Metabolic effects of sustained activation of the GLP-1 receptor alone and in combination with background GIP receptor antagonism in high fat-fed mice
Metabolic effects of sustained activation of the GLP-1 receptor alone and in combination with background GIP receptor antagonism in high fat-fed mice
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DOI：
10.1111/j.1463-1326.2009.01036.x
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发表时间：
2009-06-01
影响因子：
5.8
通讯作者：
Flatt, P. R.
中科院分区：
文献类型：
--
作者：
Irwin, N.;McClean, P. L.;Flatt, P. R.
酶抗性的GLP-1受体激动剂和GIP受体拮抗剂已被认为具有治疗2型糖尿病的潜力。这些益处是基于主要通过刺激胰岛素分泌或缓解胰岛素抵抗而产生的作用。本研究观察了稳定的GLP-1受体激动剂(d-Ala(8))GLP-1和GIP受体拮抗剂(Pro(3))GIP单独及联合应用对高脂饮食小鼠的长期作用。高脂饲料小鼠每天注射一次(d-Ala(8))GLP-1或(Pro(3))GIP(25nmol/kg体重)，连续24天。在接下来的24天里，一半的(Pro(3))GIP处理组的小鼠被额外注射了(d-Ala(8))GLP-1(25nmol/kg体重)，其余的小鼠继续他们原来的治疗方案。24天后，每天腹腔注射(d-Ala(8))GLP-1或(Pro(3))GIP使血糖控制恢复到正常水平，与高脂对照组相比，显著(p<；0.05)改善了糖耐量。食物摄入量和体重没有受到影响。在48天，与48天的高脂对照组相比，所有治疗组的糖耐量(P<；0.05)和胰岛素敏感性(P<；0.001)都有显著改善。与正常饲料对照组相比，(d-Ala(8))GLP-1单独(p<；0.05)或(Pro(3))GIP(p<；0.01)治疗小鼠的高密度脂蛋白胆固醇水平显著升高。这些结果表明，(Pro(3))GIP和(d-Ala(8))GLP-1对治疗高脂饮食引起的葡萄糖耐量异常和胰岛素抵抗有效。联合治疗似乎比任何一种单独治疗都没有什么好处。
Enzyme-resistant glucagon-like peptide-1 (GLP-1) receptor agonists and GIP receptor antagonists have been proposed to have therapeutic potential for the treatment of type 2 diabetes. Such benefits are based on actions mediated primarily through stimulation of insulin secretion or alleviation of insulin resistance respectively. This study examined the long-term actions of the stable GLP-1 receptor agonist (d-Ala(8))GLP-1 and the GIP receptor antagonist (Pro(3))GIP alone and in combination in high fat-fed mice.Mice on high-fat diet for 155 days were injected once daily with (d-Ala(8))GLP-1 or (Pro(3))GIP (25 nmol/kg body weight) for 24 days. In the following 24-day period, half of the (Pro(3))GIP-treated mice were administered an additional dose of (d-Ala(8))GLP-1 (25 nmol/kg body weight), while the remaining mice continued their original treatment regimes.Daily intraperitoneal injections of (d-Ala(8))GLP-1 or (Pro(3))GIP restored glycaemic control to normal levels and significantly (p < 0.05) improved glucose tolerance compared with high-fat controls by day 24. Food intake and body weights were not affected. On day 48, all treatment groups displayed significantly improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001) compared with high-fat controls on day 48. HDL cholesterol levels were significantly increased in mice treated with (d-Ala(8))GLP-1 alone (p < 0.05) or in combination with (Pro(3))GIP (p < 0.01) compared with normal chow-fed controls.These results illustrate efficacy of (Pro(3))GIP and (d-Ala(8))GLP-1 for treatment of glucose intolerance and insulin resistance caused by high-fat feeding. Combination therapy appeared to have little benefit over either treatment alone.