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Mechanisms uderlying nicotine-induced development of insulin resistance in mice


Cigarette smokers develop insulin resistance. However, administration of nicotine, a key toxicant of tobacco leaves, to insulin resistant animal models decreases inflammation and improves glucose tolerance. Nicotine activates nicotinic acetylcholine receptor (nAChR) system that integrates signaling in central and peripheral nervous systems and regulates glucose metabolism. Insulin sensitive animals, not suffering from inflammation, may not benefit from nicotine intake. We hypothesize that non- inflamed insulin sensitive mice, like the smokers, would develop insulin resistance upon nicotine administration due to interference with the insulin action. Glucose tolerance tests and plasma insulin assays demonstrated that the activation of nAChR by nicotine in mice fed normal chow diet (NCD) led to fasting hyperinsulinemia as well as hyperglycemia that depended on nAChR, catecholamine and nitric oxide (NO) suggesting development of insulin resistance. Nicotine-induced hyperinsulinemia did not stimulate, rather inhibited, Akt phosphorylation in liver or muscle cells. Treatment with nAChR antagonist chlorisondamine and inhibitors of NO synthase prevented nicotine-induced hyperglycemia and reversed nicotine- mediated inhibition of hepatic insulin signaling. Nicotine augmented NO production in liver cells in vitro, and caused secretion of catecholamines from the adrenal medulla, leading to activation of [alpha] and [Beta]- adrenergic receptors in liver. Net results were increased gluconeogenesis and glycogenolysis. Although [alpha]1-7, [Beta]9-10, and [Beta]1-4 subunits of nAChR are expressed in liver and muscle, their contributions have not been determined. The anti-inflammatory effects of nicotine did not prevent hyperglycemia in NCD-fed mice. The activation of nAChR in insulin-sensitive mice caused hyperglycemia through increased gluconeogenesis and glycogenolysis

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