Savontaus Eriika, Fagerholm Veronica, Rahkonen Olli, Scheinin Mika
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Itäinen Pitkäkatu 4B, FI-20520 Turku, Finland.
Eur J Pharmacol. 2008 Jan 14;578(2-3):359-64. doi: 10.1016/j.ejphar.2007.09.015. Epub 2007 Oct 2.
Alpha(2)-Adrenoceptors regulate insulin secretion and sympathetic output. In the present study, alpha(2A)-adrenoceptor knockout (alpha(2A)-KO) mice and their C57BL/6J wild-type (WT) controls were used to assess the glucoregulatory role of the alpha(2A)-adrenoceptor subtype in vivo. Fasting and glucose-stimulated blood glucose and plasma insulin levels were determined with or without (+/-)-propranolol (5 mg/kg) or atropine (10 mg/kg) pre-treatment. Intraperitoneal glucose (1 g/kg) and insulin (0.5 and 1.0 IU/kg) tolerance tests were performed. Fasting plasma glucagon and corticosterone levels were measured. Blood glucose levels (mean+/-S.E.M.) were lower in alpha(2A)-KO males (7.2+/-0.6 mM) and females (7.2+/-0.2 mM) than in WT males (9.8+/-0.3 mM) and females (9.1+/-0.3 mM). Plasma insulin levels were higher in alpha(2A)-KO males (2.2+/-0.5 microg/l) and females (1.7+/-0.3 microg/l) than in WT males (0.7+/-0.1 microg/l) and females (0.8+/-0.2 microg/l). These differences remained after pharmacological beta-adrenoceptor and muscarinic acetylcholine receptor inhibition. In spite of a tendency for slightly decreased insulin sensitivity in alpha(2A)-KO mice, glucose tolerance in alpha(2A)-KO mice was significantly better than in WT mice. However, glucose-stimulated insulin secretion was not increased in alpha(2A)-KO mice compared to WT controls. Plasma glucagon levels, but not corticosterone levels, were elevated in alpha(2A)-KO mice. These results suggest that lack of inhibitory pancreatic beta-cell alpha(2A)-adrenoceptor function results in hyperinsulinaemia, reduced blood glucose levels and improved glucose tolerance in alpha(2A)-KO mice, and demonstrate a key role for the alpha(2A)-adrenoceptor in adrenergic regulation of blood glucose and insulin homeostasis.
α（2）-肾上腺素能受体调节胰岛素分泌和交感神经输出。在本研究中，使用α（2A）-肾上腺素能受体敲除（α（2A）-KO）小鼠及其C57BL/6J野生型（WT）对照来评估α（2A）-肾上腺素能受体亚型在体内的血糖调节作用。在有或无（±）-普萘洛尔（5mg/kg）或阿托品（10mg/kg）预处理的情况下，测定空腹和葡萄糖刺激后的血糖和血浆胰岛素水平。进行腹腔注射葡萄糖（1g/kg）和胰岛素（0.5和1.0IU/kg）耐量试验。测量空腹血浆胰高血糖素和皮质酮水平。α（2A）-KO雄性小鼠（7.2±0.6mM）和雌性小鼠（7.2±0.2mM）的血糖水平（平均值±标准误）低于WT雄性小鼠（9.8±0.3mM）和雌性小鼠（9.1±0.3mM）。α（2A）-KO雄性小鼠（2.2±0.5μg/l）和雌性小鼠（1.7±0.3μg/l）的血浆胰岛素水平高于WT雄性小鼠（0.7±0.1μg/l）和雌性小鼠（0.8±0.2μg/l）。在药理学上抑制β-肾上腺素能受体和毒蕈碱型乙酰胆碱受体后，这些差异仍然存在。尽管α（2A）-KO小鼠的胰岛素敏感性有轻微下降的趋势，但α（2A）-KO小鼠的葡萄糖耐量明显优于WT小鼠。然而，与WT对照相比，α（2A）-KO小鼠的葡萄糖刺激胰岛素分泌并未增加。α（2A）-KO小鼠的血浆胰高血糖素水平升高，但皮质酮水平未升高。这些结果表明，缺乏抑制性胰腺β细胞α（2A）-肾上腺素能受体功能导致α（2A）-KO小鼠出现高胰岛素血症、血糖水平降低和葡萄糖耐量改善，并证明α（2A）-肾上腺素能受体在肾上腺素能调节血糖和胰岛素稳态中起关键作用。
