Skip to main content
Key Specialties
Anesthesiology Cardiology Dermatology Diabetology Endocrinology Gastroenterology General Medicine Geriatrics Hematology Infectious Diseases Internal Medicine Nephrology Neurology Obstetrics and Gynecology Oncology Ophthalmology Pediatrics Psychiatry Radiology Respiratory Medicine Rheumatology Surgery Urology
Congress Coverage
ASH 2024 Annual Meeting 2024 ESMO Congress 2024 ERS Congress 2024 EASD Congress 2024 ESC Congress 2024 EAN Congress 2024 ASCO Annual Meeting 2024 ACC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on adolescent vaping

LIVE: Wednesday 29th January, 18:00-19:30 CET

Growing numbers of young people are using e-cigarettes, despite warnings of respiratory effects and addiction. How can doctors tackle the epidemic, and what health effects should you prepare to manage in your clinics?
ADVANCED SEARCH
Log in
Top
Neuroscience Bulletin

04-01-2025 | Review

Type 2 Diabetes Mellitus Exacerbates Pathological Processes of Parkinson's Disease: Insights from Signaling Pathways Mediated by Insulin Receptors

Authors: Shufen Liu, Tingting Liu, Jingwen Li, Jun Hong, Ali A. Moosavi-Movahedi, Jianshe Wei

Published in: Neuroscience Bulletin

Login to get access

Abstract

Parkinson’s disease (PD), a chronic and common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion. Extensive evidence has confirmed shared pathogenic mechanisms underlying PD and T2DM, such as oxidative stress caused by insulin resistance, mitochondrial dysfunction, inflammation, and disorders of energy metabolism. Conventional drugs for treating T2DM, such as metformin and glucagon-like peptide-1 receptor agonists, affect nerve repair. Even drugs for treating PD, such as levodopa, can affect insulin secretion. This review summarizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.
Literature
1.
2.
3.
Fasano A, Visanji NP, Liu LWC, Lang AE, Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2015, 14: 625–639.PubMedCrossRef
4.
Zhou Z, Zhou R, Zhang Z, Li K. The association between vitamin D status, vitamin D supplementation, sunlight exposure, and Parkinson’s disease: A systematic review and meta-analysis. Med Sci Monit 2019, 25: 666–674.PubMedPubMedCentralCrossRef
5.
Müller T, van Laar T, Cornblath DR, Odin P, Klostermann F, Grandas FJ, et al. Peripheral neuropathy in Parkinson’s disease: Levodopa exposure and implications for duodenal delivery. Parkinsonism Relat Disord 2013, 19: 501–507.PubMedCrossRef
6.
Kim YE, Lee WW, Yun JY, Yang HJ, Kim HJ, Jeon BS. Musculoskeletal problems in Parkinson’s disease: Neglected issues. Parkinsonism Relat Disord 2013, 19: 666–669.PubMedCrossRef
7.
8.
Cheong JLY, de Pablo-Fernandez E, Foltynie T, Noyce AJ. The association between type 2 diabetes mellitus and Parkinson’s disease. J Parkinsons Dis 2020, 10: 775–789.PubMedPubMedCentralCrossRef
9.
Nowell J, Blunt E, Gupta D, Edison P. Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease. Ageing Res Rev 2023, 89: 101979.PubMedCrossRef
10.
Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014, 103: 137–149.PubMedCrossRef
11.
12.
Yip CC. The insulin-binding domain of insulin receptor is encoded by exon 2 and exon 3. J Cell Biochem 1992, 48: 19–25.PubMedCrossRef
13.
Savkur RS, Philips AV, Cooper TA, Dalton JC, Moseley ML, Ranum LPW, et al. Insulin receptor splicing alteration in myotonic dystrophy type 2. Am J Hum Genet 2004, 74: 1309–1313.PubMedPubMedCentralCrossRef
14.
Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, et al. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 1999, 19: 3278–3288.PubMedPubMedCentralCrossRef
15.
Huang Z, Bodkin NL, Ortmeyer HK, Hansen BC, Shuldiner AR. Hyperinsulinemia is associated with altered insulin receptor mRNA splicing in muscle of the spontaneously obese diabetic rhesus monkey. J Clin Invest 1994, 94: 1289–1296.PubMedPubMedCentralCrossRef
16.
17.
Zhao X, An X, Yang C, Sun W, Ji H, Lian F. The crucial role and mechanism of insulin resistance in metabolic disease. Front Endocrinol 2023, 14: 1149239.CrossRef
18.
Kellar D, Craft S. Brain insulin resistance in Alzheimer’s disease and related disorders: Mechanisms and therapeutic approaches. Lancet Neurol 2020, 19: 758–766.PubMedPubMedCentralCrossRef
19.
Akhtar A, Sah SP. Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease. Neurochem Int 2020, 135: 104707.PubMedCrossRef
20.
Labandeira CM, Fraga-Bau A, Arias Ron D, Alvarez-Rodriguez E, Vicente-Alba P, Lago-Garma J, et al. Parkinson’s disease and diabetes mellitus: Common mechanisms and treatment repurposing. Neural Regen Res 2022, 17: 1652–1658.PubMedPubMedCentralCrossRef
21.
Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY, Ahima RS, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums. Nat Rev Neurol 2018, 14: 168–181.PubMedPubMedCentralCrossRef
22.
23.
Rai SN, Dilnashin H, Birla H, Singh SS, Zahra W, Rathore AS, et al. The role of PI3K/akt and ERK in neurodegenerative disorders. Neurotox Res 2019, 35: 775–795.PubMedCrossRef
24.
Matsuda S, Ikeda Y, Murakami M, Nakagawa Y, Tsuji A, Kitagishi Y. Roles of PI3K/AKT/GSK3 pathway involved in psychiatric illnesses. Diseases 2019, 7: 22.PubMedPubMedCentralCrossRef
25.
Shima H, Pende M, Chen Y, Fumagalli S, Thomas G, Kozma SC. Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J 1998, 17: 6649–6659.PubMedPubMedCentralCrossRef
26.
Lawlor MA, Mora A, Ashby PR, Williams MR, Murray-Tait V, Malone L, et al. Essential role of PDK1 in regulating cell size and development in mice. EMBO J 2002, 21: 3728–3738.PubMedPubMedCentralCrossRef
27.
Ramasubbu K, Devi Rajeswari V. Impairment of insulin signaling pathway PI3K/Akt/mTOR and insulin resistance induced AGEs on diabetes mellitus and neurodegenerative diseases: A perspective review. Mol Cell Biochem 2023, 478: 1307–1324.PubMedCrossRef
28.
29.
30.
31.
Kitagishi Y, Kobayashi M, Kikuta K, Matsuda S. Roles of PI3K/AKT/GSK3/mTOR pathway in cell signaling of mental illnesses. Depress Res Treat 2012, 2012: 752563.PubMedPubMedCentral
32.
Akhtar A, Bishnoi M, Sah SP. Sodium orthovanadate improves learning and memory in intracerebroventricular-streptozotocin rat model of Alzheimer’s disease through modulation of brain insulin resistance induced tau pathology. Brain Res Bull 2020, 164: 83–97.PubMedCrossRef
33.
Sengupta U, Kayed R. Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases. Prog Neurobiol 2022, 214: 102270.PubMedCrossRef
34.
35.
Luo S, Kang SS, Wang ZH, Liu X, Day JX, Wu Z, et al. Akt phosphorylates NQO1 and triggers its degradation, abolishing its antioxidative activities in Parkinson’s disease. J Neurosci 2019, 39: 7291–7305.PubMedPubMedCentralCrossRef
36.
Le TKC, Dao XD, Nguyen DV, Luu DH, Bui TMH, Le TH, et al. Insulin signaling and its application. Front Endocrinol 2023, 14: 1226655.CrossRef
37.
Ahmed SA, Sarma P, Barge SR, Swargiary D, Devi GS, Borah JC. Xanthosine, a purine glycoside mediates hepatic glucose homeostasis through inhibition of gluconeogenesis and activation of glycogenesis via regulating the AMPK/FoxO1/AKT/GSK3β signaling cascade. Chem Biol Interact 2023, 371: 110347.PubMedCrossRef
38.
39.
Liang M, Wang L, Wang W. The 15-hydroxyprostaglandin dehydrogenase inhibitor SW033291 ameliorates abnormal hepatic glucose metabolism through PGE2-EP4 receptor-AKT signaling in a type 2 diabetes mellitus mouse model. Cell Signal 2023, 108: 110707.PubMedCrossRef
40.
Long HZ, Cheng Y, Zhou ZW, Luo HY, Wen DD, Gao LC. PI3K/AKT signal pathway: A target of natural products in the prevention and treatment of Alzheimer’s disease and Parkinson’s disease. Front Pharmacol 2021, 12: 648636.PubMedPubMedCentralCrossRef
41.
Li X, He Q, Zhao N, Chen X, Li T, Cheng B. High intensity interval training ameliorates cognitive impairment in T2DM mice possibly by improving PI3K/Akt/mTOR Signaling-regulated autophagy in the hippocampus. Brain Res 2021, 1773: 147703.PubMedCrossRef
42.
43.
Yin X, Xu Z, Zhang Z, Li L, Pan Q, Zheng F, et al. Association of PI3K/AKT/mTOR pathway genetic variants with type 2 diabetes mellitus in Chinese. Diabetes Res Clin Pract 2017, 128: 127–135.PubMedCrossRef
44.
Lee HK, Kwon B, Lemere CA, de la Monte S, Itamura K, Ha AY, et al. mTORC2 (rictor) in Alzheimer’s disease and reversal of amyloid-β expression-induced insulin resistance and toxicity in rat primary cortical neurons. J Alzheimers Dis 2017, 56: 1015–1036.PubMedPubMedCentralCrossRef
45.
Hosoe Y, Numoto N, Inaba S, Ogawa S, Morii H, Abe R, et al. Structural and functional properties of Grb2 SH2 dimer in CD28 binding. Biophys Physicobiol 2019, 16: 80–88.PubMedPubMedCentralCrossRef
46.
Hanke S, Mann M. The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2. Mol Cell Proteomics 2009, 8: 519–534.PubMedPubMedCentralCrossRef
47.
Cargnello M, Roux pp. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 2011, 75: 50–83.PubMedPubMedCentralCrossRef
48.
Huang Z, Tian Z, Zhao Y, Zhu F, Liu W, Wang X. MAPK signaling pathway is essential for female reproductive regulation in the cabbage beetle. Colaphellus bowringi. Cells 2022, 11: 1602.PubMedCrossRef
49.
Chakrabarti S, Bisaglia M. Oxidative stress and neuroinflammation in Parkinson’s disease: The role of dopamine oxidation products. Antioxidants 2023, 12: 955.PubMedPubMedCentralCrossRef
50.
Levy OA, Malagelada C, Greene LA. Cell death pathways in Parkinson’s disease: Proximal triggers, distal effectors, and final steps. Apoptosis 2009, 14: 478–500.PubMedPubMedCentralCrossRef
51.
Klegeris A, Pelech S, Giasson BI, Maguire J, Zhang H, McGeer EG, et al. Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia. Neurobiol Aging 2008, 29: 739–752.PubMedCrossRef
52.
Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 2010, 1802: 396–405.PubMedCrossRef
53.
Zhang K, Zhu S, Li J, Jiang T, Feng L, Pei J, et al. Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson’s disease. Acta Pharm Sin B 2021, 11: 3015–3034.PubMedPubMedCentralCrossRef
54.
Lochhead PA, Salt IP, Walker KS, Hardie DG, Sutherland C. 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes 2000, 49: 896–903.PubMedCrossRef
55.
Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 2008, 456: 269–273.PubMedPubMedCentralCrossRef
56.
Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005, 310: 1642–1646.PubMedPubMedCentralCrossRef
57.
Horike N, Sakoda H, Kushiyama A, Ono H, Fujishiro M, Kamata H, et al. AMP-activated protein kinase activation increases phosphorylation of glycogen synthase kinase 3beta and thereby reduces cAMP-responsive element transcriptional activity and phosphoenolpyruvate carboxykinase C gene expression in the liver. J Biol Chem 2008, 283: 33902–33910.PubMedPubMedCentralCrossRef
58.
Zhang BB, Zhou G, Li C. AMPK: An emerging drug target for diabetes and the metabolic syndrome. Cell Metab 2009, 9: 407–416.PubMedCrossRef
59.
Liang X, Zhang T, Shi L, Kang C, Wan J, Zhou Y, et al. Ampelopsin protects endothelial cells from hyperglycemia-induced oxidative damage by inducing autophagy via the AMPK signaling pathway. BioFactors 2015, 41: 463–475.PubMedCrossRef
60.
Lu M, Su C, Qiao C, Bian Y, Ding J, Hu G. Metformin prevents dopaminergic neuron death in MPTP/P-induced mouse model of Parkinson’s disease via autophagy and mitochondrial ROS clearance. Int J Neuropsychopharmacol 2016, 19: 047.CrossRef
61.
García-Cáceres C, Quarta C, Varela L, Gao Y, Gruber T, Legutko B, et al. Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 2016, 166: 867–880.PubMedPubMedCentralCrossRef
62.
Gad ES, Zaitone SA, Moustafa YM. Pioglitazone and exenatide enhance cognition and downregulate hippocampal beta amyloid oligomer and microglia expression in insulin-resistant rats. Can J Physiol Pharmacol 2016, 94: 819–828.PubMedCrossRef
63.
Wang R, Ren H, Kaznacheyeva E, Lu X, Wang G. Association of glial activation and α-synuclein pathology in Parkinson’s disease. Neurosci Bull 2023, 39: 479–490.PubMedCrossRef
64.
Bassil F, Canron MH, Vital A, Bezard E, Li Y, Greig NH, et al. Insulin resistance and exendin-4 treatment for multiple system atrophy. Brain 2017, 140: 1420–1436.PubMedPubMedCentralCrossRef
65.
Werther GA, Hogg A, Oldfield BJ, McKinley MJ, Figdor R, Allen AM, et al. Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology 1987, 121: 1562–1570.PubMedCrossRef
66.
Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature 1978, 272: 827–829.PubMedCrossRef
67.
Kar S, Chabot JG, Quirion R. Quantitative autoradiographic localization of[125I]insulin-like growth factor I, [125I]insulin-like growth factor II, and[125I]insulin receptor binding sites in developing and adult rat brain. J Comp Neurol 1993, 333: 375–397.PubMedCrossRef
68.
Werner H, LeRoith D. Insulin and insulin-like growth factor receptors in the brain: Physiological and pathological aspects. Eur Neuropsychopharmacol 2014, 24: 1947–1953.PubMedCrossRef
69.
Havrankova J, Roth J, Brownstein MJ. Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels. Studies of obese and streptozotocin-treated rodents. J Clin Invest 1979, 64: 636–642.PubMedPubMedCentralCrossRef
70.
Havrankova J, Brownstein M, Roth J. Insulin and insulin receptors in rodent brain. Diabetologia 1981, 20: 268–273.PubMedCrossRef
71.
Takahashi M, Yamada T, Tooyama I, Moroo I, Kimura H, Yamamoto T, et al. Insulin receptor mRNA in the substantia nigra in Parkinson’s disease. Neurosci Lett 1996, 204: 201–204.PubMedCrossRef
72.
De Iuliis A, Montinaro E, Fatati G, Plebani M, Colosimo C. Diabetes mellitus and Parkinson’s disease: Dangerous liaisons between insulin and dopamine. Neural Regen Res 2022, 17: 523–533.PubMedCrossRef
73.
Mazucanti CH, Liu QR, Lang D, Huang N, O’Connell JF, Camandola S, et al. Release of insulin produced by the choroid plexis is regulated by serotonergic signaling. JCI Insight 2019, 4: e131682.PubMedPubMedCentralCrossRef
74.
75.
Tian Y, Jing G, Zhang M. Insulin-degrading enzyme: Roles and pathways in ameliorating cognitive impairment associated with Alzheimer’s disease and diabetes. Ageing Res Rev 2023, 90: 101999.PubMedCrossRef
76.
Son SM, Cha MY, Choi H, Kang S, Choi H, Lee MS, et al. Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease. Autophagy 2016, 12: 784–800.PubMedPubMedCentralCrossRef
77.
Lee J, Kim K, Cho JH, Bae JY, O’Leary TP, Johnson JD, et al. Insulin synthesized in the paraventricular nucleus of the hypothalamus regulates pituitary growth hormone production. JCI Insight 2020, 5: e135412.PubMedPubMedCentralCrossRef
78.
Agrawal R, Reno CM, Sharma S, Christensen C, Huang Y, Fisher SJ. Insulin action in the brain regulates both central and peripheral functions. Am J Physiol Endocrinol Metab 2021, 321: E156–E163.PubMedPubMedCentralCrossRef
79.
Sabari SS, Balasubramani K, Iyer M, Sureshbabu HW, Venkatesan D, Gopalakrishnan AV, et al. Type 2 diabetes (T2DM) and Parkinson’s disease (PD): A mechanistic approach. Mol Neurobiol 2023, 60: 4547–4573.PubMedCrossRef
80.
Diggs-Andrews KA, Zhang X, Song Z, Daphna-Iken D, Routh VH, Fisher SJ. Brain insulin action regulates hypothalamic glucose sensing and the counterregulatory response to hypoglycemia. Diabetes 2010, 59: 2271–2280.PubMedPubMedCentralCrossRef
81.
Pocai A, Lam TKT, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 2005, 434: 1026–1031.PubMedCrossRef
82.
Dodd GT, Michael NJ, Lee-Young RS, Mangiafico SP, Pryor JT, Munder AC, et al. Insulin regulates POMC neuronal plasticity to control glucose metabolism. Elife 2018, 7: e38704.PubMedPubMedCentralCrossRef
83.
Kimura K, Tanida M, Nagata N, Inaba Y, Watanabe H, Nagashimada M, et al. Central insulin action activates kupffer cells by suppressing hepatic vagal activation via the nicotinic alpha 7 acetylcholine receptor. Cell Rep 2016, 14: 2362–2374.PubMedCrossRef
84.
Scherer T, O’Hare J, Diggs-Andrews K, Schweiger M, Cheng B, Lindtner C, et al. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab 2011, 13: 183–194.PubMedPubMedCentralCrossRef
85.
Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science 2000, 289: 2122–2125.PubMedCrossRef
86.
87.
Collaborators G2N. (2019) Global, regional, and national burden of neurological disorders, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol , 18: 459–480.
88.
89.
Athauda D, Foltynie T. Insulin resistance and Parkinson’s disease: A new target for disease modification? Prog Neurobiol 2016, 145(146): 98–120.PubMedCrossRef
90.
Offen D, Shtaif B, Hadad D, Weizman A, Melamed E, Gil-Ad I. Protective effect of insulin-like-growth-factor-1 against dopamine-induced neurotoxicity in human and rodent neuronal cultures: Possible implications for Parkinson’s disease. Neurosci Lett 2001, 316: 129–132.PubMedCrossRef
91.
92.
Rassu M, del Giudice MG, Sanna S, Taymans JM, Morari M, Brugnoli A, et al. Role of LRRK2 in the regulation of dopamine receptor trafficking. PLoS One 2017, 12: e0179082.PubMedPubMedCentralCrossRef
93.
Funk N, Munz M, Ott T, Brockmann K, Wenninger-Weinzierl A, Kühn R, et al. The Parkinson’s disease-linked Leucine-rich repeat kinase 2 (LRRK2) is required for insulin-stimulated translocation of GLUT4. Sci Rep 2019, 9: 4515.PubMedPubMedCentralCrossRef
94.
Fiory F, Perruolo G, Cimmino I, Cabaro S, Pignalosa FC, Miele C, et al. The relevance of insulin action in the dopaminergic system. Front Neurosci 2019, 13: 868.PubMedPubMedCentralCrossRef
95.
Ruiz-Pozo VA, Tamayo-Trujillo R, Cadena-Ullauri S, Frias-Toral E, Guevara-Ramírez P, Paz-Cruz E, et al. The molecular mechanisms of the relationship between insulin resistance and Parkinson’s disease pathogenesis. Nutrients 2023, 15: 3585.PubMedPubMedCentralCrossRef
96.
Yuan Y, Ma X, Song N, Xie J. Expanding views of mitochondria in Parkinson’s disease: Focusing on PINK1 and GBA1 mutations. Neurosci Bull 2022, 38: 825–828.PubMedPubMedCentralCrossRef
97.
Koentjoro B, Park JS, Sue CM. Nix restores mitophagy and mitochondrial function to protect against PINK1/Parkin-related Parkinson’s disease. Sci Rep 2017, 7: 44373.PubMedPubMedCentralCrossRef
98.
Hong CT, Chen KY, Wang W, Chiu JY, Wu D, Chao TY, 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. Cells 2020, 9: 740.PubMedPubMedCentralCrossRef
99.
Chen J, Sun Z, Jin M, Tu Y, Wang S, Yang X, et al. Inhibition of AGEs/RAGE/Rho/ROCK pathway suppresses non-specific neuroinflammation by regulating BV2 microglial M1/M2 polarization through the NF-κB pathway. J Neuroimmunol 2017, 305: 108–114.PubMedCrossRef
100.
Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, et al. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease. Cell 2011, 144: 689–702.PubMedPubMedCentralCrossRef
101.
Sajan M, Hansen B, Ivey R 3rd, Sajan J, Ari C, Song S, et al. Brain insulin signaling is increased in insulin-resistant states and decreases in FOXOs and PGC-1α and increases in Aβ1-40/42 and phospho-tau may abet alzheimer development. Diabetes 2016, 65: 1892–1903.PubMedPubMedCentralCrossRef
102.
Zheng L, Bernard-Marissal N, Moullan N, D’Amico D, Auwerx J, Moore DJ, et al. Parkin functionally interacts with PGC-1α to preserve mitochondria and protect dopaminergic neurons. Hum Mol Genet 2017, 26: 582–598.PubMed
103.
Albert-Gascó H, Ros-Bernal F, Castillo-Gómez E, Olucha-Bordonau FE. MAP/ERK signaling in developing cognitive and emotional function and its effect on pathological and neurodegenerative processes. Int J Mol Sci 2020, 21: 4471.PubMedPubMedCentralCrossRef
104.
Kulich SM, Chu CT. Sustained extracellular signal-regulated kinase activation by 6-hydroxydopamine: Implications for Parkinson’s disease. J Neurochem 2001, 77: 1058–1066.PubMedPubMedCentralCrossRef
105.
Zhu JH, Gusdon AM, Cimen H, van Houten B, Koc E, Chu CT. Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity: Dual roles for ERK1/2. Cell Death Dis 2012, 3: e312.PubMedPubMedCentralCrossRef
106.
Li Y, Chen N, Wu C, Lu Y, Gao G, Duan C, et al. Galectin-1 attenuates neurodegeneration in Parkinson’s disease model by modulating microglial MAPK/IκB/NFκB axis through its carbohydrate-recognition domain. Brain Behav Immun 2020, 83: 214–225.PubMedCrossRef
107.
Li Y, Hei H, Zhang S, Gong W, Liu Y, Qin J. PGC-1α participates in tumor chemoresistance by regulating glucose metabolism and mitochondrial function. Mol Cell Biochem 2023, 478: 47–57.PubMedCrossRef
108.
Ni XC, Wang HF, Cai YY, Yang D, Alolga RN, Liu B, et al. Ginsenoside Rb1 inhibits astrocyte activation and promotes transfer of astrocytic mitochondria to neurons against ischemic stroke. Redox Biol 2022, 54: 102363.PubMedPubMedCentralCrossRef
109.
110.
Hölscher C. First clinical data of the neuroprotective effects of nasal insulin application in patients with Alzheimer’s disease. Alzheimers Dement 2014, 10: S33–S37.PubMedCrossRef
111.
Ren W, Chen J, Wang W, Li Q, Yin X, Zhuang G, et al. Sympathetic nerve-enteroendocrine L cell communication modulates GLP-1 release, brain glucose utilization, and cognitive function. Neuron 2024, 112: 972-990.e8.PubMedCrossRef
112.
de Graaf C, Donnelly D, Wootten D, Lau J, Sexton PM, Miller LJ, et al. Glucagon-like peptide-1 and its class B G protein-coupled receptors: A long March to therapeutic successes. Pharmacol Rev 2016, 68: 954–1013.PubMedPubMedCentralCrossRef
113.
Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like peptide-1 and the central/peripheral nervous system: Crosstalk in diabetes. Trends Endocrinol Metab 2017, 28: 88–103.PubMedCrossRef
114.
Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, et al. Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J Neurosci Res 2008, 86: 326–338.PubMedCrossRef
115.
Athauda D, Foltynie T. The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson’s disease: Mechanisms of action. Drug Discov Today 2016, 21: 802–818.PubMedCrossRef
116.
117.
Zhao M, Li XW, Chen DZ, Hao F, Tao SX, Yu HY, et al. Neuro-protective role of metformin in patients with acute stroke and type 2 diabetes mellitus via AMPK/mammalian target of rapamycin (mTOR) signaling pathway and oxidative stress. Med Sci Monit 2019, 25: 2186–2194.PubMedPubMedCentralCrossRef
118.
Saewanee N, Praputpittaya T, Malaiwong N, Chalorak P, Meemon K. Neuroprotective effect of metformin on dopaminergic neurodegeneration and α-synuclein aggregation in C. elegans model of Parkinson’s disease. Neurosci Res 2021, 162: 13–21.PubMedCrossRef
119.
Katila N, Bhurtel S, Shadfar S, Srivastav S, Neupane S, Ojha U, et al. Metformin lowers α-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson’s disease. Neuropharmacology 2017, 125: 396–407.PubMedCrossRef
120.
Miranda HV, Szego ÉM, Oliveira LMA, Breda C, Darendelioglu E, de Oliveira RM, et al. Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies. Brain 2017, 140: 1399–1419.CrossRef
121.
González-Rodríguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, et al. Disruption of mitochondrial complex I induces progressive Parkinsonism. Nature 2021, 599: 650–656.PubMedPubMedCentralCrossRef
122.
Katila N, Bhurtel S, Park PH, Choi DY. Metformin attenuates rotenone-induced oxidative stress and mitochondrial damage via the AKT/Nrf2 pathway. Neurochem Int 2021, 148: 105120.PubMedCrossRef
123.
Zhao H, Zhuo L, Sun Y, Shen P, Lin H, Zhan S. Thiazolidinedione use and risk of Parkinson’s disease in patients with type 2 diabetes mellitus. NPJ Parkinsons Dis 2022, 8: 138.PubMedPubMedCentralCrossRef
124.
Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC. Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson’s disease. J Neurochem 2002, 82: 615–624.PubMedCrossRef
125.
Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB. Protection by pioglitazone in the MPTP model of Parkinson’s disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 2004, 88: 494–501.CrossRef
126.
Schintu N, Frau L, Ibba M, Caboni P, Garau A, Carboni E, et al. PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson’s disease. Eur J Neurosci 2009, 29: 954–963.PubMedCrossRef
127.
Hamming KSC, Soliman D, Matemisz LC, Niazi O, Lang Y, Gloyn AL, et al. Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel. Diabetes 2009, 58: 2419–2424.PubMedPubMedCentralCrossRef
128.
Zubov A, Muruzheva Z, Tikhomirova M, Karpenko M. Glibenclamide as a neuroprotective antidementia drug. Arch Physiol Biochem 2022, 128: 1693–1696.PubMedCrossRef
129.
Hill E, Gowers R, Richardson MJE, Wall MJ. α-synuclein aggregates increase the conductance of substantia nigra dopamine neurons, an effect partly reversed by the KATP channel inhibitor glibenclamide. eNeuro 2021, 8: ENEURO.0330–ENEURO.0320.2020.
130.
Alrouji M, Al-Kuraishy HM, Al-Gareeb AI, Alexiou A, Papadakis M, Jabir MS, et al. NF-κB/NLRP3 inflammasome axis and risk of Parkinson’s disease in Type 2 diabetes mellitus: A narrative review and new perspective. J Cell Mol Med. 2023, 27: 1775–1789.PubMedPubMedCentralCrossRef
131.
132.
133.
Lopez Vicchi F, Luque GM, Brie B, Nogueira JP, Garcia Tornadu I, Becu-Villalobos D. Dopaminergic drugs in type 2 diabetes and glucose homeostasis. Pharmacol Res 2016, 109: 74–80.PubMedCrossRef
134.
Tavares G, Marques D, Barra C, Rosendo-Silva D, Costa A, Rodrigues T, et al. Dopamine D2 receptor agonist, bromocriptine, remodels adipose tissue dopaminergic signalling and upregulates catabolic pathways, improving metabolic profile in type 2 diabetes. Mol Metab 2021, 51: 101241.PubMedPubMedCentralCrossRef
Metadata
Title
Type 2 Diabetes Mellitus Exacerbates Pathological Processes of Parkinson's Disease: Insights from Signaling Pathways Mediated by Insulin Receptors
Authors
Shufen Liu
Tingting Liu
Jingwen Li
Jun Hong
Ali A. Moosavi-Movahedi
Jianshe Wei
Publication date
04-01-2025
Publisher
Springer Nature Singapore
Published in
Neuroscience Bulletin
Print ISSN: 1673-7067
Electronic ISSN: 1995-8218
DOI
https://doi.org/10.1007/s12264-024-01342-8

Keynote webinar | Spotlight on menopause

Menopause can have a significant impact on the body, with effects ranging beyond the endocrine and reproductive systems. Learn about the broader systemic effects of menopause, so you can help patients in your clinics through the transition.   

Prof. Martha Hickey
Dr. Claudia Barth
Dr. Samar El Khoudary
Developed by: Springer Medicine
Watch now

Advances in Alzheimer's

Alzheimer's research and care is changing rapidly. Keep up with the latest developments from key international conferences, together with expert insights on how to integrate these advances into practice.

This content is intended for healthcare professionals outside of the UK.

Supported by:
  • Lilly
Developed by: Springer Healthcare IME
Learn more
Image Credits