有这样一种“神药”,全世界约有1.5亿人在服用它,具有多种神奇功效,但药价并不昂贵——没错,它就是二甲双胍。
二甲双胍是目前治疗2型糖尿病的一线药物,临床应用已超过60年。因其良好的降糖效果并配合降低体重、较好的安全性以及心血管保护等特点,二甲双胍被多个指南推荐为2型糖尿病控制高血糖的基础治疗药物,在临床上有着“无可撼动”的地位。
随着日渐丰富的临床应用证据,
《二甲双胍临床应用专家共识(2023年版)》重磅发布。其中特别提到了,二甲双胍之所以能“封神”,很大一部分原因是该药在降糖外的领域“大放异彩”,比如:减重、心血管保护、降血脂、抗肿瘤、改善认知功能等等。
图源:摄图网
而“神药”二甲双胍被讨论最多的临床作用之一,莫过于「减肥」。
先前的研究表明,二甲双胍的减肥功效要归因于其抑制食欲的特性,比如:诱导肝细胞表达并分泌“厌食激素”生长与分化因子15(GDF15),进而调节大脑特定区域来抑制对高脂饮食的欲望。但这并非唯一或者最主要的途径,而背后的其他机制仍不明确。
这个问题终于有答案了。
Nature Metabolism上接连刊登两篇论文给出了解答:
N-乳酰苯丙氨酸(Lac-Phe)是二甲双胍“减肥”作用中的关键一环。
具体来说,二甲双胍通过抑制复合物I、增加糖酵解通量和细胞内乳酸质量作用来促进Lac-Phe的生物合成;而代谢物Lac-Phe具有抑制食欲的作用,从而实现体重的减轻。
这两项研究分别从机制探究和人群试验入手,全方位地解读了“二甲双胍是如何发挥减肥作用”的。而早在2022年就有研究发现,剧烈运动抑制食欲的“始作俑者”也是Lac-Phe;换言之,二甲双胍和剧烈运动的减肥机制可谓是“异曲同工之妙”。
Lac-Phe是肌肽酶2(CNDP2)产生的一种代谢物,能催化乳酸和苯丙氨酸的融合作用。之前的动物实验显示,给肥胖小鼠注射Lac-Phe能够有效地抑制食欲;而类似的情况也出现在人类试验中,经常运动所致的体重减轻也与Lac-Phe有关。
于是,Lac-Phe引起了研究者的关注。该化合物是否为二甲双胍抑制食欲过程中的重中之重呢?
在
第一篇基于人群试验
的论文
中,研究者整理了7项观察性和干预性研究后发现,服用二甲双胍的受试者血液中Lac-Phe水平显著升高,从而抑制食欲的产生。
举例来说,研究者从哈佛大学附属医院布列根和妇女医院中收集到33名志愿者的血清样本,并使用高效液相色谱-串联质谱(UPLC-MS/MS)量化了1168个血清代谢物。数据显示,与肥胖的非2型糖尿病(T2D)志愿者相比,肥胖的T2D患者体内所有测得的N-乳酰基氨基酸均明显增加;即这种增加与BMI无关,而与T2D状态有关。
鉴于Lac-Phe的食欲抑制特性,研究者专注于这种特殊的N-乳酰基氨基酸。很有意思的是,与肥胖的非T2D对照组相比,肥胖的T2D患者体内的Lac-Phe水平是前者的5.7倍。此外,肥胖T2D和糖尿病前期的个体中,Lac-Phe含量也明显增加。
布列根和妇女医院队列显示,T2D患者血清中Lac-Phe水平升高
那么,为什么T2D患者血液中Lac-Phe水平会明显呢?
考虑到二甲双胍在T2D患者中的广泛使用性,研究者分析了二甲双胍和Lac-Phe两者之间的相关性,计算得到的斯皮尔曼(Spearman)相关系数为0.76,即两者之间存在强相关性。
与此同时,研究者发现在停止服用二甲双胍的T2D患者中,Lac-Phe水平降到最低值。这一发现再次证明,T2D患者血清中Lac-Phe水平的增加是由二甲双胍而非T2D本身引起的。
除了T2D患者队列外,研究者同样还在健康人群观察到“二甲双胍能够增加Lac-Phe水平”。
二甲双胍治疗增加Lac-Phe水平
综上,这项研究总结了TwinsUK队列、丹麦二甲双胍干预研究队列等等7个人群研究,发现:二甲双胍能够增加血清中Lac-Phe水平,从而发挥抑制食欲的作用;而Lac-Phe的升高是二甲双胍治疗特异性的,与T2D状态无关。
如果说人群试验只停留在“表面”,
第二篇研究则从细胞、小鼠实验和独立人类队列多角度切入
,进一步揭秘了二甲双胍的具体作用链路。
事实上,肠上皮CNDP2+细胞是Lac-Phe的主要生产源。于是,斯坦福大学医学院的研究团队开展了小鼠实验,他们敲除了小鼠的CNDP2基因后发现,即使这些小鼠服用了二甲双胍,依然会持续摄入食物且体重未发生改变。
此外,研究者还在小鼠实验中观察到了整个链路:二甲双胍能通过抑制复合物I、增加糖酵解通量和细胞内乳酸质量作用来促进Lac-Phe的生物合成,从而发挥抑制食欲的作用。但目前Lac-Phe下游信号通路还未被完全破解,亟需更多研究的开展。
不过,该研究的领头人Jonathan Long教授对此持乐观态度。他表示,通过优化口服药物二甲双胍,或能成功地控制体重、胆固醇和血压;而上述发现也为更安全、更有效的新型减肥药物的开发铺路。
二甲双胍啊二甲双胍,你还有多少惊喜是我们不知道的?
参考资料:
撰文 | Swagpp
| Swagpp
版权说明:梅斯医学(MedSci)是国内领先的医学科研与学术服务平台,致力于医疗质量的改进,为临床实践提供智慧、精准的决策支持,让医生与患者受益。欢迎个人转发至朋友圈,谢绝媒体或机构未经授权以任何形式转载至其他平台。
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#3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media screen and (min-width:1024px){body:not(.pages_skin_pc) .wx-root[data-weui-theme=dark],body:not(.pages_skin_pc) body[data-weui-theme=dark]{--appmsgExtra-BG: #121212}}@media screen and (min-width:1024px){body:not(.pages_skin_pc)body:not(.pages_skin_pc){background:var(--weui-BG-2)}}@media screen and (min-width:1024px) and (prefers-color-scheme:dark){body:not(.pages_skin_pc) .wx-root[data-weui-mode=care]:not([data-weui-theme=light]),body:not(.pages_skin_pc) body[data-weui-mode=care]:not([data-weui-theme=light]){--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .85);--weui-FG-HALF: rgba(255, 255, 255, .65);--weui-FG-1: rgba(255, 255, 255, .55);--weui-FG-2: rgba(255, 255, 255, .35);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media screen and (min-width:1024px) and (prefers-color-scheme:dark){body:not(.pages_skin_pc) .wx-root:not([data-weui-theme=light]),body:not(.pages_skin_pc) body:not([data-weui-theme=light]){--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .8);--weui-FG-HALF: rgba(255, 255, 255, .6);--weui-FG-1: rgba(255, 255, 255, .5);--weui-FG-2: rgba(255, 255, 255, .3);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media screen and (min-width:1024px) and (prefers-color-scheme:dark){body:not(.pages_skin_pc) .wx-root:not([data-weui-theme=light]),body:not(.pages_skin_pc) body:not([data-weui-theme=light]){--appmsgExtra-BG: #121212}}@media(prefers-color-scheme:dark){body:not([data-weui-theme=light]).my_comment_empty_data{background-color:#111}}body,.wx-root{--weui-BG-6: rgba(0, 0, 0, .05);--weui-ACTIVE-MASK: rgba(0, 0, 0, .05)}body,.wx-root{--weui-REDORANGE: #ff6146;--weui-BG-0: #ededed;--weui-BG-1: #f7f7f7;--weui-BG-2: #fff;--weui-BG-3: #f7f7f7;--weui-BG-4: #4c4c4c;--weui-BG-5: #fff;--weui-FG-0: rgba(0, 0, 0, .9);--weui-FG-HALF: rgba(0, 0, 0, .9);--weui-FG-1: rgba(0, 0, 0, .55);--weui-FG-2: rgba(0, 0, 0, .3);--weui-FG-3: rgba(0, 0, 0, .1);--weui-FG-4: rgba(0, 0, 0, .15);--weui-FG-5: rgba(0, 0, 0, .05);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #fa9d3b;--weui-YELLOW: #ffc300;--weui-GREEN: #91d300;--weui-LIGHTGREEN: #95ec69;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1485ee;--weui-PURPLE: #6467f0;--weui-WHITE: #fff;--weui-LINK: #576b95;--weui-TEXTGREEN: #06ae56;--weui-FG: #000;--weui-BG: #fff;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: #fa9d3b;--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: #06ae56;--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: #10aeff;--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(0, 0, 0, .5);--weui-TAG-BACKGROUND-BLACK: rgba(0, 0, 0, .05)}body,.wx-root{--weui-BG-0: #ededed;--weui-BG-1: #f7f7f7;--weui-BG-2: #fff;--weui-BG-3: #f7f7f7;--weui-BG-4: #4c4c4c;--weui-BG-5: #fff;--weui-FG-0: rgba(0, 0, 0, .9);--weui-FG-HALF: rgba(0, 0, 0, .9);--weui-FG-1: rgba(0, 0, 0, .55);--weui-FG-2: rgba(0, 0, 0, .3);--weui-FG-3: rgba(0, 0, 0, .1);--weui-FG-4: rgba(0, 0, 0, .15);--weui-FG-5: rgba(0, 0, 0, .05);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #fa9d3b;--weui-YELLOW: #ffc300;--weui-GREEN: #91d300;--weui-LIGHTGREEN: #95ec69;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1485ee;--weui-PURPLE: #6467f0;--weui-WHITE: #fff;--weui-LINK: #576b95;--weui-TEXTGREEN: #06ae56;--weui-FG: #000;--weui-BG: #fff;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: #fa9d3b;--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: #06ae56;--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: #10aeff;--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(0, 0, 0, .5);--weui-TAG-BACKGROUND-BLACK: rgba(0, 0, 0, .05)}.wx-root,body{--weui-BTN-ACTIVE-MASK: rgba(0, 0, 0, .1)}.wx-root,body{--weui-BTN-DEFAULT-ACTIVE-BG: #e6e6e6}.wx-root,body{--weui-DIALOG-LINE-COLOR: rgba(0, 0, 0, .1)}.wx-root,body{--weui-BG-COLOR-ACTIVE: #ececec}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BTN-ACTIVE-MASK: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BTN-DEFAULT-ACTIVE-BG: rgba(255, 255, 255, .126)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-DIALOG-LINE-COLOR: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--APPMSGCARD-BG: #1E1E1E}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--APPMSGCARD-LINE-BG: rgba(255, 255, 255, .07)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BG-COLOR-ACTIVE: #373737}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BG-6: rgba(255, 255, 255, .1);--weui-ACTIVE-MASK: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-REDORANGE: #ff6146;--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .8);--weui-FG-HALF: rgba(255, 255, 255, .6);--weui-FG-1: rgba(255, 255, 255, .5);--weui-FG-2: rgba(255, 255, 255, .3);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--discussInput-BG: rgba(255, 255, 255, .03)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--nickName-FG: #959595}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .8);--weui-FG-HALF: rgba(255, 255, 255, .6);--weui-FG-1: rgba(255, 255, 255, .5);--weui-FG-2: rgba(255, 255, 255, .3);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--appmsgExtra-BG: #121212}}*{margin:0;padding:0}.rich_media_content *{max-width:100%!important;box-sizing:border-box!important;-webkit-box-sizing:border-box!important;word-wrap:break-word!important}.rich_media_content em{font-style:italic}.rich_media_content p{clear:both;min-height:1em}td p{margin:0;padding:0}@media(prefers-color-scheme:dark){body:not([data-weui-theme=light]) .rich_media_content img:not(.wx_img_placeholder){filter:brightness(.8)}}@media screen and (min-width:1024px){body:not(.pages_skin_pc) :root{--appmsgPageGap: 20px;--appmsgPageBottomGap: 40px}}:root{--articleFontsize: 17px}:root{--sab: env(safe-area-inset-bottom)}:root{--wxBorderAvatarRatio: 3}:root{--discussPageGap: 20px}:root{--immersive-safe-bottom: env(safe-area-inset-bottom)}:root{--appmsgPageGap: 20px;--appmsgPageBottomGap: 40px}
div.autoTypeSetting24psection > p,div.autoTypeSetting24psection > section{margin-bottom: 24px;}