Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Kildegårdsvej 28, DK-2900, Hellerup, Denmark.
Department of In Vivo Pharmacology, Zealand Pharma A/S, Glostrup, Denmark.
Diabetologia. 2019 Apr;62(4):665-675. doi: 10.1007/s00125-018-4810-0. Epub 2019 Jan 25.
AIMS/HYPOTHESIS: Glucagon-like peptide 1 (GLP-1) reduces appetite and energy intake in humans, whereas the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), seems to have no effect on eating behaviour. Interestingly, studies in rodents have shown that concomitant activation of GIP and GLP-1 receptors may potentiate the satiety-promoting effect of GLP-1, and a novel dual GLP-1/GIP receptor agonist was recently shown to trigger greater weight losses compared with a GLP-1 receptor agonist in individuals with type 2 diabetes. The aim of this study was to delineate the effects of combined GIP and GLP-1 receptor activation on energy intake, appetite and resting energy expenditure in humans.
We examined 17 overweight/obese men in a crossover design with 5 study days. On day 1, a 50 g OGTT was performed; on the following 4 study days, the men received an isoglycaemic i.v. glucose infusion (IIGI) plus saline (154 mmol/l NaCl; placebo), GIP (4 pmol kg min), GLP-1 (1 pmol kg min) or GIP+GLP-1 (4 and 1 pmol kg min, respectively). All IIGIs were performed in a randomised order blinded for the participant and the investigators. The primary endpoint was energy intake as measured by an ad libitum meal after 240 min. Secondary endpoints included appetite ratings and resting energy expenditure, as well as insulin, C-peptide and glucagon responses.
Energy intake was significantly reduced during IIGI+GLP-1 compared with IIGI+saline infusion (2715 ± 409 vs 4483 ± 568 kJ [mean ± SEM, n = 17], p = 0.014), whereas there were no significant differences in energy intake during IIGI+GIP (4062 ± 520 kJ) or IIGI+GIP+GLP-1 (3875 ± 451 kJ) infusion compared with IIGI+saline (p = 0.590 and p = 0.364, respectively). Energy intake was higher during IIGI+GIP+GLP-1 compared with IIGI+GLP-1 infusion (p = 0.039).
CONCLUSIONS/INTERPRETATION: While GLP-1 infusion lowered energy intake in overweight/obese men, simultaneous GIP infusion did not potentiate this GLP-1-mediated effect.
ClinicalTrials.gov NCT02598791 FUNDING: This study was supported by grants from the Innovation Fund Denmark and the Vissing Foundation.
目的/假设：胰高血糖素样肽 1（GLP-1）可降低人类的食欲和能量摄入，而另一种肠促胰岛素激素葡萄糖依赖性胰岛素释放肽（GIP）似乎对进食行为没有影响。有趣的是，在啮齿动物研究中表明，同时激活 GIP 和 GLP-1 受体可能增强 GLP-1 的促饱腹感作用，最近一种新型双重 GLP-1/GIP 受体激动剂在 2 型糖尿病患者中显示出比 GLP-1 受体激动剂更大的体重减轻作用。本研究旨在描述联合 GIP 和 GLP-1 受体激活对人类能量摄入、食欲和静息能量消耗的影响。
我们采用交叉设计对 17 名超重/肥胖男性进行了研究，共进行了 5 天的研究。第 1 天进行了 50gOGTT；在接下来的 4 天研究日中，男性接受等血糖指数静脉葡萄糖输注（IIGI）加生理盐水（154mmol/LNaCl；安慰剂）、GIP（4pmolkgmin）、GLP-1（1pmolkgmin）或 GIP+GLP-1（分别为 4 和 1pmolkgmin）输注。所有 IIGI 均以随机顺序进行，参与者和研究人员均处于盲态。主要终点是 240 分钟后通过自由进食测量的能量摄入。次要终点包括食欲评分和静息能量消耗以及胰岛素、C 肽和胰高血糖素反应。
与 IIGI+生理盐水输注相比，IIGI+GLP-1 输注时能量摄入显著减少（2715±409 与 4483±568kJ[平均值±SEM，n=17]，p=0.014），而 IIGI+GIP（4062±520kJ）或 IIGI+GIP+GLP-1（3875±451kJ）输注时能量摄入与 IIGI+生理盐水输注相比无显著差异（p=0.590 和 p=0.364，分别）。与 IIGI+GLP-1 输注相比，IIGI+GIP+GLP-1 输注时能量摄入更高（p=0.039）。
结论/解释：虽然 GLP-1 输注降低了超重/肥胖男性的能量摄入，但同时输注 GIP 并没有增强这种 GLP-1 介导的作用。
ClinicalTrials.gov NCT02598791 资金来源：本研究由丹麦创新基金和 Vissing 基金会资助。
