝脏和脂肪脂肪中活性糖皮质激素的细胞内类固醇再激活发生。通过增加细胞内糖皮质激素的可用性，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与组织糖皮质激素介导胰岛素抵抗之间的这种令人兴奋的关系：1)尼古丁诱导/加剧正常小鼠和饮食性肥胖（DIO）小鼠的胰岛素抵抗及其后遗症。2)尼古丁诱导胰岛素抵抗是通过11b-HSD1表达和GR表达增加导致组织糖皮质激素作用增加介导的。我们期望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，这将为预防吸烟造成的一些破坏性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.