Nicotinic acetylcholine receptors in glucose homeostasis: the acute hyperglycemic and chronic insulin-sensitive effects of nicotine suggest dual opposing roles of the receptors in male mice.
Nicotinic acetylcholine receptors in glucose homeostasis: the acute hyperglycemic and chronic insulin-sensitive effects of nicotine suggest dual opposing roles of the receptors in male mice.
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DOI：
10.1210/en.2014-1320
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发表时间：
2014-07
期刊：
影响因子：
4.8
通讯作者：
Christine U Vu;J. Siddiqui;Paul Wadensweiler;J. Gayen;E. Avolio;G. Bandyopadhyay;Nilima Biswas;Nai-wen Chi;D. O'Connor;S. Mahata
中科院分区：
文献类型：
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作者：
Christine U Vu;J. Siddiqui;Paul Wadensweiler;J. Gayen;E. Avolio;G. Bandyopadhyay;Nilima Biswas;Nai-wen Chi;D. O'Connor;S. Mahata
吸烟会导致胰岛素抵抗。然而，尼古丁在胰岛素抵抗动物模型中诱导抗炎和改善葡萄糖耐量。在这里，我们测定了尼古丁对胰岛素敏感型C57BL/J6小鼠糖代谢的影响。急性尼古丁给药(30min)引起的空腹高血糖和胰岛素敏感性显著降低，这种作用依赖于烟碱乙酰胆碱受体(NAChRs)的激活，并与儿茶酚胺分泌增加、一氧化氮(NO)产生和糖原分解有关。NAChRs的抑制剂氯异苏丹明可降低尼古丁诱导的急性高血糖。定量逆转录聚合酶链式反应分析表明，肝脏和肌肉分别主要表达β4>；α10>；α3>；α7和β4>；α10>；β1>；α1m RNA；肾上腺表达β4>；α3>；α7>；α10m RNA。慢性尼古丁治疗显著抑制α3-nAChR(优势外周α亚单位)在肝脏的表达。虽然急性尼古丁治疗会增加血浆去甲肾上腺素(NE)和肾上腺素(Epi)水平，但长期尼古丁暴露只会增加Epi。急性尼古丁治疗增加了基础胰岛素分泌和葡萄糖刺激的胰岛素分泌(GSIS)。慢性尼古丁治疗后基础胰岛素水平升高，而急性生理盐水或尼古丁治疗后GSIS减弱。慢性尼古丁暴露导致血浆和肝脏中NO积聚增加，导致糖原储存减少，伴随而来的是PEPCK和G6Pase mRNA的抑制，从而防止高血糖。慢性尼古丁的胰岛素增敏作用与体重减轻无关。慢性尼古丁处理使PI-3-K活性增强，AKT和糖原合成酶-3β磷酸化增加，同时cAMP反应元件结合蛋白的磷酸化降低。后一种作用抑制了PEPCK和G6Pase基因的表达。因此，尼古丁会导致胰岛素抵抗和胰岛素敏感性，这取决于治疗时间的长短。
Cigarette smoking causes insulin resistance. However, nicotine induces anti-inflammation and improves glucose tolerance in insulin-resistant animal models. Here, we determined the effects of nicotine on glucose metabolism in insulin-sensitive C57BL/J6 mice. Acute nicotine administration (30 min) caused fasting hyperglycemia and lowered insulin sensitivity acutely, which depended on the activation of nicotinic-acetylcholine receptors (nAChRs) and correlated with increased catecholamine secretion, nitric oxide (NO) production, and glycogenolysis. Chlorisondamine, an inhibitor of nAChRs, reduced acute nicotine-induced hyperglycemia. qRT-PCR analysis revealed that the liver and muscle express predominantly β4 > α10 > α3 > α7 and β4 > α10 > β1 > α1 mRNA for nAChR subunits respectively, whereas the adrenal gland expresses β4 > α3 > α7 > α10 mRNA. Chronic nicotine treatment significantly suppressed expression of α3-nAChR (predominant peripheral α-subunit) in liver. Whereas acute nicotine treatment raised plasma norepinephrine (NE) and epinephrine (Epi) levels, chronic nicotine exposure raised only Epi. Acute nicotine treatment raised both basal and glucose-stimulated insulin secretion (GSIS). After chronic nicotine treatment, basal insulin level was elevated, but GSIS after acute saline or nicotine treatment was blunted. Chronic nicotine exposure caused an increased buildup of NO in plasma and liver, leading to decreased glycogen storage, along with a concomitant suppression of Pepck and G6Pase mRNA, thus preventing hyperglycemia. The insulin-sensitizing effect of chronic nicotine was independent of weight loss. Chronic nicotine treatment enhanced PI-3-kinase activities and increased Akt and glycogen synthase kinase (GSK)-3β phosphorylation in an nAChR-dependent manner coupled with decreased cAMP response element-binding protein (CREB) phosphorylation. The latter effects caused suppression of Pepck and G6Pase gene expression. Thus, nicotine causes both insulin resistance and insulin sensitivity depending on the duration of the treatment.