Exenatide can reduce glucose independent of islet hormones or gastric emptying
Exenatide can reduce glucose independent of islet hormones or gastric emptying
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DOI：
10.1152/ajpendo.90222.2008
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发表时间：
2008-08-01
影响因子：
5.1
通讯作者：
Bergman, Richard N.
中科院分区：
文献类型：
--
作者：
Ionut, Viorica;Zheng, Dan;Bergman, Richard N.
埃克塞那肽是一种长效的高血糖素样多肽-1(GLP-1)模拟物，用于治疗2型糖尿病。越来越多的证据表明，GLP-1不仅通过胰腺(胰岛素和胰高血糖素抑制)和胃排空作用影响血糖，而且还通过门静脉受体介导的独立机制影响血糖。我们研究的目的是调查埃塞那肽是否具有类似于GLP-1的胰岛和胃非依赖性的降血糖作用。首先，我们给狗喂混合食物，加或不加艾塞那肽(20微克sc)。其次，为了确定艾塞那肽诱导的血糖降低是否独立于胃排空减慢，我们在同一动物的门静脉内注入葡萄糖(模拟餐后血糖状态)，艾塞那肽+门脉内GLP-1受体拮抗剂exendin-(9-39)或生理盐水。艾塞那肽显著降低餐后血糖：净0-135分钟曲线下面积=+526+/-315和-536+/-197mg.dl(-1)。M in(-1)，分别为生理盐水和艾塞那肽(P<；0.05)。重要的是，血糖的下降并没有相应地增加餐后胰岛素，而是伴随着胃排空延迟和胰升糖素降低。在没有高胰岛素血症或胰高血糖素抑制的情况下，门脉内输注埃塞那肽引起的血糖显著低于生理盐水(92+/-1比97+/-1 mg/dl，P<；0.001)。门静脉注射艾森丁-(9-39)：95+/-3和92+/-3 mg/dl分别与艾塞那肽+拮抗剂和艾塞那肽合用可部分逆转艾塞那肽所致的低血糖(P<；0.01)。我们的结果表明，与GLP-1类似，埃塞那肽通过一种不依赖胰岛激素和减慢胃排空的新机制来降低血糖。我们假设门静脉中的受体通过神经机制独立于胰岛激素增加葡萄糖清除。
Exenatide is a long-acting glucagon-like peptide-1 (GLP-1) mimetic used in the treatment of type 2 diabetes. There is increasing evidence that GLP-1 can influence glycemia not only via pancreatic (insulinotropic and glucagon suppression) and gastric-emptying effects, but also via an independent mechanism mediated by portal vein receptors. The aim of our study was to investigate whether exenatide has an islet-and gastric-independent glycemia-reducing effect, similar to GLP-1. First, we administered mixed meals, with or without exenatide (20 mu g sc) to dogs. Second, to determine whether exenatide-induced reduction in glycemia is independent of slower gastric emptying, in the same animals we infused glucose intraportally (to simulate meal test glucose appearance) with exenatide, exenatide + the intraportal GLP-1 receptor antagonist exendin-(9-39), or saline. Exenatide markedly decreased postprandial glucose: net 0- to 135-min area under the curve = + 526 +/- 315 and -536 +/- 197 mg.dl(-1) . min(-1) with saline and exenatide, respectively (P < 0.05). Importantly, the decrease in plasma glucose occurred without a corresponding increase in postprandial insulin but was accompanied by delayed gastric emptying and lower glucagon. Significantly lower glycemia was induced by intraportal glucose infusion with exenatide than with saline (92 +/- 1 vs. 97 +/- 1 mg/dl, P < 0.001) in the absence of hyperinsulinemia or glucagon suppression. The exenatide-induced lower glycemia was partly reversed by intraportal exendin-(9-39): 95 +/- 3 and 92 +/- 3 mg/dl with exenatide + antagonist and exenatide, respectively (P < 0.01). Our results suggest that, similar to GLP-1, exenatide lowers glycemia via a novel mechanism independent of islet hormones and slowing of gastric emptying. We hypothesize that receptors in the portal vein, via a neural mechanism, increase glucose clearance independent of islet hormones.