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[CSE2011] Z.Bloomgarden教授谈肠促胰素类似物研究进展
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专家访谈 临床科研 作者:Z.Bloomgarden 来源:国际糖尿病 2011/10/19 14:05:00    加入收藏
内容概要:《国际糖尿病》:Bloomgarden教授,您在本届CSE年会上作了有关肠促胰素类药物治疗的降糖外效应的讲座。您如何看待肠促胰素类药物治疗的应用前景?

    Z. Bloomgarden    美国纽约西奈山医学院

    <International Diabetes>: Dr. Bloomgarden, you spoke at the Chinese National Conference on Endocrinology about non-glycemic effects of incretin-based therapy. What insight did you give the audience about incretin-based therapy?

   《国际糖尿病》:Bloomgarden教授,您在本届CSE年会上作了有关肠促胰素类药物治疗的降糖外效应的讲座。您如何看待肠促胰素类药物治疗的应用前景?

    Prof. Bloomgarden: All of this should be regarded as very interesting notions that may or may not be exactly right. So, I started off by pointing out the GLP-1 drugs are a tiny bit more potent that glucose lowering drugs but similar to existing agents. But glucose lowering is not the only clinical benefit. If you look for instance at weight change, the GLP-1 family is weight neutral or the weigh loss with GLP-1. As opposed to sulfonylurea, biguanides or insulin all of which promote weight gain. If you talk about hypoglycemia, we’ll find that sulfonylurea, glinides and of course insulin cause hypoglycemia. The GLP-1 drugs and the DDP-4 plus the GLP-1 analog are not intrinsically capable of causing hypoglycemia other than when they are given in combination with sulfonylurea or with insulin.

    Bloomgarden教授: 所有这些都是非常有趣的,可能会或不会完全正确。因此,我指出,GLP-1类药物的降糖疗效与现有降糖药相当,但同时具有降糖外作用。降糖并不是其唯一的临床获益。就其对体重变化的影响而言,以GLP-1为靶标的药物对体重具有中性作用或降低作用。而磺脲类药物及胰岛素等均会引起体重增加。就低血糖而言,磺脲类药物、双胍类药物及胰岛素均会导致低血糖。GLP-1类似物和DPP-4抑制剂单独应用不易引发低血糖,但是其与磺脲类药物及胰岛素联用的时候低血糖事件发生显著增高。

    <International Diabetes>: Is that due mainly because the mechanism that GLP-1 stimulates the pancreas to produce insulin only in response to glucose versus for instance, the sulfonylureas?that are just on or off and therefore the GLP-1 cannot help prevent hypoglycemia because of that mechanism? Is that how this works?

   《国际糖尿病》:这是否与GLP-1为靶标的 药物能够葡萄糖依赖性地促进胰岛素的分泌有关而磺脲类 药物只能对胰岛素分泌进行有或无的调节有关?

    Prof. Bloomgarden:  It is a little bit more subtle. What actually happens is the GLP-1 essentially amplifies the glucose signal. But it’s not inherently a glucose signal. It’s really caused by a bunch of cellular events. Sulfonylureas essentially trick a beta cell into thinking that it’s been exposed to more glucose. So in that fashion sulfonylureas plus incretin-based treatment are particularly bad in terms of causing a greater degree of hypoglycemia. It essentially eliminates the glucose sensitive nature of the incretin-based therapy and they just give you the sulfonylurea based sensitive beta cell and glucose lowering by GLP-1. It is a tiny bit subtle and that nothing extraordinary but extremely important clinically because when we use the sulfonylurea with the DDP-4 or with the GLP-1 we’re massively amplifying the hypoglycemic connection and that means the weight loss benefit is lost and the hypoglycemic benefit is lost. That is an important side effect. Sometimes we use them clinically because it is a glucose lowering combination, but we should always bear in mind that it eliminates some of the very good things about the treatment. But there are some other things that have been found clinically. So very interestingly all of these drugs are associated with a lowering of blood pressure in the incretin family. Whereas sulfonylureas, not really. Thiazolidinedione could be associated with lowering blood pressure but also cause weight gain. Really this is another very nice feature in our game in the insulin induced weight gain. There is a little bit of inherent effect of fluid retention. Not blood pressure per se but with weight gain. Sometime you can actually see in the comparative studies for example with veraglazide, blood pressure went up with vera, down with vera and up with insulin... So there are a couple of aspects of the story that you can see clinically. But then there are all sorts of cell biological evidence that incretin-based therapy might cause cell inflation and survival and might have an effect on in some fashion and GI absorption. GLP-1 has an effect with glucagon, which is part of its glucose lowering effect, but in a sense it is beyond the insulin effect.

    Bloomgarden教授: GLP-1本身不是葡萄糖信号,但其诱导的一系列细胞内事件能够放大葡萄糖信号。磺脲类药物易使β细胞误认为自己处于高血糖状态下, 故磺脲类药物与肠促胰素类药物联用具有较高的低血糖发生率。两者联用时使肠促胰素治疗的葡萄糖敏感性消失,仅保留β细胞对磺脲类药物的敏感性和GLP-1类药物的降糖作用。虽然这有点微妙,但是并没有什么不同寻常,却具有非常重要的临床意义。因为,磺脲类药物与DPP-4或GLP-1类似物联用低血糖发生率较高,这就意味着其降低体重及低血糖风险小的获益将消失。低血糖是一个重要的副作用。有时我们临床上应用上述联合治疗,主要是因为其是降糖组合之一,但是我们需要牢记该联合方案不具备许多获益。此外,临床研究发现,肠促胰素类药物能够降低血压,而磺脲类药物对血压无降低作用,噻唑烷二酮类药物虽能降低血压但会增加体重。胰岛素治疗通过影响体液储留可也会增加体重。对格列美脲与胰岛素的比较研究发现,格列美脲会降低血压,而胰岛素则会升高血压。各种细胞生物学证据表明,肠促胰素类药物能够促进细胞增殖和生存,可能有助于生存和胃肠道吸收。GLP-1可影响胰高血糖素的分泌,这是除影响胰岛素分泌外的另一降糖机制。
 



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