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肠促胰岛素(incretin)包括葡萄糖依赖性促胰岛素分泌多肽(GIP)和胰高血糖素样肽-1(GLP-1),它不仅在糖尿病治疗领域具有十分重要的作用,而且其降糖以外的作用也将为临床上一些常见病和罕见病(如肥胖症、骨质疏松症、库欣综合征、肢端肥大症等)的治疗带来新希望。本文特就此次大会中有关incretin研究的新进展作一简要综述。 Incretin的作用机制及临床意义 1964年Elirick等报道口服葡萄糖对胰岛素分泌的促进作用明显优于静脉注射,他们把这种现象描述为“incretin效应”,将肠胰之间的功能描述为“肠-胰岛轴”,并认为incretin与2型糖尿病的发病机制和治疗有关。 Nauck等研究发现,健康个体口服葡萄糖和混合餐后,incretin可刺激半数胰岛素的分泌,其作用是通过GIP和GLP-1来完成的。2型糖尿病患者incretin作用减弱,可能与进食有关的GLP-1分泌减少、β细胞对GLP-1的敏感性下降以及GIP胰岛素样作用消失或严重受损有关。 GIP与其受体(GIPR)结合后可促进胰岛β细胞释放胰岛素。GIPR分布于胰腺、胃、小肠和脂肪等多种组织,因此GIP也具有胰腺外作用。 在人类的胰岛、大脑、肺、肾脏、胃和心脏等组织中都发现了GLP-1受体(GLP-1R)的存在,但在葡萄糖代谢的外周组织中(如肝脏、骨骼肌和脂肪组织)检测不到该受体。GLP-1与胰岛β细胞上的特异性受体相结合,可促进胰岛素基因转录及葡萄糖诱导的胰岛素释放,抑制β细胞调亡和胰高血糖素的分泌,并抑制胃肠道分泌和运动。 GIP在血糖、血脂和钙离子内在平衡中的作用 多项研究证实GIP具有葡萄糖依赖性刺激胰岛素分泌的重要作用。富含糖类和脂肪的食物是刺激GIP分泌的主要物质,迷走神经可能参与了GIP分泌的调节。Yamada等发现由GIP介导的早期胰岛素分泌决定了个体在口服葡萄糖负荷后的糖耐量水平,以及由于肠-胰岛轴的缺陷导致了糖尿病的发病。 GIP也参与脂代谢的调节,并与营养过剩导致的肥胖密切相关。高脂饮食是决定肥胖的环境因素之一,阻断GIP信号途径可以阻止高脂饮食诱导的肥胖发生。饮食过量是另一个决定肥胖的环境因素,GIP的作用是独立于瘦素而存在的。GIP基因的敲除不仅可改善肥胖,而且在胰岛素分泌未减少的情况下可改善胰岛素的不敏感、葡萄糖的不耐受和血脂紊乱。因此,有学者认为对抗GIP作用可作为肥胖症的一种治疗手段,但减弱内源性GIP作用的同时必然会损伤餐后胰岛素分泌,影响血糖水平。 Bollaga等证实小鼠骨细胞和成骨细胞中存在GIPR且具有功能。GIPR缺陷的小鼠进食后血钙浓度增加,提示从代谢角度看,GIP是一个节俭基因,它不仅可促进在脂肪组织中有效地贮存脂肪,而且可促进在骨组织中有效地贮存钙。 GLP-1治疗2型糖尿病展望 近年来人们对GLP-1的研究多集中在它对糖尿病的发生发展以及治疗领域的作用上,一些相关的药物正处于研发或临床试验阶段。目前GLP-1和GLP-1R的研究已成为糖尿病领域中的热点,为开发治疗糖尿病的新药提供了三个新的作用靶点:①GLP-1长效类似物;②GLP-1降解酶抑制剂(DPP-Ⅳ);③GLP-1R激动剂。 Vildagliptin是一种选择性DPP-Ⅳ抑制剂,通过增加血浆中GLP-1和GIP的水平来降低2型糖尿病患者的糖化血红蛋白(HbA1c)水平。Kelley等的研究显示,对于肥胖的2型糖尿病患者,vildagliptin能够显著地改善胰岛素敏感性,增加葡萄糖的氧化作用和储存,抑制非酯化脂肪酸和脂质的氧化作用。 许多注射用GLP-1衍生物作为治疗2型糖尿病的药物正被广泛开发,但口服GLP-1尚处于研发阶段。Jomori等的研究显示:表达GLP-1的水稻可能对2型糖尿病具有降糖、促进胰岛素分泌的作用,有望成为一种生产口服GLP-1的新途径。
There seems to be a lot of interest from visitors about a possible Byetta Recall so we wanted to provide some information about what is happening with this drug. BYETTA (spelled with all-caps) injection is part of a class of medicines for type 2 diabetes called “incretin mimetics”. BYETTA is an injectable medicine used to improve glucose (blood sugar) control in adults with type 2 diabetes. BYETTA has NOT been recalled, but has been associated with pancreatitis and pacreatitis-related deaths. According to the FDA, “cases of acute pancreatitis have been reported in patients treated with BYETTA” which would explain all the interest in a potential BYETTA recall. The FDA reported in Augest that there were were 6 reported cases of severe pancreatitis, two of which resulted in death. This report was followed later that week with a statement by the makers of BYETTA regarding four more people who died of pancreatitis-related health problems when taking the medication. However, patients with diabetes may be at an increased risk for pancreatitis simply because they have diabetes – not because they are taking BYETTA. What to Look For – Pancreatitis Symptoms As of the date of this article there has not been a recall on BYETTA. However, if enough patients report side effects and/or confirmed cases of pancreatitis while taking BYETTA there may very well be a BYETTA recall in the near future. To learn more about a possible future recall on BYETTA Click Here. In the meantime, the FDA has told healthcare professionals to advise Byetta patients to seek emergency services if they are experiencing persistent unexplained abdominal pain.
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