胰高血糖素样肽-1对2型糖尿病合并轻度认知功能障碍患者认知功能改善的研究进展

杨蓉; 陆媛; 于德华

doi:10.16766/j.cnki.issn.1674-4152.003216

胰高血糖素样肽-1对2型糖尿病合并轻度认知功能障碍患者认知功能改善的研究进展

doi: 10.16766/j.cnki.issn.1674-4152.003216

杨蓉^{1, 2, 3, 4},
陆媛^{1, 2, 3, 4},
于德华^{1, 2, 3, 4, ,}

1.
同济大学附属杨浦医院全科医学科，上海 200090
2.
同济大学医学院全科医学系，上海 200090
3.
上海市全科医学与社区卫生发展研究中心，上海 200090
4.
上海市全科医学临床质量控制中心，上海 200090

基金项目:

上海市“医苑新星”青年医学人才培养资助计划 [2019]072号

详细信息

通讯作者:
于德华，E-mail：ydh1404@sins.con

中图分类号: R587.1 R749.24
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- 被引次数: 0
出版历程
- 收稿日期: 2022-05-13
- 网络出版日期: 2023-11-23

Research progress of glucagon-like peptide -1 in improving cognitive function in patients with type 2 diabetes mellitus complicated with mild cognitive dysfunction

YANG Rong^{1, 2, 3, 4},
LU yuan^{1, 2, 3, 4},
YU Dehua^{1, 2, 3, 4
, ,}

1.
Department of General Practice, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China

摘要

摘要: 目前糖尿病(diabetes mellitus，DM)不仅是一个全球性公共卫生问题，也已成为我国居民的常见病、多发病，其可导致多种并发症。轻度认知功能障碍(mild cognitive impairment，MCI)是阿尔茨海默病(Alzheimer's disease，AD)发展过程中的一个阶段，是介于正常与痴呆之间的一种过渡状态，发展为AD的可能性很大，严重影响患者的生活质量。已有的研究结果显示2型糖尿病(type 2 diabetes mellitus，T2DM)与MCI密切相关。由于这两种疾病之间存在相互影响和相互作用，有的学者甚至将AD称为“3型糖尿病”。正因如此，T2DM的防治方法和策略是否会对MCI患者产生有利影响，延缓其认知功能的下降，也受到越来越多的关注。特别是降糖药物治疗是否可以改善MCI患者认知功能成为近年来研究的热点，已有许多动物模型和临床研究的试验结果给出了肯定的答案。目前的研究显示胰高血糖素样肽-1(glucagon-like peptide-1，GLP-1)具有保护神经元和改善认知功能的作用。GLP-1受体激动剂(GLP-1 receptor agonist)、二肽基肽酶-4抑制剂(DDP-4 inhibitors)此两类可增加体内GLP-1水平的药物已被用于糖尿病的治疗，随着这些药物近年在临床的广泛应用，有越来越多证据表明使用此类药物后T2DM患者的认知功能有明显的改善，故GLP-1类药物有望成为治疗T2DM合并MCI的理想药物。本文针对GLP-1对T2DM合并MCI患者认知功能改善的问题进行综述，以期为进一步认识T2DM、MCI提供新的思路，为其治疗开拓新的方法。
- 2型糖尿病 /
- 轻度认知功能障碍 /
- 胰高血糖素样肽-1
Abstract: Diabetes mellitus (DM) is not only a global public health issue at present, also has become our country resident common disease, frequently-occurring disease, which can lead to a variety of complications. Mild cognitive impairment (MCI) is a stage in the development of Alzheimer's disease (AD), which is a transitional state between normal and dementia. It can progress to AD. Patients' quality of life is severely affected. Existing research suggests that type 2 diabetes mellitus (T2DM) is closely associated with MCI. Because of the interaction and interdependence between these two diseases, some researchers even refer to AD as "type 3 diabetes". For this reason, more and more attention has been paid to whether T2DM prevention and treatment methods and strategies can have beneficial effects on MCI patients and delay their cognitive decline. In particular, whether hypoglycemic drug therapy can improve the cognitive function in MCI patients has become a research hotspot in recent years, and many animal models and clinical research results have given a positive answer. Recent studies have shown that glucagon-like peptide-1 (GLP-1) can protect neurons and improve cognitive function. Glp-1 receptor agonists and DDP-4 inhibitors, which can increase GLP-1 levels in vivo, have been used in the treatment of diabetes. With the widespread clinical application of these drugs in recent years, there is increasing evidence that the cognitive function in patients with T2DM is significantly improved after the use of these drugs. Therefore, GLP-1 drugs are expected to be ideal drugs for the treatment of T2DM complicated by MCI. This article reviews the improvement of cognitive function in patients suffering from T2DM with MCI by using GLP-1, in order to provide a deeper understanding of T2DM and MCI and to explore new approaches for their treatment.
- Type 2 diabetes mellitus /
- Mild cognitive impairment /
- Glucagon-like peptide-1

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参考文献(42)

[1]	中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2020年版)[J]. 中华糖尿病杂志, 2021, 13(4): 315-409. https://www.cnki.com.cn/Article/CJFDTOTAL-HBYX202112018.htm Chinese Diabetes Society. Guideline for the prevention and treatment of type 2 diabetes mellitus in China(2020 edition)[J]. Chinese Journal Of Diabetes Mellitus, 2021, 13(4): 315-409. https://www.cnki.com.cn/Article/CJFDTOTAL-HBYX202112018.htm
[2]	CHORNENKYY Y, WANG W X, WEI A, et al. Alzheimer's disease and type 2 diabetes mellitus are distinct diseases with potential overlapping metabolic dysfunction upstream of observed cognitive decline[J]. Brain Pathol, 2019, 29(1): 3-17. doi: 10.1111/bpa.12655
[3]	CALLISAYA M L, BEARE R, MORAN C, et al. Type 2 diabetes mellitus, brain atrophy and cognitive decline in older people: a longitudinal study[J]. Diabetologia, 2019, 62(3): 448-458. doi: 10.1007/s00125-018-4778-9
[4]	余艳. 阿尔茨海默病早期认知功能障碍与血糖、血脂及炎性因子异常的相关性研究[J]. 沈阳医学院学报, 2019, 21(3): 204-206, 210. doi: 10.16753/j.cnki.1008-2344.2019.03.004 YU Y. Correlation between early cognitive impairment and abnormal blood glucose, blood lipids and inflammatory factors in Alzheimer's disease[J]. Journal of Shenyang Medical College, 2019, 21(3): 204-206, 210. doi: 10.16753/j.cnki.1008-2344.2019.03.004
[5]	NGUYEN T T, TA Q T H, NGUYEN T K O, et al. Type 3 diabetes and its role implications in Alzheimer's disease[J]. Int J Mol Sci, 2020, 21(9): 3165. doi: 10.3390/ijms21093165
[6]	ERBIL D, EREN C Y, DEMIREL C, et al. GLP-1's role in neuroprotection: a systematic review[J]. Brain Inj, 2019, 33(6): 734-819. doi: 10.1080/02699052.2019.1587000
[7]	YAN W H, PANG M, YU Y, et al. The neuroprotection of liraglutide on diabetic cognitive deficits is associated with improved hippocampal synapses and inhibited neuronal apoptosis[J]. Life Sci, 2019, 231: 116566. DOI: 10.1016/j.lfs.2019.116566.
[8]	李伟, 王梅, 董雪, 等. GLP-1类似物利拉鲁肽联合门冬胰岛素30对2型糖尿病患者认知功能障碍的影响[J]. 中国现代医学杂志, 2018, 28(31): 108-112. https://www.cnki.com.cn/Article/CJFDTOTAL-ZXDY201831023.htm LI W, WANG M, DONG X, et al. Effect of GLP-1 receptor agonist combined with insulin aspart30 on cognitive impairment of patients with type 2 diabetes mellitus[J]. China Journal of Modern Medicine, 2018, 28(32): 108-112. https://www.cnki.com.cn/Article/CJFDTOTAL-ZXDY201831023.htm
[9]	ALJANABI N M, MAMTANI S, AI-GHURAIBAWI M M H, et al. Alzheimer' s and hyperglycemia: role of the insulin signaling pathway and GSK-3 inhibition in paving a path to dementia[J]. Cureus, 2020, 12(2): e6885. DOI: 10.7759/cureus.6885.
[10]	胡金艳, 王冬. 影响老年糖尿病患者发生认知障碍的危险因素分析[J]. 医学信息, 2018, 31(16): 55-58. https://www.cnki.com.cn/Article/CJFDTOTAL-YXXX201816015.htm HU J Y, WANG D. Analysis of risk factors influencing cognitive impairment in elderly diabetic patients[J]. Medical Information, 2018, 31(16): 55-58. https://www.cnki.com.cn/Article/CJFDTOTAL-YXXX201816015.htm
[11]	侯亮, 王梅, 王德忠. 2型糖尿病患者认知功能障碍的危险因素分析[J]. 糖尿病新世界, 2019, 22(6): 20-21. https://www.cnki.com.cn/Article/CJFDTOTAL-TNBX201906010.htm HOU L, WANG M, WANG D Z. Risk factors for cognitive dysfunction in type 2 diabetes mellitus[J]. Diabetes New World, 2019, 22(6): 20-21. https://www.cnki.com.cn/Article/CJFDTOTAL-TNBX201906010.htm
[12]	SUNG D J, NOH Y H, LEE J H, et al. Diet control to achieve euglycaemia induces tau hyperphosphorylation via AMPK activation in the hippocampus of diabetic rats[J]. Food Funct, 2020, 11(1): 339-346. doi: 10.1039/C9FO00709A
[13]	LEI H, HU R, LUO G H, et al. Altered structural and functional MRI connectivity in type 2 Diabetes Mellitus related cognitive impairment: a review[J]. Front Hum Neurosci, 2022, 15: 755017. DOI: 10.3389/fnhum.2021.755017.
[14]	张伟娟, 沓世泽, 董文韬. 2型糖尿病患者血糖水平与轻度认知功能障碍的关联[J]. 黑龙江医药, 2021, 34(1): 170-172. https://www.cnki.com.cn/Article/CJFDTOTAL-HJYY202101075.htm ZHANG W J, YAO S Z, DONG W T. Association of glucose levels with mild cognitive impairment in type 2 diabetes mellitus[J]. Heilongjiang Medicine journal, 2021, 34(1): 170-172. https://www.cnki.com.cn/Article/CJFDTOTAL-HJYY202101075.htm
[15]	王静悦, 孙博, 彭延波, 等. 应激性高血糖比率与前循环穿支动脉硬化性脑梗死早期认知功能障碍的相关性研究[J]. 中华全科医学, 2021, 19(6): 908-912. doi: 10.16766/j.cnki.issn.1674-4152.001947 WANG J Y, SUN B, PENG Y B, et al. Correlation between stress hyperglycaemia ratio and early cognitive dysfunction in patients with anterior circulation perforator arteriosclerotic cerebral infarction[J]. Chinese Journal of General Practice, 2021, 19(6): 908-912. doi: 10.16766/j.cnki.issn.1674-4152.001947
[16]	XIA W Q, LUO Y, CHEN Y C, et al. Glucose fluctuations are linked to disrupted brain functional architecture and cognitive impairment[J]. J Alzheimers Dis, 2020, 74(2): 603-613.
[17]	张洁, 王琼, 曹宏伟. 老年糖尿病患者低血糖与认知功能障碍的相关性[J]. 中华全科医学, 2021, 19(10): 1677-1679. doi: 10.16766/j.cnki.issn.1674-4152.002140 ZHANG J, WANG Q, CAO H W. Correlation between hypoglycaemia and cognitive dysfunction in elderly diabetic patients[J]. Chinese Journal of General Practice, 2021, 19(10): 1677-1679. doi: 10.16766/j.cnki.issn.1674-4152.002140
[18]	MA Z Y, WU Y Y, CUI H Y L, et al. Factors influencing post-stroke cognitive impairment in patients with type 2 Diabetes Mellitus[J]. Clin Interv Aging, 2022, 17: 653-664.
[19]	杨蓉, 严飞, 陈阳, 等. 轻度认知功能障碍的危险因素[J]. 中国全科医学, 2018, 21(12): 1397-1401. https://www.cnki.com.cn/Article/CJFDTOTAL-QKYX201812009.htm YANG R, YAN F, CHEN Y, et al. Risk factors of mild cognitive impairment[J]. Chinese General Practice, 2018, 21(12): 1397-1401. https://www.cnki.com.cn/Article/CJFDTOTAL-QKYX201812009.htm
[20]	CHEN M Y, ZHANG M, WANG S L, et al. Association between insulin resistance and cognitive impairment[J]. J Coll Physicians Surg Pak, 2022, 32(2): 202-207.
[21]	SCHULTZ N, JANELIDZE S, BYMAN E, et al. Levels of islet amyloid polypeptide in cerebrospinal fluid and plasma from patients with Alzheimer's disease[J]. PLoS One, 2019, 14(6): e0218561. DOI: 10.1371/journal.pone.0218561.
[22]	JASH K, GONDALIYA P, KIRAVE P, et al. Cognitive dysfunction: a growing link between diabetes and Alzheimer's disease[J]. Drug Dev Res, 2020, 81(2): 144-164.
[23]	王凯亮, 韩旸, 刘长春, 等. 2型糖尿病患者血清胰高血糖素样肽-1水平与轻度认知功能障碍的相关性研究[J]. 中国医刊, 2021, 56(4): 396-399. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGYI202104013.htm WANG K L, HAN Y, LIU C C, et al. Correlation between the level of glucagon-like peptide-1 and mild cognitive impairment in patients with type 2 diabetes mellitus[J]. Chinese Journal of Medicine, 2021, 56(4): 396-399. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGYI202104013.htm
[24]	卢冲, 李新宇, 孙宇, 等. 胰高血糖素样肽1(GLP-1)改善阿尔茨海默病大鼠模型的认知功能及其机制研究[J]. 卒中与神经疾病, 2019, 26(2): 193-197. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZYS201902017.htm LU C, LI X Y, SUN Y, et al. The effect and mechanism of Glucagon like peptide 1(GLP-1) in improving cognitive function of Alzheimer's disease rat model[J]. Stroke and Nervous Diseases, 2019, 26(2): 193-197. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZYS201902017.htm
[25]	FEMMINELLA G D, FRANGOU E, LOVE S, et al. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study)[J]. Trials, 2019, 20(1): 191.
[26]	季正香, 何龙锦, 丁雪明, 等. 利那鲁肽对MCI合并T2DM病人认知功能的疗效观察[J]. 中西医结合心脑血管病杂志, 2019, 17(22): 3623-3625. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYYY201922046.htm JI Z X, HE L J, DING X M, et al. Effect of linalutide on cognitive function of MCI patients with T2DM[J]. Chinese Journal of Integrative Medicine on Cardio-Cerebrovascular Disease, 2019, 17(22): 3623-3625. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYYY201922046.htm
[27]	李晓玲, 杨艾格, 朱艳霞. 利拉鲁肽与甘精胰岛素对2型糖尿病患者合并轻度认知障碍的疗效分析[J]. 实用医药杂志, 2020, 37(10): 875-878. https://www.cnki.com.cn/Article/CJFDTOTAL-QEYY202010006.htm LI X L, YANG A G, ZHU Y X. Efficacy analysis of liraglutide and insulin glargin on patients with mild cognitive impairment in type 2 diabetes mellitus[J]. Practical Journal of Medicine & Pharmacy, 2020, 37(10): 875-878. https://www.cnki.com.cn/Article/CJFDTOTAL-QEYY202010006.htm
[28]	李粮, 赵凡, 陈翠娟, 等. 利拉鲁肽对2型糖尿病患者血糖和认知功能的影响研究[J]. 临中外医学研究, 2020, 18(18): 18-20. https://www.cnki.com.cn/Article/CJFDTOTAL-YLYS202233014.htm LI L, ZHAO F, CHEN C J, et al. Effect of liraglutide on blood glucose and cognitive function in patients with type 2 diabetes[J]. Chinese and Foreign Medical Research, 2020, 18(18): 18-20. https://www.cnki.com.cn/Article/CJFDTOTAL-YLYS202233014.htm
[29]	刘明德, 施庆华, 陈彦, 等. 利拉鲁肽联合吡格列酮对伴有胰岛素抵抗2型糖尿病患者轻度认知功能障碍的影响[J]. 养生保健指南, 2021, 20(45): 23-24. LIU M D, SHI Q H, CHEN Y, et al. Effect of liraglutide combined with pioglitazone on mild cognitive impairment in type 2 diabetes mellitus with insulin resistance[J]. Guidelines for Health Care, 2021, 20(45): 23-24.
[30]	赵波, 魏海萍. 利格列汀对小鼠脑缺血/再灌注损伤的神经保护作用[J]. 中国应用生理学杂志, 2020, 36(5): 452-455, 532. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGSL202005015.htm ZHAO B, WEI H P. Neuroprotective effects of linagliptin on ischemia/reperfusion in mice[J]. Chinese Journal of Applied Physiology, 2020, 36(5): 452-455, 532. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGSL202005015.htm
[31]	熊丽娇, 陈丽莉, 蔡霞, 等. 西格列汀对高糖环境下胎鼠海马神经元的影响[J]. 国际内分泌代谢杂志, 2021, 41(6): 617-622. XIONG L J, CHEN L L, CAI X, et al. Effects of sitagliptin on hippocampal neuronal apoptosis in high glucose environment[J]. International Journal of Endocrinology and Metabolism, 2021, 41(6): 617-622.
[32]	XUE J J, WANG C Q, PAN C L, et al. Effect of DPP-4 inhibitor on elderly patients with T2DM combined with MCI[J]. Exp Ther Med, 2020, 19(2): 1356-1362.
[33]	虎子颖, 张会峰, 汪艳芳, 等. 利格列汀对老年2型糖尿病患者轻度认知功能障碍的影响及机制研究[J]. 中华老年医学杂志, 2018, 37(10): 1069-1072. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGCK202008013.htm HU Z Y, ZHANG H F, WANG Y F, et al. Effect and its mechanism of Linagliptin on mild cognitive impairment in elderly type 2 diabetes mellitus patients[J]. Chinese Journal of Geriatrics, 2018, 37(10): 1069-1072. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGCK202008013.htm
[34]	杨爱格, 董闪闪, 刘璠, 等. 阿格列汀与瑞格列奈对2型糖尿病轻度认知功能障碍患者血糖、血脂及认知功能的影响[J]. 现代中西医结合杂志, 2019, 28(28): 3079-3082, 3090. https://www.cnki.com.cn/Article/CJFDTOTAL-XDJH201928002.htm YANG A G, DONG S S, LIU P, et al. Effects of alogliptin and repaglinide on blood glucose, blood lipids and cognitive function in patients with type 2 diabetes with mild cognitive impairment[J]. Modern Journal of Integrated Traditional Chinese and Western Medicine, 2019, 28(28): 3079-3082, 3090. https://www.cnki.com.cn/Article/CJFDTOTAL-XDJH201928002.htm
[35]	WICINSKI M, SOCHA M, MALINOWSKI B, et al. Liraglutide and its neuroprotective properties-focus on possible biochemical mechanisms in Alzheimer's disease and cerebral ischemic events[J]. Int J Mol Sci, 2019, 20(5): 1050.
[36]	ZHOU M, CHEN S Y, PENG P, et al. Dulaglutide ameliorates STZ induced AD-like impairment of learning and memory ability by modulating hyperphosphorylation of tau and NFs through GSK3β[J]. Biochem Biophys Res Commun, 2019, 511(1): 154-160.
[37]	LIU P, SONG J, LIU H, et al. Insulin regulates glucagon-like peptide-1 secretion by pancreatic alpha cells[J]. Endocrine, 2018, 62(2): 394-403.
[38]	LI Z, ZHU Y, LI C, et al. Liraglutide ameliorates palmitate-induced insulin resistance through inhibiting the IRS-1 serine phosphorylation in mouse skeletal muscle cells[J]. J Endocrinol Invest, 2018, 41(9): 1097-1102.
[39]	SATOH K, OUCHI M, MORITA A, et al. MARCKS phosphorylation and amylase release in GLP-1-stimulated acini isolated from rat pancreas[J]. J Physiol Sci, 2019, 69(1): 143-149.
[40]	GARCZORZ W, GALLEGO-COLON E, KOSOWSKA A, et al. Exenatide exhibits anti-inflammatory properties and modulates endothelial response to tumor necrosis factor α-mediated activation[J]. Cardiovasc Ther, 2018, 36(2). DOI: 10.1111/1755-5922.12317.
[41]	CHEN S Y, ZHOU M, SUN J, et al. DPP-4 inhibitor improves learning and memory deficits and AD-like neurodegeneration by modulating the GLP-1 signaling[J]. Neuropharmacology, 2019, 157: 107668. DOI: 10.1016/j.neuropharm.2019.107668.
[42]	SHREYASI C, AMRITPAL M. Alzheimer's disease and type 2 diabetes: a critical assessment of the shared pathological traits[J]. Front Neurosci, 2018, 12: 383.