Farr Olivia M, Tsoukas Michael A, Triantafyllou Georgios, Dincer Fadime, Filippaios Andreas, Ko Byung-Joon, Mantzoros Christos S
Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215.
Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215.
Metabolism. 2016 Jul;65(7):945-53. doi: 10.1016/j.metabol.2016.03.009. Epub 2016 Mar 18.
GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics.
Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17days (0.6mg for 7days, 1.2mg for 7days and 1.8mg for 3days) of treatment, we also studied changes in fMRI responses to food cues.
By design, to avoid any confounding by weight changes, subjects were studied for 17days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA.
We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that could over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials.
包括利拉鲁肽在内的胰高血糖素样肽-1（GLP-1）激动剂已成为治疗2型糖尿病（DM）和肥胖症的有效疗法。在此，我们试图阐明经批准用于治疗糖尿病的剂量的利拉鲁肽如何影响影响糖尿病患者能量稳态的循环激素。
我们采用一项随机、安慰剂对照、双盲、交叉试验，纳入20例2型糖尿病患者，研究了利拉鲁肽与安慰剂相比，对能量稳态重要的循环激素空腹水平的影响，这些激素包括瘦素、胃饥饿素、肽YY（PYY）和葡萄糖依赖性促胰岛素多肽（GIP）。经过17天（7天0.6mg、7天1.2mg和3天1.8mg）的治疗后，我们还研究了功能磁共振成像（fMRI）对食物线索反应的变化。
按照设计，为避免体重变化造成任何混淆，在体重改变之前，对受试者进行了为期l7天的研究。与接受安慰剂治疗的受试者相比，接受利拉鲁肽治疗的参与者的GLP-1水平显著升高（p<0.001），瘦素水平的百分比变化降低（p<0.01），GIP水平升高（p<0.03）。对食物线索作出反应的全脑功能活动回归分析显示，GIP水平升高与注意力和奖赏相关脑岛的失活有关。瘦素水平降低与奖赏相关的中脑、楔前叶和背外侧前额叶皮质（DLPFC）激活以及感觉运动相关的运动皮质激活有关，与注意力相关的顶叶皮质以及认知控制相关的丘脑和前辅助运动区（pre-SMA）失活有关。
我们在此证明了GLP-1激动剂利拉鲁肽治疗引起的GIP和瘦素循环水平的短期变化。这些发现表明，利拉鲁肽可能会改变能量稳态中重要激素的循环水平，进而影响中枢神经系统对食物线索的感知。这可能会导致能量稳态的代偿性变化，随着时间的推移，可能会限制利拉鲁肽减轻体重的疗效。这些新发现指出了联合治疗的潜在优势，可能具有治疗意义，需要通过更大规模和更长期的试验来证实。
