AbstractScientists were chasing an incretin hormone, and when GLP-1 was finally discovered, we found that it had a pronounced satiety effect, slowed down gastric emptying, and actually reduced postprandial insulin response. These mechanisms are the basis for the highly efficacious GLP-1 analogues that today offer safe and effective treatment in millions of people living with obesity.

摘要科学家正在寻找一种肠促胰岛素激素，当GLP-1最终被发现时，我们发现它具有明显的饱腹感，减缓胃排空，并实际上降低了餐后胰岛素反应。这些机制是高效GLP-1类似物的基础，这些类似物今天为数百万肥胖患者提供安全有效的治疗。

Moreover, the combined GLP-1 mechanisms of weight loss and delayed carbohydrate absorption may also be the key drivers of remission of type 2 diabetes and reduced cardiovascular events found by GLP-1 analogues..

此外，GLP-1减肥和延迟碳水化合物吸收的联合机制也可能是缓解2型糖尿病和减少GLP-1类似物发现的心血管事件的关键驱动因素。。

Development of a rigorous methodology to measure appetite and food intake in humansWith the discovery of GLP-1 in 1986 simultaneously by Jens Juul Holst and Joel Habener a cascade of important physiological discoveries followed [1] (Fig. 1). Their identification of the amino acid sequence of the biologically active GLP-1 hormone laid the groundwork for drugs in the management of type 2 diabetes.

通过Jens Juul-Holst和Joel Habener于1986年同时发现GLP-1，开发了一种严格的方法来测量人类的食欲和食物摄入量，随后出现了一系列重要的生理发现（图1）。他们对生物活性GLP-1激素的氨基酸序列的鉴定为治疗2型糖尿病的药物奠定了基础。

Gut peptide hormones such as GLP-1 could potentially also have an impact on appetite regulation by effects on gastric emptying and direct CNS effects, but we needed a robust methodology that could be used to measure acute effect of putative hormones on subjective appetite and spontaneous food intake.

肠肽激素如GLP-1也可能通过影响胃排空和直接中枢神经系统效应而对食欲调节产生影响，但我们需要一种强有力的方法来测量推定激素对主观食欲和自发食物摄入的急性影响。

We* developed a study design using visual analogue scales (VAS) for measurement of subjective appetite recordings during a fixed breakfast meal test, and combined it with a subsequent ad libitum lunch meal test that measured consumed energy. The putative satiety effect of a compound would be seen as an effect on satiety VAS during the breakfast meal and on the spontaneous caloric intake at the lunch meal.

我们*开发了一项研究设计，使用视觉模拟量表（VAS）测量固定早餐测试期间的主观食欲记录，并将其与随后的随意午餐测试相结合，以测量消耗的能量。化合物的假定饱腹感效应将被视为对早餐期间饱腹感VAS和午餐时自发热量摄入的影响。

VAS had been mainly used to measure subjective sensations (e.g. pain) and studies of appetite lacked validated measures. In an initial pilot study, we demonstrated the need for more comprehensive validation [2].Fig. 1Time line showing the discovery of GLP-1 i 1986, the satiety hormone effect i 1996, and the synthesis of the long-acting analogues liraglutide and semaglutide, and the key persons involved.Full size imageTogether with John Blundell, we developed the protocol: on two different test days we examined 55 healthy individuals and recorded their appetite sensations before breakfast and every 30 min during the 4.5 hr postprandial period under the same conditions [3].

VAS主要用于测量主观感觉（例如疼痛），而食欲研究缺乏有效的测量方法。在最初的试点研究中，我们证明了需要更全面的验证（2）。图1时间线显示了1986年GLP-1的发现，1996年的饱腹激素效应，以及长效类似物利拉鲁肽和semaglutide的合成，以及涉及的关键人员。全尺寸图像与John Blundell一起，我们开发了该方案：在两个不同的测试日，我们检查了55名健康个体，并在相同条件下，在早餐前和餐后4.5小时每30分钟记录他们的食欲感觉。

We also e.

我们也e。

*In this article “we” is used as a reference to the group of scientists, dieticians, and technical staff in my department who contributed to own studies cited, and the key collaborating scientists from other labs including Jens Juul Holst and John Blundell. Contributors from my own department are mentioned in the Acknowledgment..

*在本文中，“我们”是指我所在部门的科学家，营养师和技术人员，他们为自己的研究做出了贡献，以及来自其他实验室的关键合作科学家，包括Jens Juul Holst和John Blundell。。。

Discovery of GLP-1 as a satiety hormoneIn 1994 I took up the idea with Holst that GLP-1 could also be a mediator of meal-induced satiety, and we designed a study to infuse GLP-1 into normal human volunteers. Meanwhile, in January 1996 the first rodent study suggested that GLP-1 could be a central regulator of feeding behavior and satiety based on intracerebroventricular injection studies [4], but soon thereafter the results of other rodent studies using peripherally injected GLP-1 argued against an appetite effect [5].The study was conducted in 1995–1996, and we used commercially available synthetic, human GLP-1 (7–36 amide) [6].

GLP-1作为饱腹感激素的发现1994年，我接受了霍尔斯特的观点，即GLP-1也可能是膳食诱导饱腹感的介质，我们设计了一项研究，将GLP-1注入正常人类志愿者。同时，1996年1月，第一项啮齿动物研究表明，GLP-1可能是基于脑室内注射研究的摄食行为和饱腹感的中枢调节剂，但不久之后，其他使用外周注射GLP-1的啮齿动物研究结果反对食欲效应〔5〕。该研究于1995-1996年进行，我们使用了市售的合成人GLP-1（7-36酰胺）[6]。

We conducted the trial in 20 young, healthy, normal-weight men in a placebo-controlled, randomized, blinded, crossover design. Infusion of GLP-1 or saline was initiated simultaneously with the consumption of the breakfast test meal. VAS were used to assess appetite sensations, and at lunchtime an ad libitum test meal was offered.

我们采用安慰剂对照、随机、盲法、交叉设计，对20名年轻、健康、体重正常的男性进行了试验。在食用早餐测试餐的同时开始输注GLP-1或生理盐水。VAS用于评估食欲感觉，并在午餐时间提供随意的测试餐。

We found that, after the energy-fixed breakfast, GLP-1 markedly enhanced satiety and fullness compared with placebo (Fig. 2) [6]. Furthermore, spontaneous energy intake at the ad libitum lunch was reduced 12% by GLP-1 infusion (Fig. 2). We were quite excited by the findings, as this study was the first to demonstrate a physiological role of GLP-1 in appetite control and energy intake in humans.Fig.

我们发现，在能量固定的早餐后，与安慰剂相比，GLP-1显着增强了饱腹感和饱腹感（图2）[6]。此外，通过GLP-1输注，随意午餐的自发能量摄入减少了12%（图2）。我们对这些发现感到非常兴奋，因为这项研究首次证明了GLP-1在人类食欲控制和能量摄入中的生理作用。图。

2: Effects of GLP-1 infusion versus placebo on appetite recordings following a fixed breakfast meal, and on spontaneous energy intake during an ad libitum lunch meal in 20 healthy individuals [6].The pivotal findings of the study in which we infused GLP-1 in human subjects showed that it enhanced satiety reduced hunger during a fixed breakfast meal and reduced spontaneous energy intake by 12% during an ad libitum lunch meal .

2： GLP-1输注与安慰剂对20名健康个体固定早餐后食欲记录和随意午餐期间自发能量摄入的影响（6）。我们在人类受试者中注入GLP-1的研究的关键发现表明，它增强了饱腹感，减少了固定早餐期间的饥饿感，并在随意午餐期间减少了12%的自发能量摄入。

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Download referencesAcknowledgementsI would like to thank my former PhD students and post-docs Anne Raben, Anne Flint, Camilla Verdich, Birgitte Sloth, Helle Harder, Anita Belza and Thomas Meinert Larsen for their invaluable contributions to the research described in this article. Also, a great thanks to the kitchen staff and dieticians at my old lab where we developed the methodology to measure appetite and food intake.

下载参考文献致谢我要感谢我以前的博士生和博士后安妮·拉本（AnneRaben）、安妮·弗林特（AnneFlint）、卡米拉·威尔第（CamillaVerdich）、伯吉特·斯洛思（BirgitteSloth）、海勒·哈德（HelleHarder）、安妮塔·贝尔扎（AnitaBelza）和托马斯·梅纳特·拉森（ThomasMeinertLarsen），感谢他们为本文所述。另外，非常感谢我的老实验室的厨房工作人员和营养师，我们在那里开发了测量食欲和食物摄入量的方法。

A special thanks to the head of the metabolic kitchen at my old department (now “Department of Nutrition, Exercise and Sports”), Charlotte Kostecki, for her invaluable creativity and support, and to my former PA Tina Cuthbertson for making it possible to be head of the department and still conducting research.

特别感谢我的老部门（现为“营养、运动和体育部”）代谢厨房主任夏洛特·科斯特基（CharlotteKostecki），感谢她宝贵的创造力和支持，感谢我的前PA蒂娜·卡特伯森（TinaCuthbertson），感谢她使我有可能成为该部门的负责人，并继续进行研究。

I would also like to thank David L Ludwig for valuable discussions about the physiology and pharmacology of GLP-1 and for careful reading and commenting on the manuscript. The views and opinions expressed in this article are those of the author and do not necessarily reflect the views or positions of the Novo Nordisk Foundation.Author informationAuthors and AffiliationsDepartment of Obesity and Nutritional Sciences, Novo Nordisk Foundation, Hellerup, DenmarkArne AstrupAuthorsArne AstrupView author publicationsYou can also search for this author in.

我还要感谢David L Ludwig对GLP-1的生理学和药理学进行了有价值的讨论，并对手稿进行了仔细的阅读和评论。本文中表达的观点和意见是作者的观点和意见，并不一定反映诺和诺德基金会的观点或立场。作者信息作者和附属机构肥胖与营养科学系，诺和诺德基金会，Hellerup，DenmarkArne AstrupAuthorsArne AstrupView作者出版物您也可以在中搜索这位作者。

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Reprints and permissionsAbout this articleCite this articleAstrup, A. Reflections on the discovery GLP-1 as a satiety hormone: Implications for obesity therapy and future directions.

转载和许可本文引用本文Astrup，A。关于GLP-1作为饱腹激素的发现的反思：对肥胖治疗的影响和未来方向。

Eur J Clin Nutr (2024). https://doi.org/10.1038/s41430-024-01460-6Download citationReceived: 22 March 2024Revised: 30 May 2024Accepted: 04 June 2024Published: 18 June 2024DOI: https://doi.org/10.1038/s41430-024-01460-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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