Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
J Pharmacol Exp Ther. 2010 May;333(2):621-8. doi: 10.1124/jpet.109.164509. Epub 2010 Feb 4.
The glucose disposal effect of insulin is doubled in response to a meal. This meal-induced insulin sensitization results from insulin acting on the liver, in the presence of a permissive hepatic parasympathetic feeding signal and elevated hepatic glutathione (GSH), to release hepatic insulin-sensitizing substance (HISS), a hormone that acts selectively on skeletal muscle to stimulate insulin-mediated glucose uptake. Blockade of the parasympathetic feeding signal to the liver, either through surgical denervation or atropine-mediated antagonism of hepatic muscarinic receptors, eliminates the HISS response, resulting in HISS-dependent insulin resistance (HDIR) and decreasing the response to insulin by approximately 55% in the fed state. Insulin action in Sprague-Dawley rats, as determined with a rapidly sampled, transient euglycemic clamp in response to insulin (50 mU/kg), is decreased in a dose-dependent manner by atropine. In this study, we have used the ED75 atropine-induced model of HDIR. After a submaximal dose of atropine, potentiation of the remaining parasympathetic effect with the acetylcholinesterase antagonist neostigmine significantly restored postprandial insulin sensitization in a dose-dependent manner with peak effect at 0.1 microg/kg/min. Neostigmine reversed the insulin resistance induced by partial fasting and partial muscarinic inhibition (hepatic GSH levels are at fed levels), but not that induced by surgical hepatic denervation (GSH normal, no nerve signal) or 24-h fasting (low GSH). No potentiation of the response to insulin by neostigmine occurred in normal, fed rats. The data suggest the use of either direct or indirectly acting cholinergic agonists for the treatment of impaired postprandial insulin sensitization.
胰岛素的葡萄糖处置效应在进食后增加一倍。这种进食诱导的胰岛素敏感性增强是由于胰岛素在肝脏中作用，同时存在允许的肝副交感神经进食信号和升高的肝谷胱甘肽 (GSH)，从而释放肝胰岛素敏化物质 (HISS)，这是一种选择性作用于骨骼肌以刺激胰岛素介导的葡萄糖摄取的激素。通过手术去神经支配或阿托品介导的肝毒蕈碱受体拮抗作用阻断肝副交感神经进食信号，消除了 HISS 反应，导致 HISS 依赖性胰岛素抵抗 (HDIR)，并使进食状态下胰岛素的反应降低约 55%。通过快速取样、短暂的胰岛素（50mU/kg）正葡萄糖钳夹术测定 Sprague-Dawley 大鼠的胰岛素作用，发现阿托品呈剂量依赖性降低。在本研究中，我们使用了 ED75 阿托品诱导的 HDIR 模型。在给予亚最大剂量的阿托品后，用乙酰胆碱酯酶拮抗剂新斯的明增强剩余的副交感神经效应，以剂量依赖性方式显著恢复餐后胰岛素敏感性，峰值作用为 0.1μg/kg/min。新斯的明逆转了部分禁食和部分毒蕈碱抑制引起的胰岛素抵抗（肝 GSH 水平处于进食水平），但不能逆转手术肝去神经支配（GSH 正常，无神经信号）或 24 小时禁食（GSH 低）引起的胰岛素抵抗。新斯的明在正常进食的大鼠中没有增强胰岛素的反应。数据表明，使用直接或间接作用的胆碱能激动剂可治疗餐后胰岛素敏感性受损。
