名家说“肽” | GLP-1神经保护和骨骼作用之探寻

*仅供医学专业人士阅读参考

胰高糖素样肽-1 （GLP-1） 自被发现以来，已然成为一种“多面手”激素——其对多种代谢的影响接二连三的被发现，远远超出了肠促胰素的经典定义。GLP-1众多有益的作用使其受体激动剂类药物逐渐成为更多新兴领域治疗的冉冉之“星”，如脂肪肝、肥胖和神经退行性疾病等。时值利拉鲁肽在我国上市10周年，司美格鲁肽新上市之际，我们邀请一众专家，讲述一系列关于GLP-1的故事。本期特邀解放军总医院李春霖教授带您了解降糖药物GLP-1对下丘脑-垂体-肾上腺轴、对学习/记忆和神经保护以及对骨骼的影响。

一、GLP-1对下丘脑-垂体-肾上腺轴的影响

在应激反应中孤束核 （NTS） 的神经元对下丘脑-垂体-肾上腺 （HPA） 轴发挥着重要的调节作用。有证据表明大脑胰高糖素样肽-1受体 （GLP-1R） 信号在中枢神经系统 （CNS） 对应激和厌恶刺激的急性反应中也发挥着不可或缺的作用[1]。NTS的前胰高糖素原阳性神经元致密地投射到大脑的其他区域，包括下丘脑室旁核 （PVN） 中支配促肾上腺皮质激素释放激素 （CRH） 释放的神经元[2]。GLP-1R在与CRH共定位的PVN神经元中表达[3]。大鼠和小鼠中枢给予GLP-1可刺激HPA轴，增加皮质酮分泌，并伴有PVN中CRH阳性神经元cFos免疫反应性增加[4]。对啮齿动物和人类而言，外周给予GLP-1R激动剂可短暂刺激HPA轴，增加循环皮质酮、醛固酮和促肾上腺皮质激素 （ACTH） 水平[5-7]。外周给予Exendin-4或利拉鲁肽可在基础条件下和强迫游泳试验中增加小鼠循环皮质酮水平[8]。PVN选择性GLP-1R缺失的小鼠 （使用Sim1转基因方法） 应激时HPA轴激活能力受损，还进一步减少应激诱导的体重减轻和焦虑样行为减少[3]。与单独使用Exendin-4相比，地塞米松和Exendin-4联合给药可导致大鼠的厌食和体重减轻进一步加重[9]。在GLP-1/地塞米松 （一种单分子肽核激素耦合物，旨在优化地塞米松输送到GLP-1R阳性细胞 中[10]） 治疗的小鼠中也发现类似的结果。使用抗多巴胺-β-羟化酶-皂草素 （DSAP） 消融后脑儿茶酚胺神经元，削弱了Exendin-4刺激皮质酮分泌的能力，但增强了对摄食的抑制[9]。这些研究表明，激活HPA轴可拮抗GLP-1R激动剂的饱食效应[9]。

二、GLP-1对学习、记忆和神经保护的作用

GLP-1R在大鼠[11]和小鼠[12]海马体 （与空间学习和记忆有关的脑区[13,14]） 中也有表达。使用中枢GLP-1R激动剂，大鼠莫里斯水迷宫测试的表现改善，被动回避测试的潜伏期延长，提示大鼠的学习和记忆能力得到改善[15]。Exendin （9-39） 预处理可阻断GLP-1对学习和记忆的改善，GLP-1R缺失的小鼠中学习和记忆改善的作用消失[15]。利用腺病毒载体 （AAV） 介导的基因转移技术可以靶向恢复GLP-1R缺失小鼠的海马GLP-1R表达，逆转被动回避试验中GLP-1对学习和记忆的作用[15]。

中枢GLP-1R信号具有神经保护作用。对大鼠嗜铬细胞瘤 （PC12） 细胞和人神经母细胞瘤SK-N-SH细胞的研究中发现，GLP-1和Exendin-4可促进神经细胞分化和神经突外生长[16]。GLP-1R激动剂的神经保护作用类似于神经生长因子 （NGF） ，当PC12细胞与Exendin （9-39） 共同孵育时上述作用被阻断[16]。GLP-1和Exendin-4具有保护培养基中海马神经元抵抗谷氨酸诱导的细胞凋亡的作用[17]。与野生型对照组相比，GLP-1R敲除小鼠在给予神经毒素红藻氨酸时所诱导发生的癫痫发作时间和严重程度增强，而在靶向AAV介导GLP-1R表达恢复的海马中，GLP-1R敲除小鼠红藻氨酸的破坏性作用减弱[15]。

中枢GLP-1R激动剂的神经保护作用的分子机制还未完全阐明，现有研究显示有多种通路参与，如通过增加cAMP的形成、增强磷脂酰肌醇3 （PI3） 激酶活性、增加细胞外调节蛋白激酶 （ERK） 激活的能力等。GLP-1R激动剂可增加培养基海马神经元[826]和PC12细胞中cAMP的水平[16]。药理浓度抑制PI3激酶或ERK可以阻断GLP-1和Exendin-4对PC12细胞神经突外生长的刺激作用[16]。在PC12细胞中，PKA抑制剂H89仅部分抑制了GLP-1对神经突外生长的刺激，表明至少在部分细胞中，cAMP介导的GLP-1R激动后的PI3激酶和ERK的激活并不完全依赖于PKA信号[16,18]。

亨廷顿舞蹈病 （HD） 是由亨廷顿蛋白 （HTT） 突变引起的严重神经退行性变[19]。由于HTT自噬清除不协调，氧化应激增强，导致突变的HTT蛋白引起神经毒性和神经退行性变[20]。HD患者中T2DM患病率升高[21]，提示胰岛素敏感性受损可能也是导致HD患者神经退行性变的一个因素[21,22]。在人SK-N-MC神经元细胞中，突变的HTT过表达会损害胰岛素信号传导通路并诱导神经元凋亡[22]。用利拉鲁肽治疗SK-N-MC细胞可改善胰岛素敏感性并提高细胞活力，其机制可能包括通过刺激AMPK介导的细胞自噬改善神经元糖毒性、改善氧化应激和减少突变HTT的聚集[22]。

阿尔茨海默病 （AD） 的特征是海马胆碱能神经元的神经退行性变。在大鼠神经退行性变模型中，GLP-1和Exendin-4可能通过减少鹅膏蕈氨酸诱导的胆碱能细胞耗竭来改善神经退行性变[17]。将GLP-1R激动剂注入大鼠海马可以减轻中枢给予淀粉样蛋白β （Aβ） 引起的空间学习和记忆障碍 ，而Aβ是阿尔茨海默 病学习和记忆障碍的致病因[23,24]。已在多个小鼠AD模型中证实长效GLP-1R激动剂可以延缓小鼠记忆缺陷的发展[25-27]。AD可致血脑屏障内葡萄糖转运减少，与安慰剂相比，利拉鲁肽治疗6个月后可改善AD患者血脑屏障内葡萄糖转运[28]。一项双盲安慰剂对照研究中，使用利拉鲁肽治疗12周， AD风险患者没有出现认知功能的显著改善[29]。评估GLP-1R激动剂对AD神经保护作用的临床试验正在进行中[30]。

GLP-1类似物在治疗帕金森病 （PD） 方面也有成功案例。PD的典型特征是多巴胺能神经元退行性变，可以通过给实验动物注射多巴胺能神经毒素MPTP （1-甲基-4-苯基-1,2,3,6-四氢吡啶） 来造模[31-33]。向小鼠侧脑室连续7天输注Exendin-4，足以保护其免受MPTP诱导的多巴胺能系统损伤和由多巴胺缺乏引起的运动障碍[34]的进展。在GLP-1R激动剂治疗的各种PD啮齿类模型中也有类似的神经保护作用的报道[35-37]。经多巴胺能毒素6-羟多巴胺 （6-OHDA） 处理的原代神经元培养基中，Exendin-4可以提高细胞存活率和酪氨酸羟化酶 （产生多巴胺的关键酶） 的水平[34]。多项临床研究证实了GLP-1R激动剂可改善帕金森病的临床症状，包括长期改善运动和认知功能的潜在作用[38-41]。

三、GLP-1对骨骼的影响

GLP-1对骨骼的影响日益受到关注。有研究发现GLP-1R敲除的小鼠破骨细胞活性增高，骨小梁减少[42]。在啮齿动物中，甲状腺GLP-1R的激活可以刺激甲状腺C-细胞生长[43-44]，由此推测甲状腺C-细胞产生的降钙素可能参与了GLP-1介导的对破骨细胞的影响[43]。另有研究显示GLP-1R的激活可以引起骨基质成分改变，使胶原成熟度较低，生物力学反应下降，骨骼脆性增加[45]。而葡萄糖依赖性促胰岛素释放多肽受体（GIPR）敲除动物的骨小梁骨量虽然增高，但由于骨密度分布和胶原成熟度的改变，生物力学强度显著降低[46,47]。对双肠促胰岛素受体敲除（DIRKO）动物的观察提示GLP-1/GLP-1R通路对皮质骨的完整性很重要，而对骨小梁影响不大[48]。

GLP-1R激动剂已经应用于骨质疏松动物模型中。在卵巢切除术后的骨流失模型中，艾塞那肽可以通过激活成骨细胞促进骨生成[47]。在后肢悬吊大鼠，艾塞那肽可以通过促进骨髓干细胞成骨分化改善骨量[49]。在1型糖尿病模型中，虽然利拉鲁肽在促进成骨细胞分化方面不如抑胃肽 （GIP） 类似物有效，但它通过减少胶原的降解改善了骨组织的生物力学[50]。在2型糖尿病模型 （遗传或饮食诱导的肥胖） 中，艾塞那肽通过增加骨小梁骨量、骨生成和骨小梁微结构显著增强骨强度。艾塞那肽还能够显著改善胶原蛋白成熟度[51,52]。单分子三激动剂GIP-Oxm在提高骨强度和恢复骨小梁骨量方面也有显著作用[53]，GIP-Oxm促使胶原由编织骨向板层骨的转变，提高胶原成熟度，减少骨基质中晚期糖基化终末产物。然而，尚不清楚这些对骨强度的改善作用是由骨骼GLP-1受体的激活引起的，还是像GIP/GIPR通路中观察到的那样，需要骨骼外受体[54]。研究发现GIP激动剂可以改善大鼠的骨质量[55]， DPP-4抑制剂可改善高脂喂养小鼠的骨组成成分[56]。

GLP-1及其类似物对人体骨代谢及骨骼的作用结果不一。健康个体皮下注射GLP-1后骨形成或骨吸收标志物没有变化[57]。在非糖尿病、超重的男性中，输注GLP-1或者GIP都可以减少骨的吸收[58]。然而，在使用抗精神病药物治疗的肥胖、非糖尿病患者中，艾塞那肽未能显著改变骨重塑模式[59]。利拉鲁肽能够促进肥胖减肥女性的骨形成，而对骨吸收没有影响[60]。2型糖尿病的数据更具争议性，早期报道没有发现GLP-1R激动剂可以减少骨折的发生[61,62]，但新近发表的研究显示利拉鲁肽和利司那肽有助于减少糖尿病患者的骨折，而艾塞那肽没有类似作用[63]。

专家寄语

李春霖

解放军总医院教授

GLP-1R激动剂/类似物在中国已经有超过10年的使用经验。作为一种降糖药物，我们不仅可以看到其很好的降糖效果，也可以观察到其他一些降糖以外的作用如减轻体重，以及其对血压、认知和骨骼的影响。从1968年胰高糖素样反应被报道到现在，人们已经将GLP-1应用于2型糖尿病、肥胖、脂肪肝等多个领域。我们有理由相信随着研究的深入和经验的积累，GLP-1还会有更多的作用被发掘并应用。

参考文献：

[1] Herman, J.P. 2018. Regulation of Hypothalamo-Pituitary-Adrenocortical Responses to Stressors by the Nucleus of the Solitary Tract/Dorsal Vagal Complex. Cell Mol Neurobiol 38:25-35.

[2] Sarkar, S., Fekete, C., Legradi, G., Lechan, R.M. 2003. Glucagon like peptide-1 (7-36) amide (GLP-1) nerve terminals densely innervate corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Brain Res 985:163-168.

[3] Ghosal, S., Packard, A.E.B., Mahbod, P., McKlveen, J.M., Seeley, R.J., Myers, B., et al. 2017. Disruption of Glucagon-Like Peptide 1 Signaling in Sim1 Neurons Reduces Physiological and Behavioral Reactivity to Acute and Chronic Stress. J Neurosci 37:184-193.

[4] Rowland, N.E., Crews, E.C., Gentry, R.M. 1997. Comparison of Fos induced in rat brain by GLP-1 and amylin. Regul Pept 71:171-174.

[5] Gil-Lozano, M., Perez-Tilve, D., Alvarez-Crespo, M., Martis, A., Fernandez, A.M., Catalina, P.A., et al. 2010. GLP-1(7-36)-amide and Exendin-4 stimulate the HPA axis in rodents and humans. Endocrinology 151:2629-2640.

[6] Malendowicz, L.K., Neri, G., Nussdorfer, G.G., Nowak, K.W., Zyterska, A., Ziolkowska, A. 2003. Prolonged Exendin-4 administration stimulates pituitary-adrenocortical axis of normal and streptozotocin-induced diabetic rats. Int J Mol Med 12:593-596.

[7] Malendowicz, L.K., Nussdorfer, G.G., Nowak, K.W., Ziolkowska, A., Tortorella, C., Trejter, M. 2003. Exendin-4, a GLP-1 receptor agonist, stimulates pituitary-adrenocortical axis in the rat: Investigations into the mechanism(s) underlying Ex4 effect. Int J Mol Med 12:237-241.

[8] Krass, M., Volke, A., Runkorg, K., Wegener, G., Lund, S., Abildgaard, A., et al. 2015. GLP-1 receptor agonists have a sustained stimulatory effect on corticosterone release after chronic treatment. Acta Neuropsychiatr 27:25-32.

[9] Lee, S.J., Diener, K., Kaufman, S., Krieger, J.P., Pettersen, K.G., Jejelava, N., et al. 2016. Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4. Mol Metab 5:552-565.

[10] Quarta, C., Clemmensen, C., Zhu, Z., Yang, B., Joseph, S.S., Lutter, D., et al. 2017. Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity. Cell Metab 26:620-632 e626.

[11] Alvarez, E., Roncero, I., Chowen, J.A., Thorens, B., Blazquez, E. 1996. Expression of the glucagon-like peptide-1 receptor gene in rat brain. J Neurochem 66:920-927.

[12] Rebosio, C., Balbi, M., Passalacqua, M., Ricciarelli, R., Fedele, E. 2018. Presynaptic GLP-1 receptors enhance the depolarization-evoked release of glutamate and GABA in the mouse cortex and hippocampus. Biofactors 44:148-157.

[13] Kandel, E.R. 2001. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294:1030-1038.

[14] Lamsa, K., Lau, P. 2018. Long-term plasticity of hippocampal interneurons during in vivo memory processes. Curr Opin Neurobiol 54:20-27.

[15] During, M.J., Cao, L., Zuzga, D.S., Francis, J.S., Fitzsimons, H.L., Jiao, X., et al. 2003. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 9:1173-1179.

[16] Perry, T., Lahiri, D.K., Chen, D., Zhou, J., Shaw, K.T., Egan, J.M., et al. 2002. A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factormediated differentiation in PC12 cells. J Pharmacol Exp Ther 300:958-966.

[17] Perry, T., Haughey, N.J., Mattson, M.P., Egan, J.M., Greig, N.H. 2002. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther 302:881-888.

[18] Perry, T., Greig, N.H. 2002. The glucagon-like peptides: a new genre in therapeutic targets for intervention in Alzheimer's disease. J Alzheimers Dis 4:487-496.

[19] Warby, S.C., Montpetit, A., Hayden, A.R., Carroll, J.B., Butland, S.L., Visscher, H., et al. 2009. CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup. Am J Hum Genet 84:351-366.

[20] Vidoni, C., Castiglioni, A., Seca, C., Secomandi, E., Melone, M.A., Isidoro, C. 2016. Dopamine exacerbates mutant Huntingtin toxicity via oxidative-mediated inhibition of autophagy in SH-SY5Y neuroblastoma cells: Beneficial effects of anti-oxidant therapeutics. Neurochem Int 101:132-143.

[21] Lalic, N.M., Maric, J., Svetel, M., Jotic, A., Stefanova, E., Lalic, K., et al. 2008. Glucose homeostasis in Huntington disease: abnormalities in insulin sensitivity and early-phase insulin secretion. Arch Neurol 65:476-480.

[22] Chang, C.C., Lin, T.C., Ho, H.L., Kuo, C.Y., Li, H.H., Korolenko, T.A., et al. 2018. GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling. Int J Mol Sci 19.

[23] Qi, L., Ke, L., Liu, X., Liao, L., Ke, S., Liu, X., et al. 2016. Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3beta pathway in an amyloid beta protein induced alzheimer disease mouse model. Eur J Pharmacol 783:23-32.

[24] Wang, X.H., Li, L., Holscher, C., Pan, Y.F., Chen, X.R., Qi, J.S. 2010. Val8-glucagon-like peptide-1 protects against Abeta1-40-induced impairment of hippocampal late-phase longterm potentiation and spatial learning in rats. Neuroscience 170:1239-1248.

[25] Chen, S., Sun, J., Zhao, G., Guo, A., Chen, Y., Fu, R., et al. 2017. Liraglutide Improves Water Maze Learning and Memory Performance While Reduces Hyperphosphorylation of Tau and Neurofilaments in APP/PS1/Tau Triple Transgenic Mice. Neurochem Res 42:2326-2335.

[26] Hansen, H.H., Fabricius, K., Barkholt, P., Niehoff, M.L., Morley, J.E., Jelsing, J., et al. 2015. The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer's Disease. J Alzheimers Dis 46:877-888.

[27] McClean, P.L., Parthsarathy, V., Faivre, E., Holscher, C. 2011. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci 31:6587-6594.

[28] Gejl, M., Brock, B., Egefjord, L., Vang, K., Rungby, J., Gjedde, A. 2017. Blood-Brain Glucose Transfer in Alzheimer's disease: Effect of GLP-1 Analog Treatment. Sci Rep 7:17490.

[29] Watson, K.T., Wroolie, T.E., Tong, G., Foland-Ross, L.C., Frangou, S., Singh, M., et al. 2019. Neural correlates of liraglutide effects in persons at risk for Alzheimer's disease. Behav Brain Res 356:271-278.

[30] Femminella, G.D., Frangou, E., Love, S.B., Busza, G., Holmes, C., Ritchie, C., et al. 2019. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study). Trials 20:191.

[31] Burns, R.S., Chiueh, C.C., Markey, S.P., Ebert, M.H., Jacobowitz, D.M., Kopin, I.J. 1983. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A 80:4546-4550.

[32] Chiueh, C.C., Markey, S.P., Burns, R.S., Johannessen, J.N., Jacobowitz, D.M., Kopin, I.J. 1984. Neurochemical and behavioral effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rat, guinea pig, and monkey. Psychopharmacol Bull 20:548-553.

[33] Heikkila, R.E., Hess, A., Duvoisin, R.C. 1985. Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) in the mouse: relationships between monoamine oxidase, MPTP metabolism and neurotoxicity. Life Sci 36:231-236.

[34] Li, Y., Perry, T., Kindy, M.S., Harvey, B.K., Tweedie, D., Holloway, H.W., et al. 2009. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci U S A 106:1285-1290.

[35] Kim, S., Moon, M., Park, S. 2009. Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease. J Endocrinol 202:431-439.

[36] Liu, W., Jalewa, J., Sharma, M., Li, G., Li, L., Holscher, C. 2015. Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Neuroscience 303:42-50.

[37] Rampersaud, N., Harkavyi, A., Giordano, G., Lever, R., Whitton, J., Whitton, P. 2012. Exendin-4 reverts behavioural and neurochemical dysfunction in a pre-motor rodent model of Parkinson's disease with noradrenergic deficit. Br J Pharmacol 167:1467-1479.

[38] Athauda, D., Maclagan, K., Skene, S.S., Bajwa-Joseph, M., Letchford, D., Chowdhury, K., et al. 2017. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet 390:1664-1675.

[39] Aviles-Olmos, I., Dickson, J., Kefalopoulou, Z., Djamshidian, A., Ell, P., Soderlund, T., et al. 2013. Exenatide and the treatment of patients with Parkinson's disease. J Clin Invest 123:2730-2736.

[40] Aviles-Olmos, I., Dickson, J., Kefalopoulou, Z., Djamshidian, A., Kahan, J., Ell, P., et al. 2014. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson's disease. J Parkinsons Dis 4:337-344.

[41] Foltynie, T., Aviles-Olmos, I. 2014. Exenatide as a potential treatment for patients with Parkinson's disease: first steps into the clinic. Alzheimers Dement 10:S38-46.

[42] Yamada, C., Yamada, Y., Tsukiyama, K., Yamada, K., Udagawa, N., Takahashi, N., et al. 2008. The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology 149:574-579.

[43] Hegedus, L., Moses, A.C., Zdravkovic, M., Le Thi, T., Daniels, G.H. 2011. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab 96:853-860.

[44] Bjerre Knudsen, L., Madsen, L.W., Andersen, S., Almholt, K., de Boer, A.S., Drucker, D.J., et al. 2010. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 151:1473-1486.

[45] Mabilleau, G., Mieczkowska, A., Irwin, N., Flatt, P.R., Chappard, D. 2013. Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor. J Endocrinol 219:59-68.

[46] Mieczkowska, A., Irwin, N., Flatt, P.R., Chappard, D., Mabilleau, G. 2013. Glucosedependent insulinotropic polypeptide (GIP) receptor deletion leads to reduced bone strength and quality. Bone 56:337-342.

[47] Gaudin-Audrain, C., Irwin, N., Mansur, S., Flatt, P.R., Thorens, B., Basle, M., et al. 2013. Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice. Bone 53:221-230.

[48] Mieczkowska, A., Mansur, S., Bouvard, B., Flatt, P.R., Thorens, B., Irwin, N., et al. 2015.Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength. Osteoporos Int 26:209-218.

[49] Meng, J., Ma, X., Wang, N., Jia, M., Bi, L., Wang, Y., et al. 2016. Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through beta-Catenin. Stem Cell Reports 6:633.

[50] Mansur, S.A., Mieczkowska, A., Bouvard, B., Flatt, P.R., Chappard, D., Irwin, N., et al. 2015. Stable Incretin Mimetics Counter Rapid Deterioration of Bone Quality in Type 1 Diabetes Mellitus. J Cell Physiol 230:3009-3018.

[51] Pereira, M., Gohin, S., Roux, J.P., Fisher, A., Cleasby, M.E., Mabilleau, G., et al. 2017. Exenatide Improves Bone Quality in a Murine Model of Genetically Inherited Type 2 Diabetes Mellitus. Front Endocrinol (Lausanne) 8:327.

[52] Mansur, S.A., Mieczkowska, A., Flatt, P.R., Chappard, D., Irwin, N., Mabilleau, G. 2019. The GLP-1 Receptor Agonist Exenatide Ameliorates Bone Composition and Tissue Material Properties in High Fat Fed Diabetic Mice. Front Endocrinol (Lausanne) 10:51.

[53] Mansur, S.A., Mieczkowska, A., Flatt, P.R., Bouvard, B., Chappard, D., Irwin, N., et al. 2016. A new stable GIP-Oxyntomodulin hybrid peptide improved bone strength both at the organ and tissue levels in genetically-inherited type 2 diabetes mellitus. Bone 87:102-113.

[54] Mabilleau, G., Gobron, B., Mieczkowska, A., Perrot, R., Chappard, D. 2018. Efficacy of targeting bone-specific GIP receptor in ovariectomy-induced bone loss. J Endocrinol.

[55] Mabilleau, G., Mieczkowska, A., Irwin, N., Simon, Y., Audran, M., Flatt, P.R., et al. 2014. Beneficial effects of a N-terminally modified GIP agonist on tissue-level bone material properties. Bone 63:61-68.

[56] Mansur, S.A., Mieczkowska, A., Flatt, P.R., Chappard, D., Irwin, N., Mabilleau, G. 2019. Sitagliptin Alters Bone Composition in High-Fat-Fed Mice. Calcif Tissue Int 104:437-448.

[57] Henriksen, D.B., Alexandersen, P., Bjarnason, N.H., Vilsboll, T., Hartmann, B., Henriksen, E.E., et al. 2003. Role of gastrointestinal hormones in postprandial reduction of bone resorption. J Bone Miner Res 18:2180-2189.

[58] Bergmann, N.C., Lund, A., Gasbjerg, L.S., Meessen, E.C.E., Andersen, M.M., Bergmann, S., et al. 2019. Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study. Diabetologia 62:665-675.

[59] Eriksson, R., Broberg, B.V., Ishoy, P.L., Bak, N., Andersen, U.B., Jorgensen, N.R., et al. 2018. Bone Status in Obese, Non-diabetic, Antipsychotic-Treated Patients, and Effects of the Glucagon-Like Peptide-1 Receptor Agonist Exenatide on Bone Turnover Markers and Bone Mineral Density. Front Psychiatry 9:781.

[60] Iepsen, E.W., Lundgren, J.R., Hartmann, B., Pedersen, O., Hansen, T., Jorgensen, N.R., et al. 2015. GLP-1 Receptor Agonist Treatment Increases Bone Formation and Prevents Bone Loss in Weight-Reduced Obese Women. J Clin Endocrinol Metab 100:2909-2917.

[61] Mabilleau, G., Mieczkowska, A., Chappard, D. 2014. Use of glucagon-like peptide-1 receptor agonists and bone fractures: a meta-analysis of randomized clinical trials. J Diabetes 6:260-266.

[62] Driessen, J.H., Henry, R.M., van Onzenoort, H.A., Lalmohamed, A., Burden, A.M., Prieto-Alhambra, D., et al. 2015. Bone fracture risk is not associated with the use of glucagon-like peptide-1 receptor agonists: a population-based cohort analysis. Calcif Tissue Int 97:104-112.

[63] Cheng, L., Hu, Y., Li, Y.Y., Cao, X., Bai, N., Lu, T.T., et al. 2019. Glucagon-like peptide-1 receptor agonists and risk of bone fracture in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials. Diabetes Metab Res Rev:e3168.

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