Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Br J Pharmacol. 2010 Jan;159(1):166-75. doi: 10.1111/j.1476-5381.2009.00469.x. Epub 2009 Dec 4.
Alagebrium is a breaker of cross-links in advanced glycation endproducts. However, the acute effects of alagebrium on methylglyoxal (MG), a major precursor of advanced glycation endproducts have not been reported. MG is a highly reactive endogenous metabolite, and its levels are elevated in diabetic patients. We investigated whether alagebrium attenuated the acute effects of exogenous MG on plasma MG levels, glucose tolerance and distribution of administered MG in different organs in Sprague-Dawley rats.
We measured MG levels (by HPLC), glucose tolerance, adipose tissue glucose uptake, GLUT4, insulin receptor and insulin receptor substrate 1 (IRS-1) protein expression, and phosporylated IRS-1 in rats treated with MG at doses of either 17.25 mgkg(-1) i.p. (MG-17 i.p.) or 50 mgkg(-1) i.v. (MG-50 i.v.) with or without alagebrium, 100 mg*kg(-1) i.p.
Alagebrium attenuated the increased MG levels in the plasma, aorta, heart, kidney, liver, lung and urine after MG administration. In MG-treated rats, glucose tolerance was impaired, plasma insulin levels were higher and insulin-stimulated glucose uptake by adipose tissue was reduced, relative to the corresponding control groups. In rats treated with MG-50 i.v., GLUT4 protein expression and IRS-1 tyrosine phosphorylation were decreased. Alagebrium pretreatment attenuated these effects of MG. In an in vitro assay, alagebrium reduced the amount of detectable MG.
Alagebrium acutely attenuated MG-induced glucose intolerance, suggesting a possible preventive role for alagebrium against the harmful effects of MG.
阿魏酸戊酯是晚期糖基化终产物交联的断裂剂。然而，阿魏酸戊酯对甲基乙二醛（MG）的急性作用，MG 是晚期糖基化终产物的主要前体，尚未见报道。MG 是一种高度反应性的内源性代谢物，糖尿病患者的水平升高。我们研究了阿魏酸戊酯是否减轻了外源性 MG 对血浆 MG 水平、葡萄糖耐量以及不同器官中给予的 MG 分布的急性影响，在 Sprague-Dawley 大鼠中。
我们通过 HPLC 测量 MG 水平，葡萄糖耐量，脂肪组织葡萄糖摄取，GLUT4、胰岛素受体和胰岛素受体底物 1（IRS-1）蛋白表达，以及磷酸化 IRS-1 在 MG 剂量为 17.25 mgkg(-1) i.p.（MG-17 i.p.）或 50 mgkg(-1) i.v.（MG-50 i.v.）的大鼠中治疗，或不与阿魏酸戊酯一起治疗，100 mg*kg(-1) i.p.
阿魏酸戊酯减轻了 MG 给药后血浆、主动脉、心脏、肾脏、肝脏、肺和尿液中 MG 水平的升高。在 MG 治疗的大鼠中，葡萄糖耐量受损，血浆胰岛素水平升高，脂肪组织对胰岛素刺激的葡萄糖摄取减少，与相应的对照组相比。在 MG-50 i.v. 治疗的大鼠中，GLUT4 蛋白表达和 IRS-1 酪氨酸磷酸化减少。阿魏酸戊酯预处理减轻了 MG 的这些作用。在体外试验中，阿魏酸戊酯减少了可检测到的 MG 的量。
阿魏酸戊酯急性减轻了 MG 诱导的葡萄糖不耐受，表明阿魏酸戊酯可能具有预防阿魏酸戊酯对 MG 有害影响的作用。
