Discussion on effect and mechanism of hypoglycemic drugs on Parkinson disease

doi:10.16138/j.1673-6087.2025.05.10

Abstract

Abstract:

Parkinson disease (PD) is a chronic neurodegenerative disease, and the pathgenesis is mainly related to neuronal degeneration and abnormal accumulation of αSyn. Some studies have shown that patients with PD are more likely to suffer from type 2 diabetes mellitus. Hypoglycemic drugs regulate blood glucose through modulating glucose metabolism and improving insulin sensitivity. Some of hypoglycemic drugs also have neuroprotective or antioxidant effect, and their mechanisms of action in neurodegenerative diseases have been extensively studied in recent years. This article reviews the pathological basis and related pathogenesis of PD, exploring the effect of hypoglycemic drugs on the progression of PD.

Key words: Parkinson disease, Diabetes mellitus, Hypoglycemic agent

CLC Number:

R742

ZHANG Haihan, JING Wei, SHAN Yuetong, ZHANG Yuling, CHEN Anan, LONG Siqi, WANG Yuze, LI Wei, PAN Weidong. Discussion on effect and mechanism of hypoglycemic drugs on Parkinson disease[J]. Journal of Internal Medicine Concepts & Practice, 2025, 20(05): 399-404.

Figures/Tables 1

Table 1

Studies on the effects of selected oral hypoglycemic agents on PD

降糖药	研究对象	剂量/浓度	评价参数	结论
双胍类	T2DM患者	不同暴露量和使用强度	糖尿病患者3年和5年PD发生率	接受低剂量和低强度二甲双胍患者PD发生率低^[32]
	成年雄性大鼠	每天口服500 mg/kg	大鼠脑组织中丙二醛、TNF-α水平等	二甲双胍改善糖尿病合并PD大鼠的炎性标志物^[33]
	12周龄小鼠	不同浓度范围	线粒体活性、神经元进程的长度	二甲双胍降低PD发病风险^[34]
	中老年退伍军人	不同平均日剂量	糖尿病患者使用二甲双胍2年后PD发生率	使用二甲双胍的患者PD风险更低^[35]
	荟萃分析，基于19份报告	/	基于STATA V.14.2 进行分析	二甲双胍单一疗法使PD发生率增加^[19]
	荟萃分析，纳入 10 项研究	/	基于Review Manager分析	二甲双胍会显著增加 PD风险^[36]
SGLT-2抑制剂	10周龄雄性大鼠	恩格列净每天口服 10 mg/kg和20 mg/kg	大鼠僵值杆测试、转棒测试、组织学检查	恩格列净在 PD大鼠中诱导有益的神经调节作用^[37]
SGLT-2抑制剂	40岁以上糖尿病患者	/	PD发病率	SGLT-2抑制剂与PD发病风险降低相关^[38]
DPP-4抑制剂、GLP-1激动剂	回顾性研究，纳入697例患者	/	多巴胺转运体可用性、运动并发症发生率等	DPP-4抑制剂在PD患者中减少运动并发症风险^[39]
	接受二甲双胍治疗的糖尿病患者	患者中位限定日剂量为0.32	PD发病率	糖尿病患者使用 DPP-4抑制剂和二甲双胍降低 PD发生风险^[40]
	荟萃研究，涉及15项研究	/	应用Review Manager 5.3进行分析	DPP-4抑制剂可能降低糖尿病患者患特发性 PD发生风险^[41]
	野生8周龄C57BL/6J雄鼠	艾塞那肽每天50 μg/kg，利格列汀每天5 mg/kg，小鼠颈后皮下注射	大鼠旷场测试、爬杆测试、步态分析等	艾塞那肽、利格列汀可逆转PD小鼠运动功能障碍^[42]
胰岛素增敏剂	回顾性研究，纳入62 400例糖尿病患者	/	PD年发病率	噻唑烷二酮的使用与 PD发生率呈负相关^[43]
胰岛素增敏剂	回顾性研究，纳入38 521例糖尿病患者	非TZD治疗组和TZD治疗组	PD发病率	噻唑烷二酮治疗组PD风险降低，且与使用剂量相关^[44]

Table 1

References 52

[1]	Du MR, Gao QY, Liu CL, et al. Exploring the pharmacological potential of metformin for neurodegenerative diseases[J]. Front Aging Neurosci, 2022, 14: 838173. doi: 10.3389/fnagi.2022.838173
[2]	张森, 赵晓悦, 梁宇, 等. 帕金森病致病因素及发病机制研究进展[J]. 药学学报, 2020, 55(10): 2264-2272.
	Zhang S, Zhao XY. Liang Y, et al. Advances in understanding the pathogenic factors and pathogenesis of Parkinson's disease [J]. Acta Pharmaceutica Sinica, 2020, 55(10): 2264-2272.
[3]	Paillusson S, Gomez-Suaga P, Stoica R, et al. α-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca²⁺ homeostasis and mitochondrial ATP production[J]. Acta Neuropathol, 2017, 134(1): 129-149. doi: 10.1007/s00401-017-1704-z
[4]	范磊, 邓文娟, 岳秉宏, 等. 合并2型糖尿病的帕金森病患者的临床症状特点及GLP-1类似物联合美多巴的干预效果[J]. 广西医学, 2021, 43(17): 2067-2073.
	Fan L, Deng WJ, Yue BH, et al. Clinical symptoms characteristics of concomitant type 2 diabetes mellitus and intervention effect of GLP-1 analogues combined with Madopar in patients with Parkinson's disease[J]. Guangxi Medical Journal, 2021, 43(17): 2067-2073.
[5]	卢明芬, 付强, 胡贞贞. 二甲双胍治疗慢性神经精神疾病的研究进展[J]. 南昌大学学报（医学版）, 2022, 62(3): 68-72.
	Lu MF, Fu Q, Hu ZZ. Research progress of metformin in treatment of chronic neuropsychiatric disease[J]. Journal of Nanchang University (Medical Sciences), 2022, 62(3): 68-72.
[6]	De Pablo-Fernandez E, Goldacre R, Pakpoor J, et al. Association between diabetes and subsequent Parkinson disease: a record-linkage cohort study[J]. Neurology, 2018, 91(2): e139-e142.
[7]	Lv YQ, Yuan L, Sun Y, et al. Long-term hyperglycemia aggravates α-synuclein aggregation and dopaminergic neuronal loss in a Parkinson's disease mouse model[J]. Transl Neurodegener, 2022, 11(1): 14. doi: 10.1186/s40035-022-00288-z
[8]	Sun Y, Guo C, Yuan L, et al. Cynomolgus monkeys with spontaneous type-2-diabetes-mellitus-like pathology develop alpha-synuclein alterations reminiscent of prodromal Parkinson's disease and related diseases[J]. Front Neurosci, 2020, 14: 63. doi: 10.3389/fnins.2020.00063
[9]	罗阳赋. 高糖对α-synuclein等帕金森病相关蛋白的机制性研究 [D]. 2020. 广州: 南方医科大学.
	Luo YF. Mechanism study of high glucose on PD-related proteins such as α-synuclein [D]. 2020. Guangzhou: Southern Medical University.
[10]	Morris JK, Bomhoff GL, Stanford JA, et al. Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet[J]. Am J Physiol Regul Integr Comp Physiol, 2010, 299(4): R1082-90. doi: 10.1152/ajpregu.00449.2010
[11]	Paudel YN, Angelopoulou E, Piperi C, et al. Emerging neuroprotective effect of metformin in Parkinson's disease: a molecular crosstalk[J]. Pharmacol Res, 2020, 152: 104593. doi: 10.1016/j.phrs.2019.104593
[12]	Paglialunga S, Ludzki A, Root-McCaig J, et al. In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice[J]. Diabetologia, 2015, 58(5): 1071-80. doi: 10.1007/s00125-015-3531-x
[13]	Hong CT, Chen KY, Wang W, et al. Insulin resistance promotes Parkinson's disease through aberrant expression of α-synuclein, mitochondrial dysfunction, and deregulation of the polo-like kinase 2 signaling[J]. Cells, 2020, 9(3): 740. doi: 10.3390/cells9030740
[14]	Zhu X, Shen J, Feng S, et al. Akkermansia muciniphila, which is enriched in the gut microbiota by metformin, improves cognitive function in aged mice by reducing the proinflammatory cytokine interleukin-6[J]. Microbiome, 2023, 11(1): 120. doi: 10.1186/s40168-023-01567-1
[15]	Newby D, Linden AB, Fernandes M, et al. Comparative effect of metformin versus sulfonylureas with dementia and Parkinson's disease risk in US patients over 50 with type 2 diabetes mellitus[J]. BMJ Open Diabetes Res Care, 2022, 10(5): e003036. doi: 10.1136/bmjdrc-2022-003036
[16]	Cha JH, Yang WH, Xia W, et al. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1 [J]. Mol Cell, 2018, 71(4): 606-620.
[17]	李喆, 张振坤, 李亚, 等. 二甲双胍在神经退行性疾病预防和治疗中的研究进展[J]. 郑州大学学报（医学版）, 2021, 56(2): 204-210.
	Li Z, Zhang ZK, Li Y, et al. Research progress on metformin in the prevention and treatment of neurodegenerative diseases[J]. Journal of Zhengzhou University (Medical Sciences), 2021, 56(2): 204-210.
[18]	Kang H, Khang R, Ham S, et al. Activation of the ATF2/CREB-PGC-1α pathway by metformin leads to dopaminergic neuroprotection[J]. Oncotarget, 2017, 8(30): 48603-48618. doi: 10.18632/oncotarget.18122
[19]	李珊, 马莎, 高源, 等. 帕金森病伴2型糖尿病患者血糖水平、运动功能及左旋多巴等效剂量[J]. 中国老年学杂志, 2018, 38(21): 5160-5162.
	Li S, Ma S, Gao Y, et al. Blood glucose levels, motor function, and levodopa equivalent dose in patients with Parkinson's disease and type 2 diabetes[J]. Chinese Journal of Gerontology, 2018, 38(21): 5160-5162.
[20]	王姗姗, 杨霄鹏, 王雨童, 等. 二甲双胍调控自噬促PD神经细胞修复的研究[J]. 脑与神经疾病杂志, 2022, 30(1): 41-44.
	Wang SS, Yang XP, Wang YT, et al. Metformin regulates autophagy to promote repair of nerve cell in Parkinson’s disease[J]. Journal of Brain and Nervous Diseases, 2022, 30(1): 41-44.
[21]	Ping F, Jiang N, Li Y. Association between metformin and neurodegenerative diseases of observational studies: systematic review and meta-analysis[J]. BMJ Open Diabetes Res Care, 2020, 8(1): e001370. doi: 10.1136/bmjdrc-2020-001370
[22]	路粉蕾, 王惠娟, 王梁, 等. PD与维生素B12、叶酸、Hcy水平研究进展[J]. 脑与神经疾病杂志, 2022, 30(9): 585-588.
	Lu FL, Wang HJ, Wang L, et al. Research progress on vitamin B12, folate, and homocysteine levels in Parkinson's disease[J]. Journal of Brain and Nervous Diseases, 2022, 30(9): 585-588.
[23]	Sim AY, Barua S, Kim JY, et al. Role of DPP-4 and SGLT2 inhibitors connected to Alzheimer disease in type 2 diabetes mellitus[J]. Front Neurosci, 2021, 15: 708547. doi: 10.3389/fnins.2021.708547
[24]	汪洋, 王可, 刘宝兰. 达格列净对高糖诱导人视网膜血管内皮细胞凋亡及氧化应激的影响[J]. 国际眼科杂志, 2022, 22(3): 378-382.
	Wang Y, Wang K, Liu BL. Effect of Dapagliflozin on high glucose-induced apoptosis and oxidative stress in human retinal vascular endothelial cells[J]. Int Eye Sci, 2022, 22(3): 378-382.
[25]	Hayden MR, Grant DG, Aroor AR, et al. Empagliflozin ameliorates type 2 diabetes-induced ultrastructural remodeling of the neurovascular unit and neuroglia in the female db/ db mouse[J]. Brain Sci, 2019, 9(3): 57. doi: 10.3390/brainsci9030057
[26]	Mousa SA, Ayoub BM. Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 agonists as potential neuroprotective agent[J]. Neural Regen Res, 2019, 14(5): 745-748. doi: 10.4103/1673-5374.249217
[27]	Pipatpiboon N, Pintana H, Pratchayasakul W, et al. DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption[J]. Eur J Neurosci, 2013, 37(5): 839-49. doi: 10.1111/ejn.12088
[28]	李革. 2, 4-噻唑烷二酮对MPP+损伤SH-SY5Y细胞的保护作用 [D]. 2016. 石家庄: 河北师范大学.
	Li G. Protective effects of 2, 4-Thiazolidinedione on the SH-SY5Y cell damaged by MPP+ [D]. 2016. Shijiazhuang: Hebei Normal University.
[29]	Wang Y, Zhao W, Li G, et al. Neuroprotective effect and mechanism of thiazolidinedione on dopaminergic neurons in vivo and in vitro in Parkinson's disease[J]. PPAR Res, 2017, 2017: 4089214.
[30]	Zhu Y, Pu J, Chen Y, et al. Decreased risk of Parkinson's disease in diabetic patients with thiazolidinediones therapy: an exploratory meta-analysis[J]. PLoS One, 2019, 14(10): e0224236. doi: 10.1371/journal.pone.0224236
[31]	Sunnarborg K, Tiihonen M, Huovinen M, et al. Association between different diabetes medication classes and risk of Parkinson's disease in people with diabetes[J]. Pharmacoepidemiol Drug Saf, 2022, 31(8): 875-882. doi: 10.1002/pds.5448
[32]	Huang KH, Chang YL, Gau SY, et al. Dose-response association of metformin with Parkinson's disease odds in type 2 diabetes mellitus[J]. Pharmaceutics, 2022, 14(5): 946. doi: 10.3390/pharmaceutics14050946
[33]	Norradee C, Khwanraj K, Balit T, et al. Evaluation of the combination of metformin and rapamycin in an MPP+-Treated SH-SY5Y model of Parkinson's disease[J]. Adv Pharmacol Pharm Sci, 2023, 2023: 3830861.
[34]	Ay M, Charli A, Langley M, et al. Mito-metformin protects against mitochondrial dysfunction and dopaminergic neuronal degeneration by activating upstream PKD1 signaling in cell culture and MitoPark animal models of Parkinson's disease[J]. Front Neurosci, 2024, 18: 1356703. doi: 10.3389/fnins.2024.1356703
[35]	Shi Q, Liu S, Fonseca VA, et al. Effect of metformin on neurodegenerative disease among elderly adult US veterans with type 2 diabetes mellitus[J]. BMJ Open, 2019, 9(7): e024954. doi: 10.1136/bmjopen-2018-024954
[36]	Qin X, Zhang X, Li P, et al. Association between diabetes medications and the risk of Parkinson's disease: a systematic review and meta-analysis[J]. Front Neurol, 2021, 12: 678649. doi: 10.3389/fneur.2021.678649
[37]	Motawi TK, Al-Kady RH, Abdelraouf SM, et al. Empagliflozin alleviates endoplasmic reticulum stress and augments autophagy in rotenone-induced Parkinson's disease in rats: targeting the GRP78/PERK/eIF2α/CHOP pathway and miR-211-5p[J]. Chem Biol Interact, 2022, 362: 110002. doi: 10.1016/j.cbi.2022.110002
[38]	Kim HK, Biessels GJ, Yu MH, et al. SGLT2 inhibitor use and risk of dementia and Parkinson disease among patients with type 2 diabetes[J]. Neurology, 2024, 103(8): e209805. doi: 10.1212/WNL.0000000000209805
[39]	Jeong SH, Chung SJ, Yoo HS, et al. Beneficial effects of dipeptidyl peptidase-4 inhibitors in diabetic Parkinson's disease[J]. Brain, 2021, 144(4): 1127-1137. doi: 10.1093/brain/awab015
[40]	Lin YH, Hsu CC, Liu JS, et al. Use of dipeptidyl peptidase-4 inhibitors was associated with a lower risk of Parkinson's disease in diabetic patients[J]. Sci Rep, 2023, 13(1): 22489. doi: 10.1038/s41598-023-49870-z
[41]	Xie Y, Wang J, Jiang J, et al. Do oral antidiabetic medications alter the risk of Parkinson's disease? An updated systematic review and meta-analysis[J]. Neurol Sci, 2023, 44(12): 4193-4203. doi: 10.1007/s10072-023-06965-9
[42]	Yu HY, Sun T, Wang Z, et al. Exendin-4 and linagliptin attenuate neuroinflammation in a mouse model of Parkinson's disease[J]. Neural Regen Res, 2023, 18(8): 1818-1826.
[43]	Zhao H, Zhuo L, Sun Y, et al. Thiazolidinedione use and risk of Parkinson's disease in patients with type 2 diabetes mellitus[J]. NPJ Parkinsons Dis, 2022, 8(1): 138. doi: 10.1038/s41531-022-00406-8
[44]	Lin HL, Lin HC, Tseng YF, et al. Association of thiazolidinedione with a lower risk of Parkinson's disease in a population with newly-diagnosed diabetes mellitus[J]. Ann Med, 2018, 50(5): 430-436. doi: 10.1080/07853890.2018.1488083
[45]	Braak H, de Vos RA, Bohl J, et al. Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology[J]. Neurosci Lett, 2006, 396(1): 67-72. doi: 10.1016/j.neulet.2005.11.012
[46]	Helwig M, Ulusoy A, Rollar A, et al. Neuronal hyperactivity-induced oxidant stress promotes in vivo α-synuclein brain spreading[J]. Sci Adv, 2022, 8(35): eabn0356. doi: 10.1126/sciadv.abn0356
[47]	Wallen ZD, Demirkan A, Twa G, et al. Metagenomics of Parkinson's disease implicates the gut microbiome in multiple disease mechanisms[J]. Nat Commun, 2022, 13(1): 6958. doi: 10.1038/s41467-022-34667-x
[48]	Dogra N, Mani RJ, Katare DP. The gut-brain axis: two ways signaling in Parkinson's disease[J]. Cell Mol Neurobiol, 2022, 42(2): 315-332. doi: 10.1007/s10571-021-01066-7
[49]	Sikalidis AK, Maykish A. The gut microbiome and type 2 diabetes mellitus: discussing a complex relationship[J]. Biomedicines, 2020, 8(1): 8. doi: 10.3390/biomedicines8010008
[50]	Cao J, Chen M, Xu R, et al. Therapeutic mechanisms of berberine to improve the intestinal barrier function via modulating gut microbiota, TLR4/NF-κ B/MTORC pathway and autophagy in cats[J]. Front Microbiol, 2022, 13: 961885. doi: 10.3389/fmicb.2022.961885
[51]	鲁扬, 宣丽萍, 姜宏伟, 等. 一例可能与服用中药膏方有关的胰岛素自身免疫综合征[J]. 中华内分泌代谢杂志, 2017, 33(12): 1047-1049.
	Lu Y, Xuan LP, Jiang HW, et al. A case of insulin autoimmune syndrome which might be induced by Chinese herbal extracts[J]. Chin J Endocrinol Metab, 2017, 33(12): 1047-1049.
[52]	Triggle CR, Mohammed I, Bshesh K, et al. Metformin: is it a drug for all reasons and diseases?[J]. Metabolism, 2022, 133: 155223. doi: 10.1016/j.metabol.2022.155223