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[胰高血糖素样肽-1(GLP-1),2型糖尿病治疗的新靶点]

[Glucagon-like peptide-1 (GLP-1), new target for the treatment of type 2 diabetes].

作者信息

Scheen A J

机构信息

Université de Liege, Service de Diabétologie, Nutrition et Maladies métaboliques et Unité de Pharmacologie clinique, CHU Liège, Belgique.

出版信息

Rev Med Liege. 2007 Apr;62(4):217-21.

Abstract

Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted in response to the ingestion of a meal. It exerts various favourable metabolic effects among which a glucose-dependent stimulation of insulin secretion, an inhibition of glucagon secretion, a slow down of gastric emptying, and a central anorectic effect. In rodents, a protective effect, or even a trophic effect, on B cell has also been reported. Interestingly, GLP-1 secretion is decreased in patients with type 2 diabetes. This observation stimulated the pharmaceutical research with the aim of restoring appropriate GLP-1 circulating levels able to exert the numerous positive effects of the hormone. One of the main objectives was to solve the problem due to the very short half-life of GLP-1. We here briefly describe the main two proposed approaches : ether to subcutaneously inject an incretinomimetic agent closed to GLP-1 (exenatide) or a long-acting GLP-1 analogue (liraglutide), both being partially resistant to the action of dipeptidylpeptidase-IV (DPP-IV), either to orally administer a selective DPP-IV inhibitor, an enzyme metabolising endogenous GLP-1 (sitagliptin, vildagliptin, .... These new drugs offer the advantage of improving blood glucose control of type 2 diabetic patients, without inducing severe hypoglycaemia and without promoting weight gain (instead a weight reduction is generally observed). These agents should occupy a key place in the overall pharmacological strategy of type 2 diabetes in a near future, especially if the additional favourable effects on B cells are confirmed in clinical practice.

摘要

胰高血糖素样肽-1(GLP-1)是一种在进食后分泌的肠道激素。它具有多种有益的代谢作用,包括葡萄糖依赖性刺激胰岛素分泌、抑制胰高血糖素分泌、减缓胃排空以及中枢性食欲抑制作用。在啮齿动物中,也有报道称其对B细胞具有保护作用甚至营养作用。有趣的是,2型糖尿病患者的GLP-1分泌会减少。这一观察结果刺激了药物研究,旨在恢复能够发挥该激素众多积极作用的适当GLP-1循环水平。主要目标之一是解决由于GLP-1半衰期极短而产生的问题。我们在此简要描述两种主要的提议方法:要么皮下注射一种与GLP-1类似的促胰岛素分泌剂(艾塞那肽)或一种长效GLP-1类似物(利拉鲁肽),二者对二肽基肽酶-IV(DPP-IV)的作用均有部分抗性;要么口服一种选择性DPP-IV抑制剂,即一种代谢内源性GLP-1的酶(西他列汀、维格列汀等)。这些新药具有改善2型糖尿病患者血糖控制的优势,不会引发严重低血糖,也不会促进体重增加(相反,通常会观察到体重减轻)。在不久的将来,这些药物在2型糖尿病的整体药物治疗策略中应占据关键地位,尤其是如果对B细胞的额外有益作用在临床实践中得到证实。

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